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Sample records for susceptible mice poliovirus

  1. Wild Poliovirus List

    Science.gov (United States)

    ... Polio + Prevention The Virus Vaccine-Derived Polioviruses The Vaccines IPV OPV The Communities History of Polio Polio Now This Week Wild poliovirus list Public Health Emergency status Circulating vaccine-derived poliovirus Surveillance Indicators The Global Polio Laboratory ...

  2. THE SUSCEPTIBILITY OF MICE TO BACTERIAL ENDOTOXINS

    Science.gov (United States)

    Schaedler, Russell W.; Dubos, Rene J.

    1961-01-01

    Albino mice (Rockefeller NCS strain) raised and maintained free of ordinary bacterial pathogens, as well as of intestinal Escherichia coli and of Proteus bacilli, were found to be highly resistant to the lethal effect of bacterial endotoxins. When newborn mice of this NCS colony were nursed by foster mothers from another colony raised under ordinary conditions (SS colony from which the NCS colony was derived), they acquired the intestinal flora of the latter animals and became susceptible to the lethal effects of endotoxins. NCS adult mice could be rendered susceptible to the lethal effect of endotoxins by vaccination with heat killed Gram-negative bacilli. The susceptibility thus induced exhibited a certain degree of specificity for the bacterial strain used in vaccination. Although untreated NCS mice were resistant to the lethal effect of endotoxins, they proved exquisitively susceptible to the infection-enhancing effect of these materials. For example, 1 µg. or less of endotoxin was found sufficient to help establish a rapidly fatal septicemia with Staphylococcus aureus. Small amounts of endotoxin (1 µg. or less), administered alone, caused a marked but transient loss of weight. Vaccination with heat-killed Gram-negative bacilli or with killed BCG increased the resistance of NCS mice to the infection-enhancing effect of small amounts of endotoxin. This protective effect exhibited a certain degree of specificity for the bacterial strain from which the toxin used in the infection-enhancing test was derived. These various findings can be explained by assuming that the pathological effects of endotoxins involve at least two unrelated mechanisms; (a) a primary toxicity illustrated in this study by the loss of weight and enhancement of infection resulting from the injection of small doses of toxin; (b) an immunological reaction with lethal consequences which became manifest only in animals sensitized to the endotoxin by prior exposure to Gram-negative bacilli. PMID

  3. Influence of age of mice on the susceptibility to murine ...

    African Journals Online (AJOL)

    Intensity of human schistosomiasis infection increases with age, a peak being attained at early puberty. Hormones could be involved in the age-related changes in susceptibility to schistosomiasis. Male BALB/c mice were infected with Schistosoma mansoni either before or after puberty and worm numbers, cellular immune ...

  4. Suppressive oligodeoxynucleotides reduce lung cancer susceptibility in mice with silicosis.

    Science.gov (United States)

    Bode, Christian; Kinjo, Takeshi; Alvord, W Gregory; Klinman, Dennis M

    2014-05-01

    Silicosis is an inflammatory lung disease induced by the inhalation of silica-containing dust particles. There is conflicting data on whether patients with silicosis are more susceptible to lung cancer induced by cigarette smoke. To examine this issue experimentally, a model was developed in which one of the most abundant and potent carcinogens present in cigarette smoke [4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK)] was administered to mice at the peak of silica-induced pulmonary inflammation. Results show that the incidence of lung tumors in silicotic mice treated with NNK was significantly increased compared with mice exposed to silica or NNK alone. Synthetic oligonucleotides (ODN) containing repetitive TTAGGG motifs can block pathologic inflammation. We therefore examined whether treatment with these suppressive (Sup) ODN could block silica-induced pulmonary inflammation and thereby reduce susceptibility to lung cancer. Results show that Sup (but not control) ODN inhibit pulmonary fibrosis and other inflammatory manifestations of chronic silicosis. Of greater import, Sup ODN reduced lung tumor incidence and multiplicity in silicotic mice exposed to NNK. These findings establish an experimental model for examining the role of silicotic inflammation in cancer susceptibility and demonstrate that Sup ODN represent a novel therapy for chronic silicosis.

  5. Nod2 mediates susceptibility to Yersinia pseudotuberculosis in mice.

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    Ulrich Meinzer

    Full Text Available Nucleotide oligomerisation domain 2 (NOD2 is a component of the innate immunity known to be involved in the homeostasis of Peyer patches (PPs in mice. However, little is known about its role during gut infection in vivo. Yersinia pseudotuberculosis is an enteropathogen causing gastroenteritis, adenolymphitis and septicaemia which is able to invade its host through PPs. We investigated the role of Nod2 during Y. pseudotuberculosis infection. Death was delayed in Nod2 deleted and Crohn's disease associated Nod2 mutated mice orogastrically inoculated with Y. pseudotuberculosis. In PPs, the local immune response was characterized by a higher KC level and a more intense infiltration by neutrophils and macrophages. The apoptotic and bacterial cell counts were decreased. Finally, Nod2 deleted mice had a lower systemic bacterial dissemination and less damage of the haematopoeitic organs. This resistance phenotype was lost in case of intraperitoneal infection. We concluded that Nod2 contributes to the susceptibility to Y. pseudotuberculosis in mice.

  6. Polytrauma Increases Susceptibility to Pseudomonas Pneumonia in Mature Mice.

    Science.gov (United States)

    Turnbull, Isaiah R; Ghosh, Sarbani; Fuchs, Anja; Hilliard, Julia; Davis, Christopher G; Bochicchio, Grant V; Southard, Robert E

    2016-05-01

    Pneumonia is the most common complication observed in patients with severe injuries. Although the average age of injured patients is 47 years, existing studies of the effect of injury on the susceptibility to infectious complications have focused on young animals, equivalent to a late adolescent human. We hypothesized that mature adult animals are more susceptible to infection after injury than younger counterparts. To test this hypothesis, we challenged 6 to 8-month-old mature mice to a polytrauma injury followed by Pseudomonas aeruginosa pneumonia and compared them to young (8-10-week-old) animals. We demonstrate that polytrauma injury increases mortality from pneumonia in mature animals (sham-pneumonia 21% vs. polytrauma-pneumonia 62%) but not younger counterparts. After polytrauma, pneumonia in mature mice is associated with higher bacterial burden in lung, increased incidence of bacteremia, and elevated levels of bacteria in the blood, demonstrating that injury decreases the ability to control the infectious challenge. We further find that polytrauma did not induce elevations in circulating cytokine levels (TNF-alpha, IL-6, KC, and IL-10) 24  h after injury. However, mature mice subjected to polytrauma demonstrated an exaggerated circulating inflammatory cytokine response to subsequent Pseudomonas pneumonia. Additionally, whereas prior injury increases LPS-stimulated IL-6 production by peripheral blood leukocytes from young (8-10-week-old) mice, injury does not prime IL-6 production by cell from mature adult mice. We conclude that in mature mice polytrauma results in increased susceptibility to Pseudomonas pneumonia while priming an exaggerated but ineffective inflammatory response.

  7. Toluene exposure increases aminophylline-induced seizure susceptibility in mice.

    Science.gov (United States)

    Chan, Ming-Huan; Chen, Hwei-Hsien

    2003-12-01

    The effects of toluene on the sensitivity to seizures induced by aminophylline were investigated. Mice were pretreated with an ip injection of corn oil or toluene (100-500 mg/kg) followed by a timed intravenous infusion of aminophylline at various time intervals to assess the seizure thresholds and lethal doses. Toluene increased seizure susceptibility to aminophylline in a dose- and time-dependent manner. Toluene-induced enhancement of seizure susceptibility to aminophylline occurred as early as 30 min and persisted for at least 3 days after a single administration of toluene (500 mg/kg). Treatment of benzaldehyde, one of toluene's metabolites, also showed an increase in the susceptibility to aminophylline. The enhancing effect was also observed in caffeine-induced seizures 1 h, but not 1 day after toluene treatment. These results suggest that individuals with toluene exposure may increase the risk for convulsive and even lethal complications associated with the therapeutic use of aminophylline.

  8. Renal proteome in mice with different susceptibilities to fluorosis.

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    Juliane Guimarães Carvalho

    Full Text Available A/J and 129P3/J mouse strains have different susceptibilities to dental fluorosis due to their genetic backgrounds. They also differ with respect to several features of fluoride (F metabolism and metabolic handling of water. This study was done to determine whether differences in F metabolism could be explained by diversities in the profile of protein expression in kidneys. Weanling, male A/J mice (susceptible to dental fluorosis, n = 18 and 129P3/J mice (resistant, n = 18 were housed in pairs and assigned to three groups given low-F food and drinking water containing 0, 10 or 50 ppm [F] for 7 weeks. Renal proteome profiles were examined using 2D-PAGE and LC-MS/MS. Quantitative intensity analysis detected between A/J and 129P3/J strains 122, 126 and 134 spots differentially expressed in the groups receiving 0, 10 and 50 ppmF, respectively. From these, 25, 30 and 32, respectively, were successfully identified. Most of the proteins were related to metabolic and cellular processes, followed by response to stimuli, development and regulation of cellular processes. In F-treated groups, PDZK-1, a protein involved in the regulation of renal tubular reabsorption capacity was down-modulated in the kidney of 129P3/J mice. A/J and 129P3/J mice exhibited 11 and 3 exclusive proteins, respectively, regardless of F exposure. In conclusion, proteomic analysis was able to identify proteins potentially involved in metabolic handling of F and water that are differentially expressed or even not expressed in the strains evaluated. This can contribute to understanding the molecular mechanisms underlying genetic susceptibility to dental fluorosis, by indicating key-proteins that should be better addressed in future studies.

  9. Renal Proteome in Mice with Different Susceptibilities to Fluorosis

    Science.gov (United States)

    Peres-Buzalaf, Camila; Salvato, Fernanda; Labate, Carlos Alberto; Everett, Eric T.; Whitford, Gary Milton; Buzalaf, Marília Afonso Rabelo

    2013-01-01

    A/J and 129P3/J mouse strains have different susceptibilities to dental fluorosis due to their genetic backgrounds. They also differ with respect to several features of fluoride (F) metabolism and metabolic handling of water. This study was done to determine whether differences in F metabolism could be explained by diversities in the profile of protein expression in kidneys. Weanling, male A/J mice (susceptible to dental fluorosis, n = 18) and 129P3/J mice (resistant, n = 18) were housed in pairs and assigned to three groups given low-F food and drinking water containing 0, 10 or 50 ppm [F] for 7 weeks. Renal proteome profiles were examined using 2D-PAGE and LC-MS/MS. Quantitative intensity analysis detected between A/J and 129P3/J strains 122, 126 and 134 spots differentially expressed in the groups receiving 0, 10 and 50 ppmF, respectively. From these, 25, 30 and 32, respectively, were successfully identified. Most of the proteins were related to metabolic and cellular processes, followed by response to stimuli, development and regulation of cellular processes. In F-treated groups, PDZK-1, a protein involved in the regulation of renal tubular reabsorption capacity was down-modulated in the kidney of 129P3/J mice. A/J and 129P3/J mice exhibited 11 and 3 exclusive proteins, respectively, regardless of F exposure. In conclusion, proteomic analysis was able to identify proteins potentially involved in metabolic handling of F and water that are differentially expressed or even not expressed in the strains evaluated. This can contribute to understanding the molecular mechanisms underlying genetic susceptibility to dental fluorosis, by indicating key-proteins that should be better addressed in future studies. PMID:23308176

  10. Tubular overexpression of gremlin induces renal damage susceptibility in mice.

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    Alejandra Droguett

    Full Text Available A growing number of patients are recognized worldwide to have chronic kidney disease. Glomerular and interstitial fibrosis are hallmarks of renal progression. However, fibrosis of the kidney remains an unresolved challenge, and its molecular mechanisms are still not fully understood. Gremlin is an embryogenic gene that has been shown to play a key role in nephrogenesis, and its expression is generally low in the normal adult kidney. However, gremlin expression is elevated in many human renal diseases, including diabetic nephropathy, pauci-immune glomerulonephritis and chronic allograft nephropathy. Several studies have proposed that gremlin may be involved in renal damage by acting as a downstream mediator of TGF-β. To examine the in vivo role of gremlin in kidney pathophysiology, we generated seven viable transgenic mouse lines expressing human gremlin (GREM1 specifically in renal proximal tubular epithelial cells under the control of an androgen-regulated promoter. These lines demonstrated 1.2- to 200-fold increased GREM1 expression. GREM1 transgenic mice presented a normal phenotype and were without proteinuria and renal function involvement. In response to the acute renal damage cause by folic acid nephrotoxicity, tubule-specific GREM1 transgenic mice developed increased proteinuria after 7 and 14 days compared with wild-type treated mice. At 14 days tubular lesions, such as dilatation, epithelium flattening and hyaline casts, with interstitial cell infiltration and mild fibrosis were significantly more prominent in transgenic mice than wild-type mice. Tubular GREM1 overexpression was correlated with the renal upregulation of profibrotic factors, such as TGF-β and αSMA, and with increased numbers of monocytes/macrophages and lymphocytes compared to wild-type mice. Taken together, our results suggest that GREM1-overexpressing mice have an increased susceptibility to renal damage, supporting the involvement of gremlin in renal damage

  11. Immunity to poliovirus serotypes in children population of selected ...

    African Journals Online (AJOL)

    Background: Poliovirus outbreaks are still reported in Nigeria despite renewed efforts to improve vaccine coverage, thus suggesting the existence of susceptible hosts. Also, there is anecdotal evidence of variation in vaccine coverage by region and specifically between urban and rural communities. Consequently, this study ...

  12. Importance of Interleukin-10 in Genetic Susceptibility of Mice to Coccidioides immitis

    Science.gov (United States)

    Fierer, Joshua; Walls, Lorraine; Eckmann, Lars; Yamamoto, Tomoko; Kirkland, Theo N.

    1998-01-01

    Inbred strains of mice vary in their susceptibility to Coccidioides immitis. We infected resistant DBA/2 (D2) mice and three susceptible strains of mice (C57BL/6 [B6], BALB/c, and CAST/Ei) by intraperitoneal injection of arthroconidia and determined the severity of infection based on colony counts of fungus in the spleens and lungs 14 days after infection. We used quantitative reverse transcription-PCR to measure the amounts of cytokines made in the spleens and lungs of infected mice. Susceptible mice made 1,000-fold more interleukin-10 (IL-10) than resistant D2 mice and about 10-fold more IL-4. In contrast, D2 mice had more IL-12 p40 in their lungs than did B6 mice. Resistant and susceptible mice made equivalent amounts of gamma interferon, IL-6, and IL-2. In order to determine whether IL-10 adversely affected the response to C. immitis, we infected IL-10-deficient mice, and they were found to be as resistant as D2 mice. This result indicates that IL-10 plays a crucial role in determining susceptibility to C. immitis in inbred mice. Because IL-4 mRNA levels were higher in most strains of susceptible mice, we also infected IL-4-deficient B6 mice. They were more resistant than B6 controls but not as resistant as IL-10-deficient mice. Thus, both IL-10 and IL-4 adversely affect the ability of C57BL mice to resist infection with C. immitis, but IL-10 has a larger effect and is the cytokine that is consistently associated with susceptibility in all strains of inbred mice. PMID:9712793

  13. Fluconazole treatment of Candida albicans infection in mice: does in vitro susceptibility predict in vivo response?

    OpenAIRE

    Graybill, J R; Najvar, L K; Holmberg, J D; Correa, A.; Luther, M F

    1995-01-01

    A series of fluconazole-susceptible and-fluconazole resistant Candida albicans fungal isolates were used to infect mice intravenously. Mice were treated with varying doses of fluconazole beginning one day after infection. For all of the 6 fluconazole-susceptible isolates, fluconazole was highly effective at or = 40 mg/kg twice daily in 4 fluconazole-resistant isolates. Although the correlation is not precise, in vitro susceptibility testing of C. albicans can predict in vivo response to fluc...

  14. Blood Supply--Susceptible Formation of Melanin Pigment in Hair Bulb Melanocytes of Mice

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    Shogo Maeda, MD

    2015-03-01

    Conclusions: Melanin pigment formation in the hair bulb melanocytes appeared to be susceptible to the blood supply, and melanocytosis was promoted in the follicles and in the epidermis of Kitl-Tg C57BL/6 mice.

  15. Colitis susceptibility in p47(phox-/-) mice is mediated by the microbiome.

    Science.gov (United States)

    Falcone, E Liana; Abusleme, Loreto; Swamydas, Muthulekha; Lionakis, Michail S; Ding, Li; Hsu, Amy P; Zelazny, Adrian M; Moutsopoulos, Niki M; Kuhns, Douglas B; Deming, Clay; Quiñones, Mariam; Segre, Julia A; Bryant, Clare E; Holland, Steven M

    2016-04-05

    Chronic granulomatous disease (CGD) is caused by defects in nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) complex subunits (gp91(phox) (a.k.a. Nox2), p47(phox), p67(phox), p22(phox), p40(phox)) leading to reduced phagocyte-derived reactive oxygen species production. Almost half of patients with CGD develop inflammatory bowel disease, and the involvement of the intestinal microbiome in relation to this predisposing immunodeficiency has not been explored. Although CGD mice do not spontaneously develop colitis, we demonstrate that p47(phox-/-) mice have increased susceptibility to dextran sodium sulfate colitis in association with a distinct colonic transcript and microbiome signature. Neither restoring NOX2 reactive oxygen species production nor normalizing the microbiome using cohoused adult p47(phox-/-) with B6Tac (wild type) mice reversed this phenotype. However, breeding p47(phox+/-) mice and standardizing the microflora between littermate p47(phox-/-) and B6Tac mice from birth significantly reduced dextran sodium sulfate colitis susceptibility in p47(phox-/-) mice. We found similarly decreased colitis susceptibility in littermate p47(phox-/-) and B6Tac mice treated with Citrobacter rodentium. Our findings suggest that the microbiome signature established at birth may play a bigger role than phagocyte-derived reactive oxygen species in mediating colitis susceptibility in CGD mice. These data further support bacteria-related disease in CGD colitis.

  16. Trypanosoma cruzi: infection patterns in intact and athymic mice of susceptible and resistant genotypes.

    Science.gov (United States)

    Gonçalves da Costa, S C; Calabrese, K S; Zaverucha do Valle, T; Lagrange, P H

    2002-01-01

    Inbred strains of mice inoculated with the T cruzi Y strain behaved as susceptible (A/J, C3H/HeN), intermediate (BALB/c) or relatively resistant (C57BL/6) with respect to the magnitude of parasitaemia and mortality rate. C57BL/10 mice were susceptible in relation to parasitaemia but resistant when mortality was analyzed. Infection with T cruzi CL strain presented the same results, except for C57BL/6 which behaved as susceptible mice. Athymic mice of various backgrounds revealed no differences in susceptibility, presenting the same dramatic parasitaemia, tissue colonization pattern and no inflammatory reaction in any of the tissues studied. Infection of euthymic and athymic BALB/c mice elicited the production of parasite-specific antibodies, which reached similar levels on the first 9 days but differed after day 13. Serum transfer experiments in BALB/c mice did not show great differences in parasitaemia but altered T. cruzi polymorphism reducing the slender forms in athymic mice. Histopathology of athymic BALB/c mice showed the same tissue tropism when infected either with T cruzi Y or CL strain.

  17. Transthyretin knockout mice display decreased susceptibility to AMPA-induced neurodegeneration

    DEFF Research Database (Denmark)

    Nunes, Ana Filipa; Montero, Maria; Franquinho, Filipa

    2009-01-01

    Transthyretin (TTR) has been regarded as a neuroprotective protein given that TTR knockout (KO) mice display increased susceptibility for amyloid beta deposition and memory deficits during aging. In parallel, TTR KO mice have increased levels of neuropeptide Y (NPY), which promotes neuroprotection...... and neuroproliferation. In this work, we aimed at evaluating TTR neuroprotective effect against an excitotoxic insult that is known to be prevented by NPY action. We show that despite a putative neuroprotective role of TTR, hippocampal slice cultures from TTR KO mice display a decreased susceptibility to AMPA...

  18. Infection susceptibility and immune senescence with advancing age replicated in accelerated aging Lmna(Dhe) mice.

    Science.gov (United States)

    Xin, Lijun; Jiang, Tony T; Kinder, Jeremy M; Ertelt, James M; Way, Sing Sing

    2015-12-01

    Aging confers increased susceptibility to common pathogens including influenza A virus. Despite shared vulnerability to infection with advancing age in humans and rodents, the relatively long time required for immune senescence to take hold practically restricts the use of naturally aged mice to investigate aging-induced immunological shifts. Here, we show accelerated aging Lmna(Dhe) mice with spontaneous mutation in the nuclear scaffolding protein, lamin A, replicate infection susceptibility, and substantial immune cell shifts that occur with advancing age. Naturally aged (≥ 20 month) and 2- to 3-month-old Lmna(Dhe) mice share near identically increased influenza A susceptibility compared with age-matched Lmna(WT) control mice. Increased mortality and higher viral burden after influenza infection in Lmna(Dhe) mice parallel reduced accumulation of lung alveolar macrophage cells, systemic expansion of immune suppressive Foxp3⁺ regulatory T cells, and skewed immune dominance among viral-specific CD8⁺T cells similar to the immunological phenotype of naturally aged mice. Thus, aging-induced infection susceptibility and immune senescence are replicated in accelerated aging Lmna(Dhe) mice. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  19. Persistent poliovirus infection in mouse motoneurons.

    Science.gov (United States)

    Destombes, J; Couderc, T; Thiesson, D; Girard, S; Wilt, S G; Blondel, B

    1997-01-01

    Poliovirus (PV) is the causal agent of paralytic poliomyelitis. Many survivors of the acute disease, after decades of clinical stability, develop new muscular symptoms called postpolio syndrome. It has been hypothesized that the persistence of PV in the spinal cord is involved in the etiology of this syndrome. To investigate the ability of PV to persist in the spinal cord after the onset of paralysis, we exploited a mouse model in which most animals inoculated with a mouse-adapted mutant survived after the onset of paralysis. Light microscopy and ultrastructural immunohistochemical studies and reverse transcription followed by nested PCR performed on spinal cord from paralyzed mice demonstrated that PV persisted in the mouse spinal cord for at least 12 months after the onset of paralysis. This mouse model provides a new tool for studying poliomyelitis evolution after the onset of paralysis. PMID:8995689

  20. Three-dimensional structure of poliovirus receptor bound to poliovirus

    Science.gov (United States)

    Belnap, David M.; McDermott, Brian M.; Filman, David J.; Cheng, Naiqian; Trus, Benes L.; Zuccola, Harmon J.; Racaniello, Vincent R.; Hogle, James M.; Steven, Alasdair C.

    2000-01-01

    Poliovirus initiates infection by binding to its cellular receptor (Pvr). We have studied this interaction by using cryoelectron microscopy to determine the structure, at 21-Å resolution, of poliovirus complexed with a soluble form of its receptor (sPvr). This density map aided construction of a homology-based model of sPvr and, in conjunction with the known crystal structure of the virus, allowed delineation of the binding site. The virion does not change significantly in structure on binding sPvr in short incubations at 4°C. We infer that the binding configuration visualized represents the initial interaction that is followed by structural changes in the virion as infection proceeds. sPvr is segmented into three well-defined Ig-like domains. The two domains closest to the virion (domains 1 and 2) are aligned and rigidly connected, whereas domain 3 diverges at an angle of ≈60°. Two nodules of density on domain 2 are identified as glycosylation sites. Domain 1 penetrates the “canyon” that surrounds the 5-fold protrusion on the capsid surface, and its binding site involves all three major capsid proteins. The inferred pattern of virus–sPvr interactions accounts for most mutations that affect the binding of Pvr to poliovirus. PMID:10618373

  1. Establishment of Stable, Cell-Mediated Immunity that Makes "Susceptible" Mice Resistant to Leishmania major

    Science.gov (United States)

    Bretscher, Peter A.; Wei, Guojian; Menon, Juthika N.; Bielefeldt-Ohmann, Helle

    1992-07-01

    Cell-mediated, but not antibody-mediated, immune responses protect humans against certain pathogens that produce chronic diseases such as leishmaniasis. Effective vaccination against such pathogens must therefore produce an immunological "imprint" so that stable, cell-mediated immunity is induced in all individuals after natural infection. BALB/c mice "innately susceptible" to Leishmania major produce antibodies after substantial infection. In the present study, "susceptible" mice injected with a small number of parasites mounted a cell-mediated response and acquired resistance to a larger, normally pathogenic, challenge. This vaccination strategy may be applicable in diseases in which protection is dependent on cell-mediated immunity.

  2. Sex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice.

    Science.gov (United States)

    Dorfman, Mauricio D; Krull, Jordan E; Douglass, John D; Fasnacht, Rachael; Lara-Lince, Fernando; Meek, Thomas H; Shi, Xiaogang; Damian, Vincent; Nguyen, Hong T; Matsen, Miles E; Morton, Gregory J; Thaler, Joshua P

    2017-02-22

    Female mice are less susceptible to the negative metabolic consequences of high-fat diet feeding than male mice, for reasons that are incompletely understood. Here we identify sex-specific differences in hypothalamic microglial activation via the CX3CL1-CX3CR1 pathway that mediate the resistance of female mice to diet-induced obesity. Female mice fed a high-fat diet maintain CX3CL1-CX3CR1 levels while male mice show reductions in both ligand and receptor expression. Female Cx3cr1 knockout mice develop 'male-like' hypothalamic microglial accumulation and activation, accompanied by a marked increase in their susceptibility to diet-induced obesity. Conversely, increasing brain CX3CL1 levels in male mice through central pharmacological administration or virally mediated hypothalamic overexpression converts them to a 'female-like' metabolic phenotype with reduced microglial activation and body-weight gain. These data implicate sex differences in microglial activation in the modulation of energy homeostasis and identify CX3CR1 signalling as a potential therapeutic target for the treatment of obesity.

  3. Immunity to poliovirus after infection and vaccination

    NARCIS (Netherlands)

    Herremans, Martina Maria Petronella Theresia

    1999-01-01

    The aim of this thesis was defined as the study of the contribution of IPV vaccination to the induction of a) protection against poliovirus infection and b) mucosal immunity.We have described the development of new immunological tools for the rapid detection of poliovirus-specific antibodies and

  4. Strain differentiation of polioviruses with monoclonal antibodies.

    NARCIS (Netherlands)

    A.D.M.E. Osterhaus (Albert); A.L. van Wezel; A.J.H. Stegmann; J.A.A.M. van Asten (Jack)

    1984-01-01

    textabstractPanels of monoclonal antibodies raised against different poliovirus type 1, 2 and 3 strains, were tested in a micro-neutralization test and in a micro-enzyme linked immunosorbent assay against a large number of poliovirus strains. The results were compared with those obtained with the

  5. Poliovirus trafficking toward central nervous system via human poliovirus receptor-dependent and -independent pathway.

    Directory of Open Access Journals (Sweden)

    Seii eOHKA

    2012-04-01

    Full Text Available In humans, paralytic poliomyelitis results from the invasion of the central nervous system by circulating poliovirus (PV via the blood-brain barrier (BBB. After the virus enters the central nervous system (CNS, it replicates in neurons, especially in motor neurons (MNs, inducing the cell death that causes paralytic poliomyelitis. Along with this route of dissemination, neural pathway has been reported in humans, monkeys, and PV-sensitive human PV receptor (hPVR/CD155-transgenic (Tg mice. We demonstrated that a fast retrograde axonal transport process is required for PV dissemination through the sciatic nerve of hPVR-Tg mice and that intramuscularly inoculated PV causes paralysis in a hPVR-dependent manner. We also showed that hPVR-independent axonal transport of PV exists in hPVR-Tg and non-Tg mice, indicating that several different pathways for PV axonal transport exist in these mice. Circulating PV after intravenous inoculation in mice cross the BBB at a high rate in a hPVR-independent manner. Recently, we identified transferrin receptor 1 (TfR1 of mouse brain capillary endothelial cells as a binding protein to PV, implicating that TfR1 is a possible receptor for PV to permeate the BBB.

  6. Cigarette Smoke Induces Immune Responses to Vimentin in both, Arthritis-Susceptible and -Resistant Humanized Mice.

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    Mitali Bidkar

    Full Text Available Rheumatoid arthritis (RA is an autoimmune disease marked by chronic synovial inflammation and both, genetic and environmental factors are involved in its pathogenesis. Human leukocyte antigen (HLA DRB1*0401 is associated with susceptibility to develop RA, while cigarette smoke (CS exposure promotes seropositive disease with increased severity in DRB1*0401+ individuals. Smokers have higher levels of antibodies against citrullinated peptides. In this study, we determined whether the response to a known autoantigen, Vimentin (Vim is shared epitope specific and how CS influences this response using transgenic-mice carrying RA-susceptible,*0401, and -resistant, *0402, genes. Following relatively brief exposure to CS, peptidyl arginine deiminase (PAD enzyme expression was increased in murine lungs. Cigarette smoking led to production of Interferon (IFN-γ with reduced levels of Interleukin (IL-10 by splenocytes of *0401 mice. In contrast, CS augmented Th2 cytokines along with T-regulatory cells in *0402 mice. An increase in levels of antibodies to native and citrullinated Vim was observed in naïve mice of both strains following CS exposure. Our data showed that both arthritis-susceptible and -resistant mice can generate cellular and humoral immunity to Vim; however CS-induced modulation of host immunity is dependent on the interaction with the host HLA genes.

  7. Claudin 2 deficiency reduces bile flow and increases susceptibility to cholesterol gallstone disease in mice.

    Science.gov (United States)

    Matsumoto, Kengo; Imasato, Mitsunobu; Yamazaki, Yuji; Tanaka, Hiroo; Watanabe, Mitsuhiro; Eguchi, Hidetoshi; Nagano, Hiroaki; Hikita, Hayato; Tatsumi, Tomohide; Takehara, Tetsuo; Tamura, Atsushi; Tsukita, Sachiko

    2014-11-01

    Bile formation and secretion are essential functions of the hepatobiliary system. Bile flow is generated by transepithelial transport of water and ionic/nonionic solutes via transcellular and paracellular pathways that is mainly driven by osmotic pressure. We examined the role of tight junction-based paracellular transport in bile secretion. Claudins are cell-cell adhesion molecules in tight junctions that create the paracellular barrier. The claudin family has 27 reported members, some of which have paracellular ion- and/or water-channel-like functions. Claudin 2 is a paracellular channel-forming protein that is highly expressed in hepatocytes and cholangiocytes; we examined the hepatobiliary system of claudin 2 knockout (Cldn2(-/-)) mice. We collected liver and biliary tissues from Cldn2(-/-) and Cldn2(+/+) mice and performed histologic, biochemical, and electrophysiologic analyses. We measured osmotic movement of water and/or ions in Cldn2(-/-) and Cldn2(+/+) hepatocytes and bile ducts. Mice were placed on lithogenic diets for 4 weeks and development of gallstone disease was assessed. The rate of bile flow in Cldn2(-/-) mice was half that of Cldn2(+/+) mice, resulting in significantly more concentrated bile in livers of Cldn2(-/-) mice. Consistent with these findings, osmotic gradient-driven water flow was significantly reduced in hepatocyte bile canaliculi and bile ducts isolated from Cldn2(-/-) mice, compared with Cldn2(+/+) mice. After 4 weeks on lithogenic diets, all Cldn2(-/-) mice developed macroscopically visible gallstones; the main component of the gallstones was cholesterol (>98%). In contrast, none of the Cldn2(+/+) mice placed on lithogenic diets developed gallstones. Based on studies of Cldn2(-/-) mice, claudin 2 regulates paracellular ion and water flow required for proper regulation of bile composition and flow. Dysregulation of this process increases susceptibility to cholesterol gallstone disease in mice. Copyright © 2014 AGA Institute

  8. Different Susceptibilities between Apoe- and Ldlr-Deficient Mice to Inflammation-Associated Colorectal Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Takuji Tanaka

    2016-10-01

    Full Text Available Hypercholesterolemia resulting in atherosclerosis is associated with an increased risk of ischemic heart disease and colorectal cancer (CRC. However, the roles of apoliprotein (Apo E (Apoe and low-density lipoprotein (Ldl receptor (Ldlr in colorectal carcinogenesis have not yet been investigated. In this study, we examined the susceptibility of Apoe-deficient and Ldlr-deficient mice, which are genetic animal models of atherosclerosis to azoxymethane (AOM/dextran sodium sulfate (DSS-induced colorectal carcinogenesis. In Experiment 1, male Apoe-deficient (n = 20 and wild type (WT mice (C57BL/6J, n = 21 were treated with a single intraperitoneal (i.p. injection of AOM (10 mg/kg body weight and then given 1.5% DSS in drinking water for seven days. They were maintained up to week 20 and sacrificed for the histopathological examination of colorectal tumors. The mRNA expression of cyclooxygenase (Cox-2, inducible nitric oxide synthase (Nos2, tumor necrosis factor (Tnf-α interleukin (Il-1β, and Il-6 was assayed in the colorectal mucosa. In Experiment 2, male Ldlr-deficient (n = 14 and WT mice (C57BL/6J, n = 10 were given a single i.p. injection of AOM (10 mg/kg body weight and then given 2% DSS in drinking water for seven days. They were sacrificed at week 20 to evaluate their colorectum histopathologically. In Experiment 1, the multiplicity of CRCs was significantly higher in the Apoe-deficient mice (2.75 ± 1.48 than in the WT mice (0.62 ± 0.67. The serum lipoprotein levels in the Apoe-deficient mice were also significantly higher than in the WT mice. In Experiment 2, the incidence (29% and multiplicity (0.50 ± 0.94 of CRCs in the Ldlr mice were significantly lower than in the WT mice (80% incidence and 3.10 ± 2.38 multiplicity. The mRNA expression of two inducible enzymes and certain pro-inflammatory cytokines in the colorectum of each genotype was greater than in the respective WT mice. The values in the Apoe-deficient mice were much greater

  9. Cytokines produced by susceptible and resistant mice in the course of Paracoccidioides brasiliensis infection

    Directory of Open Access Journals (Sweden)

    Calich V.L.G.

    1998-01-01

    Full Text Available Paracoccidioidomycosis (PCM is the most prevalent deep mycosis in Latin America and presents a wide spectrum of clinical manifestations. We established a genetically controlled murine model of PCM, where A/Sn mice develop an infection which mimics the benign disease (immune responses which favor cellular immunity and B10.A animals present the progressive disseminated form of PCM (preferential activation of B cells and impairment of cellular immune responses. To understand the immunoregulatory phenomena associated with resistance and susceptibility in experimental PCM, A/Sn and B10.A mice were studied regarding antigen-elicited secretion of monokines (TNF-a and TGF-ß and type-1 (IL-2 and IFN-g and type-2 (IL-4,5,10 cytokines. Total lymph node cells from resistant mice infected ip with P. brasiliensis produced early and sustained levels of IFN-g and IL-2; type-2 cytokines (IL-4 and IL-5 started to appear 8 weeks after infection. In contrast, susceptible mice produced low levels of IFN-g concomitant with significant levels of IL-5 and IL-10 early in the infection. In the chronic phase of the disease, susceptible animals presented a transitory secretion of IL-2, and IL-4. In the pulmonary infection IL-4, IL-5 and IL-10 were preferentially detected in the lung cells washings of susceptible animals. After in vitro challenge with fungal antigens, normal peritoneal macrophages from B10.A mice secreted high levels of TGF-ß and low levels of TNF-a. In contrast, macrophages from A/Sn animals released high levels of TNF-a associated with a small production of TGF-ß. The in vivo depletion of IFN-g not only abrogated the resistance of A/Sn mice but also diminished the relative resistance of B10.A animals. The in vivo depletion of IL-4 did not alter the disease outcome, whereas administration of rIL-12 significantly enhanced resistance in susceptible animals. Taken together, these results suggest that an early secretion of high levels of TNF-a and IFN

  10. Strain variation in the susceptibility and immune response to Clonorchis sinensis infection in mice.

    Science.gov (United States)

    Uddin, Md Hafiz; Li, Shunyu; Bae, Young Mee; Choi, Min-Ho; Hong, Sung-Tae

    2012-03-01

    Mice have shown various susceptibility to infection by Clonorchis sinensis. To compare the intra-specific variation in the host-parasite relationship of C. sinensis, 6 strains of mice (ICR, BALB/c, C57BL/6, DDY, CBA/N, and C3H/HeN) with 3 different haplotypes were evaluated on their susceptibility. The worm recovery rate and immunological responses were observed after 4 and 8 weeks of infection with 30 metacercariae. The highest worm recovery rate was observed as 20.7% in the C3H/HeN strain after 4 weeks of infection along with histopathological changes. The rate was 10.0% in C57BL/6 mice after 8 weeks. ICR, BALB/c, and CBA/N showed elevated levels of IgE at both time points when compared to the rest of the strains. The serum IgG1 and IgG2a levels were elevated in most of the strains; however, the C57BL/6 strain showed a lower level of IgG2a that indicated the IgG1 predominance over IgG2a. The production of IL-4 after concanavalin-A stimulation of splenocytes slightly increased among the mouse strains except C3H/HeN after 4 or 8 weeks of infection, but each strain produced high levels of IFN-γ after 8 weeks, which implied mixed Th1/Th2 responses. ICR, DDY, CBA/N, and C3H/HeN strains showed a significantly increased level of IL-10 after 8 weeks as compared to C57BL/6. All of the strains showed an increased level of IL-13 and suggested fibrotic changes in the mice. In conclusion, mice are insusceptible to infection with C. sinensis; however, the C57BL/6, BALB/c and ICR strains are relatively susceptible after 8 weeks of infection among the six strains. Worm expulsion may be one of the causes of low susceptibility of C3H/HeN mice strain at the 8th week. Elevated IgE, IFN-γ, and IL-13 of infected mice suggest both Th1 and Th2 responses that may be related to the low host susceptibility. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  11. Susceptibility to hippocampal kindling seizures is increased in aging C57 black mice

    Directory of Open Access Journals (Sweden)

    Kurt R. Stover

    2017-12-01

    Full Text Available The incidence of seizures increases with old age. Stroke, dementia and brain tumors are recognized risk factors for new-onset seizures in the aging populations and the incidence of these conditions also increased with age. Whether aging is associated with higher seizure susceptibility in the absence of the above pathologies remains unclear. We used classic kindling to explore this issue as the kindling model is highly reproducible and allows close monitoring of electrographic and motor seizure activities in individual animals. We kindled male young and aging mice (C57BL/6 strain, 2–3 and 18–22 months of age via daily hippocampal CA3 stimulation and monitored seizure activity via video and electroencephalographic recordings. The aging mice needed fewer stimuli to evoke stage-5 motor seizures and exhibited longer hippocampal afterdischarges and more frequent hippocampal spikes relative to the young mice, but afterdischarge thresholds and cumulative afterdischarge durations to stage 5 motor seizures were not different between the two age groups. While hippocampal injury and structural alterations at cellular and micro-circuitry levels remain to be examined in the kindled mice, our present observations suggest that susceptibility to hippocampal CA3 kindling seizures is increased with aging in male C57 black mice.

  12. Mice lacking functional STAT1 are highly susceptible to lethal infection with Lassa virus.

    Science.gov (United States)

    Yun, Nadezhda E; Seregin, Alexey V; Walker, David H; Popov, Vsevolod L; Walker, Aida G; Smith, Jeanon N; Miller, Milagros; de la Torre, Juan C; Smith, Jennifer K; Borisevich, Viktoriya; Fair, Joseph N; Wauquier, Nadia; Grant, Donald S; Bockarie, Bayon; Bente, Dennis; Paessler, Slobodan

    2013-10-01

    Lassa fever (LF) is a potentially lethal human disease that is caused by the arenavirus Lassa virus (LASV). Annually, around 300,000 infections with up to 10,000 deaths occur in regions of Lassa fever endemicity in West Africa. Here we demonstrate that mice lacking a functional STAT1 pathway are highly susceptible to infection with LASV and develop lethal disease with pathology similar to that reported in humans.

  13. Identification of candidate susceptibility and resistance genes of mice infected with Streptococcus suis type 2.

    Directory of Open Access Journals (Sweden)

    Jie Rong

    Full Text Available Streptococcus suis type 2 (SS2 is an important swine pathogen and zoonosis agent. A/J mice are significantly more susceptible than C57BL/6 (B6 mice to SS2 infection, but the genetic basis is largely unknown. Here, alterations in gene expression in SS2 (strain HA9801-infected mice were identified using Illumina mouse BeadChips. Microarray analysis revealed 3,692 genes differentially expressed in peritoneal macrophages between A/J and B6 mice due to SS2 infection. Between SS2-infected A/J and control A/J mice, 2646 genes were differentially expressed (1469 upregulated; 1177 downregulated. Between SS2-infected B6 and control B6 mice, 1449 genes were differentially expressed (778 upregulated; 671 downregulated. These genes were analyzed for significant Gene Ontology (GO categories and signaling pathways using the Kyoto Encylopedia of Genes and Genomes (KEGG database to generate a signaling network. Upregulated genes in A/J and B6 mice were related to response to bacteria, immune response, positive regulation of B cell receptor signaling pathway, type I interferon biosynthesis, defense and inflammatory responses. Additionally, upregulated genes in SS2-infected B6 mice were involved in antigen processing and presentation of exogenous peptides, peptide antigen stabilization, lymphocyte differentiation regulation, positive regulation of monocyte differentiation, antigen receptor-mediated signaling pathway and positive regulation of phagocytosis. Downregulated genes in SS2-infected B6 mice played roles in glycolysis, carbohydrate metabolic process, amino acid metabolism, behavior and muscle regulation. Microarray results were verified by quantitative real-time PCR (qRT-PCR of 14 representative deregulated genes. Four genes differentially expressed between SS2-infected A/J and B6 mice, toll-like receptor 2 (Tlr2, tumor necrosis factor (Tnf, matrix metalloproteinase 9 (Mmp9 and pentraxin 3 (Ptx3, were previously implicated in the response to S. suis

  14. Type I IFN signaling triggers immunopathology in tuberculosis-susceptible mice by modulating lung phagocyte dynamics.

    Science.gov (United States)

    Dorhoi, Anca; Yeremeev, Vladimir; Nouailles, Geraldine; Weiner, January; Jörg, Sabine; Heinemann, Ellen; Oberbeck-Müller, Dagmar; Knaul, Julia K; Vogelzang, Alexis; Reece, Stephen T; Hahnke, Karin; Mollenkopf, Hans-Joachim; Brinkmann, Volker; Kaufmann, Stefan H E

    2014-08-01

    General interest in the biological functions of IFN type I in Mycobacterium tuberculosis (Mtb) infection increased after the recent identification of a distinct IFN gene expression signature in tuberculosis (TB) patients. Here, we demonstrate that TB-susceptible mice lacking the receptor for IFN I (IFNAR1) were protected from death upon aerogenic infection with Mtb. Using this experimental model to mimic primary progressive pulmonary TB, we dissected the immune processes affected by IFN I. IFNAR1 signaling did not affect T-cell responses, but markedly altered migration of inflammatory monocytes and neutrophils to the lung. This process was orchestrated by IFNAR1 expressed on both immune and tissue-resident radioresistant cells. IFNAR1-driven TB susceptibility was initiated by augmented Mtb replication and in situ death events, along with CXCL5/CXCL1-driven accumulation of neutrophils in alveoli, followed by the discrete compartmentalization of Mtb in lung phagocytes. Early depletion of neutrophils rescued TB-susceptible mice to levels observed in mice lacking IFNAR1. We conclude that IFN I alters early innate events at the site of Mtb invasion leading to fatal immunopathology. These data furnish a mechanistic explanation for the detrimental role of IFN I in pulmonary TB and form a basis for understanding the complex roles of IFN I in chronic inflammation. © 2014 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Infection Susceptibility in Gastric Intrinsic Factor (Vitamin B12-Defective Mice Is Subject to Maternal Influences

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    Lynda Mottram

    2016-06-01

    Full Text Available Mice harboring a mutation in the gene encoding gastric intrinsic factor (Gif, a protein essential for the absorption of vitamin B12/cobalamin (Cbl, have potential as a model to explore the role of vitamins in infection. The levels of Cbl in the blood of Giftm1a/tm1a mutant mice were influenced by the maternal genotype, with offspring born to heterozygous (high Cbl, F1 mothers exhibiting a significantly higher serum Cbl level than those born to homozygous (low Cbl, F2 equivalents. Low Cbl levels correlated with susceptibility to an infectious challenge with Salmonella enterica serovar Typhimurium or Citrobacter rodentium, and this susceptibility phenotype was moderated by Cbl administration. Transcriptional and metabolic profiling revealed that Cbl deficient mice exhibited a bioenergetic shift similar to a metabolic phenomenon commonly found in cancerous cells under hypoxic conditions known as the Warburg effect, with this metabolic effect being exacerbated further by infection. Our findings demonstrate a role for Cbl in bacterial infection, with potential general relevance to dietary deficiency and infection susceptibility.

  16. Basal blood corticosterone level is correlated with susceptibility to chronic restraint stress in mice.

    Science.gov (United States)

    Kim, Jae-Gon; Jung, Hye-Seung; Kim, Ki-Joon; Min, Sun-Seek; Yoon, Bong-June

    2013-10-25

    Corticosterone is released in response to stress and manifests as various bodily stress responses in rodents. While corticosterone reflects acute adaptive responses, how the basal steady-state corticosterone level relates to the subsequent stress response is largely unknown. Here, we investigated how basal corticosterone levels can affect the susceptibility to chronic restraint stress in mice. We designed a longitudinal experiment, enabling us to compare the basal corticosterone level and the subsequent response to repeated restraint stress within the same animal. We found that the mice had differential changes in plasma corticosterone levels, which either increased or decreased, with exposure to chronic stress. These differential changes reflected the differential stress susceptibility of the mice, as evaluated by changes in body weight. The extent of the changes in corticosterone level during chronic stress exposure was predicted by the basal corticosterone level. In addition, the behavioral consequence of chronic stress was also correlated with the basal corticosterone level prior to chronic stress experience. These data reveal that the basal steady-state corticosterone level is a predictor of stress susceptibility or resilience to subsequent stress exposures. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  17. Narcolepsy susceptibility gene CCR3 modulates sleep-wake patterns in mice.

    Science.gov (United States)

    Toyoda, Hiromi; Honda, Yoshiko; Tanaka, Susumu; Miyagawa, Taku; Honda, Makoto; Honda, Kazuki; Tokunaga, Katsushi; Kodama, Tohru

    2017-01-01

    Narcolepsy is caused by the loss of hypocretin (Hcrt) neurons and is associated with multiple genetic and environmental factors. Although abnormalities in immunity are suggested to be involved in the etiology of narcolepsy, no decisive mechanism has been established. We previously reported chemokine (C-C motif) receptor 3 (CCR3) as a novel susceptibility gene for narcolepsy. To understand the role of CCR3 in the development of narcolepsy, we investigated sleep-wake patterns of Ccr3 knockout (KO) mice. Ccr3 KO mice exhibited fragmented sleep patterns in the light phase, whereas the overall sleep structure in the dark phase did not differ between Ccr3 KO mice and wild-type (WT) littermates. Intraperitoneal injection of lipopolysaccharide (LPS) promoted wakefulness and suppressed both REM and NREM sleep in the light phase in both Ccr3 KO and WT mice. Conversely, LPS suppressed wakefulness and promoted NREM sleep in the dark phase in both genotypes. After LPS administration, the proportion of time spent in wakefulness was higher, and the proportion of time spent in NREM sleep was lower in Ccr3 KO compared to WT mice only in the light phase. LPS-induced changes in sleep patterns were larger in Ccr3 KO compared to WT mice. Furthermore, we quantified the number of Hcrt neurons and found that Ccr3 KO mice had fewer Hcrt neurons in the lateral hypothalamus compared to WT mice. We found abnormalities in sleep patterns in the resting phase and in the number of Hcrt neurons in Ccr3 KO mice. These observations suggest a role for CCR3 in sleep-wake regulation in narcolepsy patients.

  18. Narcolepsy susceptibility gene CCR3 modulates sleep-wake patterns in mice.

    Directory of Open Access Journals (Sweden)

    Hiromi Toyoda

    Full Text Available Narcolepsy is caused by the loss of hypocretin (Hcrt neurons and is associated with multiple genetic and environmental factors. Although abnormalities in immunity are suggested to be involved in the etiology of narcolepsy, no decisive mechanism has been established. We previously reported chemokine (C-C motif receptor 3 (CCR3 as a novel susceptibility gene for narcolepsy. To understand the role of CCR3 in the development of narcolepsy, we investigated sleep-wake patterns of Ccr3 knockout (KO mice. Ccr3 KO mice exhibited fragmented sleep patterns in the light phase, whereas the overall sleep structure in the dark phase did not differ between Ccr3 KO mice and wild-type (WT littermates. Intraperitoneal injection of lipopolysaccharide (LPS promoted wakefulness and suppressed both REM and NREM sleep in the light phase in both Ccr3 KO and WT mice. Conversely, LPS suppressed wakefulness and promoted NREM sleep in the dark phase in both genotypes. After LPS administration, the proportion of time spent in wakefulness was higher, and the proportion of time spent in NREM sleep was lower in Ccr3 KO compared to WT mice only in the light phase. LPS-induced changes in sleep patterns were larger in Ccr3 KO compared to WT mice. Furthermore, we quantified the number of Hcrt neurons and found that Ccr3 KO mice had fewer Hcrt neurons in the lateral hypothalamus compared to WT mice. We found abnormalities in sleep patterns in the resting phase and in the number of Hcrt neurons in Ccr3 KO mice. These observations suggest a role for CCR3 in sleep-wake regulation in narcolepsy patients.

  19. Loss of Sex and Age Driven Differences in the Gut Microbiome Characterize Arthritis-Susceptible *0401 Mice but Not Arthritis-Resistant *0402 Mice

    OpenAIRE

    Andres Gomez; David Luckey; Yeoman, Carl J.; Marietta, Eric V; Margret E Berg Miller; Joseph A Murray; White, Bryan A.; Veena Taneja

    2012-01-01

    BACKGROUND: HLA-DRB1 0401 is associated with susceptibility, while HLA-DRB1 0402 is associated with resistance to developing rheumatoid arthritis (RA) and collagen-induced arthritis in humans and transgenic mice respectively. The influence of gut-joint axis has been suggested in RA, though not yet proven. METHODOLOGY/PRINCIPAL FINDINGS: We have used HLA transgenic mice carrying arthritis susceptible and -resistant HLA-DR genes to explore if genetic factors and their interaction with gut flora...

  20. Different radiation susceptibility among five strains of mice detected by a skin reaction

    Energy Technology Data Exchange (ETDEWEB)

    Iwakawa, Mayumi; Noda, Shuhei; Ohta, Toshie [National Inst. of Radiological Sciences, Chiba (Japan). Frontier Research Center] [and others

    2003-03-01

    Published reports about skin reactions to radiotherapy, especially among breast-cancer patients, suggest that there are interindividual differences in the normal tissue response, and genetic factors are thought to be involved in this variation. An analysis of murine strain differences may reveal the mechanism of genetic factors in the extent of normal tissue damage from irradiation for several endpoints. The variation in the radiation susceptibility was observed when the skin of mice from strains A/J, C3H/HeMs, C57BL/6J, C.B.17/Icr-scid and C3H-scid was irradiated with a single dose ranging from 10 to 60 Gy, using Cs-137 gamma rays. The active skin reaction of A/J mice lasted for months. C3H/HeMs mice showed dose-dependent skin damage, and consequently recovered to a state of mild damage within 40 days after local irradiation. The time course of the response in C57BL/6J mice was shorter than in A/J mice. The 2 strains of scid mice exhibited severe damage after irradiation at any dose from 20 to 50 Gy, and did not show any dose dependency. The variation between murine strains in macroscopic and histopathological changes in skin during the progression and resolution of damage caused by irradiation suggests an inter-strain variation in the expression of genes involved in injury, apoptosis, repair, and remodeling. (author)

  1. Working memory deficits, increased anxiety-like traits, and seizure susceptibility in BDNF overexpressing mice

    Science.gov (United States)

    Papaleo, Francesco; Silverman, Jill L.; Aney, Jordan; Tian, Qingjun; Barkan, Charlotte L.; Chadman, Kathryn K.; Crawley, Jacqueline N.

    2011-01-01

    BDNF regulates components of cognitive processes and has been implicated in psychiatric disorders. Here we report that genetic overexpression of the BDNF mature isoform (BDNF-tg) in female mice impaired working memory functions while sparing components of fear conditioning. BDNF-tg mice also displayed reduced breeding efficiency, higher anxiety-like scores, high self-grooming, impaired prepulse inhibition, and higher susceptibility to seizures when placed in a new empty cage, as compared with wild-type (WT) littermate controls. Control measures of general health, locomotor activity, motor coordination, depression-related behaviors, and sociability did not differ between genotypes. The present findings, indicating detrimental effects of life-long increased BDNF in mice, may inform human studies evaluating the role of BDNF functional genetic variations on cognitive abilities and vulnerability to psychiatric disorders. PMID:21791566

  2. The type 2 cannabinoid receptor regulates susceptibility to osteoarthritis in mice.

    Science.gov (United States)

    Sophocleous, A; Börjesson, A E; Salter, D M; Ralston, S H

    2015-09-01

    Cannabinoid receptors and their ligands have been implicated in the regulation of various physiological processes but their role in osteoarthritis has not been investigated. The aim of this study was to evaluate the role of the type 2 cannabinoid receptor (Cnr2) in regulating susceptibility to osteoarthritis in mice. We analysed the severity of knee osteoarthritis as assessed by the Osteoarthritis Research Society International (OARSI) scoring system in mice with targeted deletion of Cnr2 (Cnr2(-/-)) and wild type (WT) littermates. Studies were conducted in mice subjected to surgical destabilisation of the medial meniscus (DMM) and in those with spontaneous age-related osteoarthritis (OA). Osteoarthritis was more severe following DMM in the medial compartment of the knee in Cnr2(-/-) compared with WT mice (mean ± sem score = 4.9 ± 0.5 vs 3.6 ± 0.3; P = 0.017). Treatment of WT mice with the CB2-selective agonist HU308 following DMM reduced the severity of OA in the whole joint (HU308 = 8.4 ± 0.2 vs vehicle = 10.4 ± 0.6; P = 0.007). Spontaneous age related osteoarthritis was also more severe in the medial compartment of the knee in 12-month old Cnr2(-/-) mice compared with WT (5.6 ± 0.5 vs 3.5 ± 0.3, P = 0.008). Cultured articular chondrocytes from Cnr2(-/-) mice produced less proteoglycans in vitro than wild type chondrocytes. These studies demonstrate that the Cnr2 pathway plays a role in the pathophysiology of osteoarthritis in mice and shows that pharmacological activation of CB2 has a protective effect. Further studies of the role of cannabinoid receptors in the pathogenesis of osteoarthritis in man are warranted. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

  3. Divergent metabolic adaptations to intestinal parasitic nematode infection in mice susceptible or resistant to obesity.

    Science.gov (United States)

    Wong, Tracie; Hildebrandt, Marie A; Thrasher, Seana M; Appleton, Judith A; Ahima, Rexford S; Wu, Gary D

    2007-12-01

    Diet-induced obesity results from increased ingestion of energy-dense food and sedentary lifestyle in genetically susceptible individuals. An environmental factor that may have shaped our energy homeostasis throughout evolution is parasitic nematode infection. To test the hypothesis that a metabolically "thrifty phenotype" is advantageous during intestinal nematode infection, we compared the responses to Heligmosomoides polygyrus infection between 2 mouse strains: obesity-prone C57Bl/6J vs obesity-resistant SWR/J. Metabolic phenotyping was performed using indirect calorimetry, dual energy x-ray absorptiometry, and magnetic resonance imaging scanning. Gene expression was assessed by quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. Body weight was maintained in both strains during nematode infection via different mechanisms. There was no apparent change in energy expenditure between the strains; however, SWR/J mice exhibited a marked hyperphagia (calorie intake 60% higher than C57Bl/6J) to maintain body weight. The importance of hyperphagia was confirmed by severe weight loss in a group of infected SWR/J mice whose food intake was restricted to that of naïve mice. Furthermore, SWR/J mice expelled nematodes more rapidly than C57Bl/6J mice, an effect related to a T helper cell 2 immune response. C57Bl/6J mice are more energy efficient during parasitic nematode infection, which may explain their ability to tolerate the infection. SWR/J mice, on the other hand, require an increase in food intake to maintain energy stores during nematode infection. In addition, a strong T helper cell 2-mediated immune response that facilitates a prompt clearance of nematode infection in SWR/J mice may have evolved to conserve energy in this strain.

  4. Susceptibility to glaucoma damage related to age and connective tissue mutations in mice.

    Science.gov (United States)

    Steinhart, Matthew R; Cone-Kimball, Elizabeth; Nguyen, Cathy; Nguyen, Thao D; Pease, Mary E; Chakravarti, Shukti; Oglesby, Ericka N; Quigley, Harry A

    2014-02-01

    The purpose of this research was to study the effects of age and genetic alterations in key connective tissue proteins on susceptibility to experimental glaucoma in mice. We used mice haploinsufficient in the elastin gene (EH) and mice without both alleles of the fibromodulin gene (FM KO) and their wild type (WT) littermates of B6 and CD1 strains, respectively. FM KO mice were tested at two ages: 2 months and 12 months. Intraocular pressure (IOP) was measured by Tonolab tonometer, axial lengths and widths measured by digital caliper post-enucleation, and chronic glaucoma damage was measured using a bead injection model and optic nerve axon counts. IOP in EH mice was not significantly different from WT, but FM KO were slightly lower than their controls (p = 0.04). Loss of retinal ganglion cell (RGC) axons was somewhat, but not significantly greater in young EH and younger or older FM KO strains than in age-matched controls (p = 0.48, 0.34, 0.20, respectively, multivariable regression adjusting for IOP exposure). Older CD1 mice lost significantly more RGC axons than younger CD1 (p = 0.01, multivariable regression). The CD1 mouse strain showed age-dependence of experimental glaucoma damage to RGC in the opposite, and more expected, direction than in B6 mice in which older mice are more resistant to damage. Genetic alteration in two genes that are constituents of sclera, fibromodulin and elastin do not significantly affect RGC loss. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Genetic variance is associated with susceptibility for cigarette smoke-induced DAMP release in mice.

    Science.gov (United States)

    Pouwels, Simon D; Faiz, Alen; den Boef, Lisette E; Gras, Reneé; van den Berge, Maarten; Boezen, H Marike; Korstanje, Ron; Ten Hacken, Nick H T; van Oosterhout, Antoon J M; Heijink, Irene H; Nawijn, Martijn C

    2017-09-01

    Chronic obstructive pulmonary disease (COPD) is characterized by unresolved neutrophilic airway inflammation and is caused by chronic exposure to toxic gases, such as cigarette smoke (CS), in genetically susceptible individuals. Recent data indicate a role for damage-associated molecular patterns (DAMPs) in COPD. Here, we investigated the genetics of CS-induced DAMP release in 28 inbred mouse strains. Subsequently, in lung tissue from a subset of strains, the expression of the identified candidate genes was analyzed. We tested whether small interfering RNA-dependent knockdown of candidate genes altered the susceptibility of the human A549 cell line to CS-induced cell death and DAMP release. Furthermore, we tested whether these genes were differentially regulated by CS exposure in bronchial brushings obtained from individuals with a family history indicative of either the presence or absence of susceptibility for COPD. We observed that, of the four DAMPs tested, double-stranded DNA (dsDNA) showed the highest correlation with neutrophilic airway inflammation. Genetic analyses identified 11 candidate genes governing either CS-induced or basal dsDNA release in mice. Two candidate genes ( Elac2 and Ppt1 ) showed differential expression in lung tissue on CS exposure between susceptible and nonsusceptible mouse strains. Knockdown of ELAC2 and PPT1 in A549 cells altered susceptibility to CS extract-induced cell death and DAMP release. In bronchial brushings, CS-induced expression of ENOX1 and ARGHGEF11 was significantly different between individuals susceptible or nonsusceptible for COPD. Our study shows that genetic variance in a mouse model is associated with CS-induced DAMP release, and that this might contribute to susceptibility for COPD. Copyright © 2017 the American Physiological Society.

  6. Blood supply--susceptible formation of melanin pigment in hair bulb melanocytes of mice.

    Science.gov (United States)

    Maeda, Shogo; Ueda, Koichi; Yamana, Hidenori; Tashiro-Yamaji, Junko; Ibata, Minenori; Mikura, Ayako; Okada, Masashi; Yasuda, Emi; Shibayama, Yuro; Yoshino, Miya; Kubota, Takahiro; Yoshida, Ryotaro

    2015-03-01

    Allogeneic skin grafts onto C57BL/6 mice are rejected, and the rejected skin is replaced by surrounding skin with black hair. In contrast, syngeneic skin grafts are tolerated, and gray hair grows on the grafts. To explore the mechanism of gray hair growing on the tolerated skin grafts, we prepared full-thickness skin (2-cm square) autografts, 2 (2 cm + 2 cm) horizontal or vertical parallel incisions, and U-shaped (2 cm × 2 cm × 2 cm) flaps with or without pedicle vessels. The grafts, incisions, and flaps were fixed by suturing with string and protected by a transparent bandage. On day 14 after the operation, the bandages were removed to observe the color of the hair growing on the skin. Skin autografts from wild-type or hepatocyte growth factor-transgenic (Tg) C57BL/6 mice survived with gray hair, whereas those from steel factor (Kitl)-Tg C57BL/6 mice survived with black hair. In addition, U-shaped flaps lacking both of the 2 main feeding vessels of wild-type mice had gray hair at the tip of the flaps. Light microscopy after staining with hematoxylin and eosin or dihydroxyphenylalanine showed that the formation of melanin pigment in the follicles, but not in the interadnexal skin, was susceptible to the blood supply. Melanin pigment formation in the hair bulb melanocytes appeared to be susceptible to the blood supply, and melanocytosis was promoted in the follicles and in the epidermis of Kitl-Tg C57BL/6 mice.

  7. Visceral leishmaniasis in congenic mice of susceptible and resistant phenotypes: immunosuppression by adherent spleen cells.

    Science.gov (United States)

    Nickol, A D; Bonventre, P F

    1985-10-01

    Visceral leishmaniasis is one of several parasitic diseases of humans characterized by immune suppression. A murine model of disseminated leishmaniasis utilizing inbred strains of specific genetic constitution was used to study the mechanisms of immunosuppression elicited during the course of infection. Resistant (Lshr) and susceptible (Lshs) strains of mice were challenged with amastigotes of Leishmania donovani and evaluated as to immune status at intervals between 2 and 40 weeks after challenge. The proliferative responses of splenic lymphocytes to T-cell mitogens, a B-cell mitogen, and parasite antigens were measured to evaluate the relative immune status of parasitized mice and noninfected control mice. Lymphocytes from resistant C3Heb/FeJ (C3H) mice responded normally to concanavalin A and phytohemagglutinin throughout the course of infection. Parasite antigen responses appeared 2 weeks after challenge of C3H mice and remained vigorous for periods up to 6 months. In contrast, immune suppression during infection was profound in both the curing (C57B1/10) and noncuring (B10.D2) phenotypes of Lshs congenic mice. Both Lshs strains developed severe infection as evidenced by high parasite burdens in the liver and spleen 4 to 5 weeks after challenge; splenic lymphocytes taken from these mice between 2 and 8 weeks became increasingly unresponsive to the T-cell mitogens as well as to parasite antigens. The noncuring B10.D2 mice which suffered chronic infection continued to be suppressed for as long as 40 weeks. C57B1/10 (curing) mice, in contrast, cleared infection between 12 and 16 weeks. After spontaneous recovery or elimination of parasites by antimonial drug therapy, the response of spleen cells to T-cell mitogens or parasite antigens were restored to normal. The spleen cells from the Lshs strains of mice obtained during the height of infection suppressed the proliferative responses of spleen cells from their uninfected counterparts upon cocultivation in vitro

  8. Sabin and wild type polioviruses from children who presented with ...

    African Journals Online (AJOL)

    polioviruses will continue to increase in importance. Objective: Isolating and identifying poliovirus strains from children of pediatrics age in Nigeria. Methods: A total of 120 fecal samples were randomly collected from children under the age of five who ...

  9. Liver proteome of mice with different genetic susceptibilities to the effects of fluoride

    Directory of Open Access Journals (Sweden)

    Zohaib Nisar KHAN

    Full Text Available ABSTRACT A/J and 129P3/J mice strains have been widely studied over the last few years because they respond quite differently to fluoride (F exposure. 129P3/J mice are remarkably resistant to the development of dental fluorosis, despite excreting less F in urine and having higher circulating F levels. These two strains also present different characteristics regardless of F exposure. Objective In this study, we investigated the differential pattern of protein expression in the liver of these mice to provide insights on why they have different responses to F. Material and Methods Weanling male A/J and 129P3/J mice (n=10 from each strain were pared and housed in metabolic cages with ad libitum access to low-F food and deionized water for 42 days. Liver proteome profiles were examined using nLC-MS/MS. Protein function was classified by GO biological process (Cluego v2.0.7 + Clupedia v1.0.8 and protein-protein interaction network was constructed (PSICQUIC, Cytoscape. Results Most proteins with fold change were increased in A/J mice. The functional category with the highest percentage of altered genes was oxidation-reduction process (20%. Subnetwork analysis revealed that proteins with fold change interacted with Disks large homolog 4 and Calcium-activated potassium channel subunit alpha-1. A/J mice had an increase in proteins related to energy flux and oxidative stress. Conclusion This could be a possible explanation for the high susceptibility of these mice to the effects of F, since the exposure also induces oxidative stress.

  10. Dysregulated CD4+ T cells from SLE-susceptible mice are sufficient to accelerate atherosclerosis in LDLr−/− mice

    Science.gov (United States)

    Wilhelm, Ashley J; Rhoads, Jillian P; Wade, Nekeithia S; Major, Amy S

    2015-01-01

    Objective Accelerated atherosclerosis is a major source of morbidity in systemic lupus erythematosus (SLE). However, the cause of SLE-accelerated atherosclerosis remains unclear. Methods CD4+ T cells from C57/Bl/6 (B6) or SLE-susceptible B6.Sle1.2.3 (B6.SLE) mice were transferred into LDLr−/−, Rag−/− mice. T cells were examined for cytokine production and expression of interleukin-10 receptor (IL-10R) and functional markers. T cells were isolated based on FoxP3GFP expression and transferred to LDLr−/−, Rag−/− mice to establish a role for B6.SLE effector T cells (Teff) in atherosclerosis. Results Mice receiving whole B6.SLE CD4+ T cells displayed no other SLE phenotype; however, atherosclerosis was increased nearly 40%. We noted dysregulated IL-17 production and reduced frequency of IL-10R expression by B6.SLE regulatory T cells (Treg). Functional assays indicated resistance of B6.SLE Teff to suppression by both B6.SLE and B6 Treg. Transfer experiments with CD4+FoxP3− Teff and CD4+FoxP3+ Treg from B6.SLE and B6 mice, respectively, resulted in increased atherosclerosis compared with B6 Teff and Treg recipients. Treg isolated from mice receiving B6.SLE Teff with B6 Treg had increased production of IL-17 and fewer expressed IL-10R compared with B6 Teff and Treg transfer. Conclusions Transfer of B6.SLE Teff to LDLr−/−, Rag−/− mice results in accelerated atherosclerosis independent of the source of Treg. In addition, the presence of B6.SLE Teff resulted in more IL-17-producing Treg and fewer expressing IL-10R, suggesting that B6.SLE Teff may mediate phenotypic changes in Treg. To our knowledge, this is the first study to provide direct evidence of the role of B6.SLE Teff in accelerating atherosclerosis through resistance to Treg suppression. PMID:24395554

  11. Dysregulated CD4+ T cells from SLE-susceptible mice are sufficient to accelerate atherosclerosis in LDLr-/- mice.

    Science.gov (United States)

    Wilhelm, Ashley J; Rhoads, Jillian P; Wade, Nekeithia S; Major, Amy S

    2015-04-01

    Accelerated atherosclerosis is a major source of morbidity in systemic lupus erythematosus (SLE). However, the cause of SLE-accelerated atherosclerosis remains unclear. CD4(+) T cells from C57/Bl/6 (B6) or SLE-susceptible B6.Sle1.2.3 (B6.SLE) mice were transferred into LDLr(-/-), Rag(-/-) mice. T cells were examined for cytokine production and expression of interleukin-10 receptor (IL-10R) and functional markers. T cells were isolated based on FoxP3(GFP) expression and transferred to LDLr(-/-), Rag(-/-) mice to establish a role for B6.SLE effector T cells (Teff) in atherosclerosis. Mice receiving whole B6.SLE CD4(+) T cells displayed no other SLE phenotype; however, atherosclerosis was increased nearly 40%. We noted dysregulated IL-17 production and reduced frequency of IL-10R expression by B6.SLE regulatory T cells (Treg). Functional assays indicated resistance of B6.SLE Teff to suppression by both B6.SLE and B6 Treg. Transfer experiments with CD4(+)FoxP3(-) Teff and CD4(+)FoxP3(+) Treg from B6.SLE and B6 mice, respectively, resulted in increased atherosclerosis compared with B6 Teff and Treg recipients. Treg isolated from mice receiving B6.SLE Teff with B6 Treg had increased production of IL-17 and fewer expressed IL-10R compared with B6 Teff and Treg transfer. Transfer of B6.SLE Teff to LDLr(-/-), Rag(-/-) mice results in accelerated atherosclerosis independent of the source of Treg. In addition, the presence of B6.SLE Teff resulted in more IL-17-producing Treg and fewer expressing IL-10R, suggesting that B6.SLE Teff may mediate phenotypic changes in Treg. To our knowledge, this is the first study to provide direct evidence of the role of B6.SLE Teff in accelerating atherosclerosis through resistance to Treg suppression. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  12. Acute exposure of mice to high-dose ultrafine carbon black decreases susceptibility to pneumococcal pneumonia

    Directory of Open Access Journals (Sweden)

    Gordon Stephen

    2010-10-01

    Full Text Available Abstract Background Epidemiological studies suggest that inhalation of carbonaceous particulate matter from biomass combustion increases susceptibility to bacterial pneumonia. In vitro studies report that phagocytosis of carbon black by alveolar macrophages (AM impairs killing of Streptococcus pneumoniae. We have previously reported high levels of black carbon in AM from biomass smoke-exposed children and adults. We therefore aimed to use a mouse model to test the hypothesis that high levels of carbon loading of AM in vivo increases susceptibility to pneumococcal pneumonia. Methods Female outbred mice were treated with either intranasal phosphate buffered saline (PBS or ultrafine carbon black (UF-CB in PBS; 500 μg on day 1 and day 4, and then infected with S. pneumoniae strain D39 on day 5. Survival was assessed over 72 h. The effect of UF-CB on AM carbon loading, airway inflammation, and a urinary marker of pulmonary oxidative stress was assessed in uninfected animals. Results Instillation of UF-CB in mice resulted a pattern of AM carbon loading similar to that of biomass-smoke exposed humans. In uninfected animals, UF-CB treated animals had increased urinary 8-oxodG (P = 0.055, and an increased airway neutrophil differential count (P . pneumoniae, whereas morbidity and mortality after infection was reduced in UF-CB treated animals (median survival 48 h vs. 30 h, P . pneumoniae colony forming unit counts, and lower airway levels of keratinocyte-derived chemokine/growth-related oncogene (KC/GRO, and interferon gamma. Conclusion Acute high level loading of AM with ultrafine carbon black particles per se does not increase the susceptibility of mice to pneumococcal infection in vivo.

  13. The postpolio syndrome: no evidence for poliovirus persistence

    NARCIS (Netherlands)

    Melchers, W.; de Visser, M.; Jongen, P.; van Loon, A.; Nibbeling, R.; Oostvogel, P.; Willemse, D.; Galama, J.

    1992-01-01

    To investigate the possibility of poliovirus persistence in patients with the postpolio syndrome, we examined skeletal muscle biopsy specimens, cerebrospinal fluid specimens, and sera for the presence of poliovirus RNA by the polymerase chain reaction, and for IgM antibodies by a poliovirus

  14. Increased susceptibility to diet-induced obesity in GPRC6A receptor knockout mice

    DEFF Research Database (Denmark)

    Clemmensen, Christoffer; Smajilovic, Sanela; Madsen, Andreas N

    2013-01-01

    complications is still elusive. In the present study, we investigated the impact of GPRC6A deficiency in a murine model of diet-induced obesity (DIO). Male Gprc6a knockout (KO) mice and WT littermates were subjected to a high-fat diet (HFD) for 25 weeks and exposed to comprehensive metabolic phenotyping...... in glucose metabolism showing that Gprc6a KO mice on an HFD display increased susceptibility to develop metabolic-related disorders. Altogether, these data suggest that the amino acid sensing receptor GPRC6A plays an important role in resistance to DIO and metabolic complications. Future studies......The recently identified G protein-coupled receptor GPRC6A is activated by dietary amino acids and expressed in multiple tissues. Although the receptor is hypothesised to exert biological impact on metabolic and endocrine-related parameters, the role of the receptor in obesity and metabolic...

  15. Retinoid levels influence enterohemorrhagic Escherichia coli infection and Shiga toxin 2 susceptibility in mice.

    Science.gov (United States)

    Cabrera, Gabriel; Fernández-Brando, Romina J; Abrey-Recalde, María Jimena; Baschkier, Ariela; Pinto, Alipio; Goldstein, Jorge; Zotta, Elsa; Meiss, Roberto; Rivas, Marta; Palermo, Marina S

    2014-09-01

    Enterohemorrhagic Escherichia coli (EHEC) is a food-borne pathogen that produces Shiga toxin (Stx) and causes hemorrhagic colitis. Under some circumstances, Stx produced within the intestinal tract enters the bloodstream, leading to systemic complications that may cause the potentially fatal hemolytic-uremic syndrome. Although retinoids like vitamin A (VA) and retinoic acid (RA) are beneficial to gut integrity and the immune system, the effect of VA supplementation on gastrointestinal infections of different etiologies has been controversial. Thus, the aim of this work was to study the influence of different VA status on the outcome of an EHEC intestinal infection in mice. We report that VA deficiency worsened the intestinal damage during EHEC infection but simultaneously improved survival. Since death is associated mainly with Stx toxicity, Stx was intravenously inoculated to analyze whether retinoid levels affect Stx susceptibility. Interestingly, while VA-deficient (VA-D) mice were resistant to a lethal dose of Stx2, RA-supplemented mice were more susceptible to it. Given that peripheral blood polymorphonuclear cells (PMNs) are known to potentiate Stx2 toxicity, we studied the influence of retinoid levels on the absolute number and function of PMNs. We found that VA-D mice had decreased PMN numbers and a diminished capacity to produce reactive oxygen species, while RA supplementation had the opposite effect. These results are in line with the well-known function of retinoids in maintaining the homeostasis of the gut but support the idea that they have a proinflammatory effect by acting, in part, on the PMN population. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  16. Low dose chronic Schistosoma mansoni infection increases susceptibility to Mycobacterium bovis BCG infection in mice.

    Science.gov (United States)

    Elias, D; Akuffo, H; Thors, C; Pawlowski, A; Britton, S

    2005-03-01

    The incidence of mycobacterial diseases is high and the efficacy of Bacillus Calmette Guerin (BCG) is low in most areas of the world where chronic worm infections are common. However, if and how concurrent worm infections could affect immunity to mycobacterial infections has not been elucidated. In this study we investigated whether infection of mice with Schistosoma mansoni could affect the ability of the animals to control Mycobacterium bovis BCG infection and the immune response to mycobacterial antigens. BALB/c mice subclinically infected with S. mansoni were challenged with M. bovis BCG via the intravenous route. The ability of the animals to contain the replication of M. bovis BCG in their organs, lung pathology as well as the in vitro mycobacterial and worm antigen induced immune responses were evaluated. The results showed that S. mansoni coinfected mice had significantly higher levels of BCG bacilli in their organs and sustained greater lung pathology compared to Schistosoma uninfected controls. Moreover, Schistosoma infected mice show depressed mycobacterial antigen specific Th1 type responses. This is an indication that chronic worm infection could affect resistance/susceptibility to mycobacterial infections by impairing mycobacteria antigen specific Th1 type responses. This finding is potentially important in the control of TB in helminth endemic parts of the world.

  17. Differences in susceptibility to German cockroach frass and its associated proteases in induced allergic inflammation in mice

    Directory of Open Access Journals (Sweden)

    Herman Nancy

    2007-12-01

    Full Text Available Abstract Background Cockroach exposure is a major risk factor for the development of asthma. Inhalation of fecal remnants (frass is the likely sensitizing agent; however isolated frass has not been tested for its ability to induce experimental asthma in mice. Methods Mice (Balb/c or C57Bl/6 were sensitized and challenged with GC frass or GC frass devoid of proteases and measurements of airway inflammation and hyperresponsiveness were performed (interleukin (IL-5, -13, and interferon gamma (IFNγ levels in bronchoalveolar lavage fluid, serum IgE levels, airway hyperresponsiveness, cellular infiltration, and mucin production. Results Sensitization and challenge of Balb/c mice with GC frass resulted in increased airway inflammation and hyperresponsiveness. C57Bl/6 mice were not susceptible to this model of sensitization; however they were sensitized to GC frass using a more aggressive sensitization and challenge protocol. In mice that were sensitized by inhalation, the active serine proteases in GC frass played a role in airway hyperresponsiveness as these mice had less airway hyperresponsiveness to acetylcholine and less mucin production. Proteases did not play a role in mediating the allergic inflammation in mice sensitized via intraperitoneal injection. Conclusion While both strains of mice were able to induce experimental asthma following GC frass sensitization and challenge, the active serine proteases in GC frass only play a role in airway hyperresponsiveness in Balb/c mice that were susceptible to sensitization via inhalation. The differences in the method of sensitization suggest genetic differences between strains of mice.

  18. Female Nur77-deficient mice show increased susceptibility to diet-induced obesity.

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    Sonia Perez-Sieira

    Full Text Available Adipose tissue is essential in the regulation of body weight. The key process in fat catabolism and the provision of energy substrate during times of nutrient deprivation or enhanced energy demand is the hydrolysis of triglycerides and the release of fatty acids and glycerol. Nur77 is a member of the NR4A subfamily of nuclear receptors that plays an important metabolic role, modulating hepatic glucose metabolism and lipolysis in muscle. However, its endogenous role on white adipose tissue, as well as the gender dependency of these mechanisms, remains largely unknown. Male and female wild type and Nur77 deficient mice were fed with a high fat diet (45% calories from fat for 4 months. Mice were analyzed in vivo with the indirect calorimetry system, and tissues were analyzed by real-time PCR and Western blot analysis. Female, but not male Nur77 deficient mice, gained more weight and fat mass when compared to wild type mice fed with high fat diet, which can be explained by decreased energy expenditure. The lack of Nur77 also led to a decreased pHSL/HSL ratio in white adipose tissue and increased expression of CIDEA in brown adipose tissue of female Nur77 deficient mice. Overall, these findings suggest that Nur77 is an important physiological modulator of lipid metabolism in adipose tissue and that there are gender differences in the sensitivity to deletion of the Nur77 signaling. The decreased energy expenditure and the actions of Nur77 on liver, muscle, brown and white adipose tissue contribute to the increased susceptibility to diet-induced obesity in females lacking Nur77.

  19. Differential Susceptibility to Hepatic Inflammation and Proliferation in AXB Recombinant Inbred Mice Chronically Infected with Helicobacter hepaticus

    OpenAIRE

    Ihrig, Melanie; Schrenzel, Mark D.; Fox, James G.

    1999-01-01

    Helicobacter hepaticus is a naturally occurring pathogen of mice and has been used to develop models of chronic hepatitis, liver cancer, and, more recently, inflammatory bowel disease, in selected mouse strains. A/JCr mice are particularly susceptible to H. hepaticus-induced hepatitis and subsequent development of liver neoplasms, whereas C57BL/6 mice are resistant. In this study, we inoculated nine AXB recombinant inbred (RI) mouse strains, derived from A/J and C57BL/6 mice, with H. hepaticu...

  20. P2X7 receptor-deficient mice are susceptible to bone cancer pain

    DEFF Research Database (Denmark)

    Hansen, Rikke Rie; Nielsen, Christian K.; Nasser, Arafat

    2011-01-01

    The purinergic P2X7 receptor is implicated in both neuropathic and inflammatory pain, and has been suggested as a possible target in pain treatment. However, the specific role of the P2X7 receptor in bone cancer pain is unknown. We demonstrated that BALB/cJ P2X7 receptor knockout (P2X7R KO) mice...... were susceptible to bone cancer pain and moreover had an earlier onset of pain-related behaviours compared with cancer-bearing, wild-type mice. Furthermore, acute treatment with the selective P2X7 receptor antagonist, A-438079, failed to alleviate pain-related behaviours in models of bone cancer pain...... with and without astrocyte activation (BALB/cJ or C3H mice inoculated with 4T1 mammary cancer cells or NCTC 2472 osteosarcoma cells, respectively), suggesting that astrocytic P2X7 receptors play a negligible role in bone cancer pain. The results support the hypothesis that bone cancer pain is a separate pain state...

  1. Disaccharidase activity in the small intestine of susceptible and resistant mice after primary and challenge infections with Giardia muris.

    Science.gov (United States)

    Daniels, C W; Belosevic, M

    1992-04-01

    The activities of four disaccharidases were examined in resistant (C57Bl/6) and susceptible (C3H/HeN) mice during the primary infection with Giardia muris and after challenge with either trophozoite extract or cysts. Significant decreases in lactase, sucrase, trehalase, and maltase activities in C57Bl/6 mice and lactase and sucrase activities in C3H/HeN mice in the anterior 25% of the small intestine were observed on day 10 after infection. The activities of maltase, sucrase, trehalase, and lactase in the jejunum of C3H/HeN mice were significantly reduced after challenge with trophozoite extract, when compared with the uninfected or infected, but not challenged animals. Decreases in enzyme activities of C3H/HeN mice were evident as early as 12 hours after challenge with the extract. The resistant C57Bl/6 mice showed little change in disaccharidase activity after challenge with trophozoite extract. On the other hand, challenge with cysts resulted in a few decreases in disaccharidase activities in both strains of mice: C57Bl/6 mice showed decreases in the duodenum, while disaccharidases of C3H/HeN mice had lower activity more posteriorly. Thus, challenge with parasite antigen results in a more severe disaccharidase deficiency in susceptible hosts when compared with resistant ones.

  2. Loss of sex and age driven differences in the gut microbiome characterize arthritis-susceptible 0401 mice but not arthritis-resistant 0402 mice.

    Directory of Open Access Journals (Sweden)

    Andres Gomez

    Full Text Available BACKGROUND: HLA-DRB1 0401 is associated with susceptibility, while HLA-DRB1 0402 is associated with resistance to developing rheumatoid arthritis (RA and collagen-induced arthritis in humans and transgenic mice respectively. The influence of gut-joint axis has been suggested in RA, though not yet proven. METHODOLOGY/PRINCIPAL FINDINGS: We have used HLA transgenic mice carrying arthritis susceptible and -resistant HLA-DR genes to explore if genetic factors and their interaction with gut flora gut can be used to predict susceptibility to develop arthritis. Pyrosequencing of the 16S rRNA gene from the fecal microbiomes of DRB1 0401 and DRB1 0402 transgenic mice revealed that the guts of 0401 mice is dominated by a Clostridium-like bacterium, whereas the guts of 0402 mice are enriched for members of the Porphyromonadaceae family and Bifidobacteria. DRB1 0402 mice harbor a dynamic sex and age-influenced gut microbiome while DRB1 0401 mice did not show age and sex differences in gut microbiome even though they had altered gut permeability. Cytokine transcripts, measured by rtPCR, in jejuna showed differential TH17 regulatory network gene transcripts in 0401 and 0402 mice. CONCLUSIONS/SIGNIFICANCE: We have demonstrated for the first time that HLA genes in association with the gut microbiome may determine the immune environment and that the gut microbiome might be a potential biomarker as well as contributor for susceptibility to arthritis. Identification of pathogenic commensal bacteria would provide new understanding of disease pathogenesis, thereby leading to novel approaches for therapy.

  3. Neuropsychological deficits in mice depleted of the schizophrenia susceptibility gene CSMD1.

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    Vidar M Steen

    Full Text Available Recent meta-analyses of schizophrenia genome-wide association studies (GWASs have identified the CUB and SUSHI multiple domains 1 (CSMD1 gene as a statistically strong risk factor. CSMD1 is a complement control-related protein suggested to inhibit the classical complement pathway, being expressed in developing neurons. However, expression of CSMD1 is largely uncharacterized and relevance for behavioral phenotypes is not previously demonstrated. Here, we assess neuropsychological behaviors of a Csmd1 knockout (KO mouse in a selection of standard behavioral tests. Deregulation of neuropsychological responses were observed in both the open field and the elevated plus maze tests, in which KO mice spent 55% and 33% less time than WT littermate mice in open areas, respectively. Altered behaviors were also observed in tail suspension and to higher acoustic stimuli, for which Csmd1 KO mice showed helplessness and moderate increase in startle amplitude, respectively. Furthermore, Csmd1 KO mice also displayed increased weight-gain and glucose tolerance, similar to a major phenotype of the metabolic syndrome that also has been associated to the human CSMD1 locus. Consistent with a role in the control of behaviors, Csmd1 was found highly expressed in the central nervous system (CNS, and with some expression in visceral fat and ovary, under tissue-specific control by a novel promoter-associated lncRNA. In summary, disruption of Csmd1 induces behaviors reminiscent of blunted emotional responses, anxiety and depression. These observations suggest an influence of the CSMD1 schizophrenia susceptibility gene on psychopathology and endophenotypes of the negative symptom spectra.

  4. Poliovirus Laboratory Based Surveillance: An Overview.

    Science.gov (United States)

    Zaidi, Syed Sohail Zahoor; Asghar, Humayun; Sharif, Salmaan; Alam, Muhammad Masroor

    2016-01-01

    World Health Assembly (WHA) in 1988 encouraged the member states to launch Global Polio Eradication Initiative (GPEI) (resolution WHA41.28) against "the Crippler" called poliovirus, through strong routine immunization program and intensified surveillance systems. Since its launch, global incidence of poliomyelitis has been reduced by more than 99 % and the disease squeezed to only three endemic countries (Afghanistan, Pakistan, and Nigeria) out of 125. Today, poliomyelitis is on the verge of eradication, and their etiological agents, the three poliovirus serotypes, are on the brink of extinction from the natural environment. The last case of poliomyelitis due to wild type 2 strain occurred in 1999 in Uttar Pradesh, India whereas the last paralytic case due to wild poliovirus type 3 (WPV3) was seen in November, 2012 in Yobe, Nigeria. Despite this progress, undetected circulation cannot fully rule out the eradication as most of the poliovirus infections are entirely subclinical; hence sophisticated environmental surveillance is needed to ensure the complete eradication of virus. Moreover, the vaccine virus in under-immunized communities can sometimes revert and attain wild type characteristics posing a big challenge to the program.

  5. Recombinant Poliovirus circulation among healthy children ...

    African Journals Online (AJOL)

    Recombinant Poliovirus circulation among healthy children immunized with oral polio vaccine in Abidjan. ... African Journal of Biotechnology ... In order to assess the level of polio virus with natural recombinant genome and wild polio virus circulating in the environment of healthy children aged 0 to 5 years in Abidjan, 130 ...

  6. Cold-Adapted Viral Attenuation (CAVA: Highly Temperature Sensitive Polioviruses as Novel Vaccine Strains for a Next Generation Inactivated Poliovirus Vaccine.

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    Barbara P Sanders

    2016-03-01

    Full Text Available The poliovirus vaccine field is moving towards novel vaccination strategies. Withdrawal of the Oral Poliovirus Vaccine and implementation of the conventional Inactivated Poliovirus Vaccine (cIPV is imminent. Moreover, replacement of the virulent poliovirus strains currently used for cIPV with attenuated strains is preferred. We generated Cold-Adapted Viral Attenuation (CAVA poliovirus strains by serial passage at low temperature and subsequent genetic engineering, which contain the capsid sequences of cIPV strains combined with a set of mutations identified during cold-adaptation. These viruses displayed a highly temperature sensitive phenotype with no signs of productive infection at 37°C as visualized by electron microscopy. Furthermore, decreases in infectious titers, viral RNA, and protein levels were measured during infection at 37°C, suggesting a block in the viral replication cycle at RNA replication, protein translation, or earlier. However, at 30°C, they could be propagated to high titers (9.4-9.9 Log10TCID50/ml on the PER.C6 cell culture platform. We identified 14 mutations in the IRES and non-structural regions, which in combination induced the temperature sensitive phenotype, also when transferred to the genomes of other wild-type and attenuated polioviruses. The temperature sensitivity translated to complete absence of neurovirulence in CD155 transgenic mice. Attenuation was also confirmed after extended in vitro passage at small scale using conditions (MOI, cell density, temperature anticipated for vaccine production. The inability of CAVA strains to replicate at 37°C makes reversion to a neurovirulent phenotype in vivo highly unlikely, therefore, these strains can be considered safe for the manufacture of IPV. The CAVA strains were immunogenic in the Wistar rat potency model for cIPV, inducing high neutralizing antibody titers in a dose-dependent manner in response to D-antigen doses used for cIPV. In combination with the

  7. T regulatory cells control susceptibility to invasive pneumococcal pneumonia in mice.

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    Daniel R Neill

    Full Text Available Streptococcus pneumoniae is an important human pathogen responsible for a spectrum of diseases including pneumonia. Immunological and pro-inflammatory processes induced in the lung during pneumococcal infection are well documented, but little is known about the role played by immunoregulatory cells and cytokines in the control of such responses. We demonstrate considerable differences in the immunomodulatory cytokine transforming growth factor (TGF-β between the pneumococcal pneumonia resistant BALB/c and susceptible CBA/Ca mouse strains. Immunohistochemistry and flow cytometry reveal higher levels of TGF-β protein in BALB/c lungs during pneumococcal pneumonia that correlates with a rapid rise in lung Foxp3(+Helios(+ T regulatory cells. These cells have protective functions during pneumococcal pneumonia, because blocking their induction with an inhibitor of TGF-β impairs BALB/c resistance to infection and aids bacterial dissemination from lungs. Conversely, adoptive transfer of T regulatory cells to CBA/Ca mice, prior to infection, prolongs survival and decreases bacterial dissemination from lungs to blood. Importantly, strong T regulatory cell responses also correlate with disease-resistance in outbred MF1 mice, confirming the importance of immunoregulatory cells in controlling protective responses to the pneumococcus. This study provides exciting new evidence for the importance of immunomodulation during pulmonary pneumococcal infection and suggests that TGF-β signalling is a potential target for immunotherapy or drug design.

  8. Homeopathic medicine Cantharis modulates uropathogenic E. coli (UPEC)-induced cystitis in susceptible mice.

    Science.gov (United States)

    de Paula Coelho, Cidéli; Motta, Priscilla Dias; Petrillo, Mariana; de Oliveira Iovine, Renata; Dalboni, Luciane Costa; Santana, Fabiana Rodrigues; Correia, Michelle Sanchez Freitas; Casarin, Renato Corrêa Viana; Carvalho, Vania Maria; Bonamin, Leoni Villano

    2017-04-01

    This is a random blinded placebo controlled murine experimental model to study the effects of Cantharis 6 CH, a homeopathic medicine, on E coli-induced cystitis. 24 adult susceptible female BALB/c mice were inoculated with E coli - UPEC O4:K-:H5 by a transurethral catheter. Cantharis 6cH or vehicle (placebo) was offered to mice by free access into the drinking water (1:100), during 24 h after infection. Spleen, bladder and kidneys were processed for quantitative histopathology after immunohistochemistry, using anti-CD3, CD79, MIF, NK and VEGF antibodies; the cytokines present in the bladder washing fluid were measured using a LUMINEX-Magpix KIT. Mann-Whitney and Fisher exact test were used as statistical analysis. Cantharis 6 CH increased IL12p40, IFN-γ and decreased IL10 concentrations in the bladder fluid (p⩽0.05); in the bladder mucosa, it increased the ratio between B and T lymphocytes (31%) and between B lymphocytes and MIF+ macrophages (57%, p⩽0.05). In the pelvis, instead, it decreased the B/T cells ratio (41%, p⩽0.05) and increased the M1/M2 macrophage ratio (42%, p⩽0.05). No differences were seen in the kidney and spleen analysis. The inverted balance of inflammatory cells and cytokines in bladder and pelvis mucosa shows specific local immune modulation induced by Cantharis 6cH. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Enamel crystals of mice susceptible or resistant to dental fluorosis: an AFM study

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    Marília Afonso Rabelo BUZALAF

    2014-06-01

    Full Text Available Objective: This study aimed to assess the overall apatite crystals profile in the enamel matrix of mice susceptible (A/J strain or resistant (129P3/J strain to dental fluorosis through analyses by atomic force microscopy (AFM. Material and Methods: Samples from the enamel matrix in the early stages of secretion and maturation were obtained from the incisors of mice from both strains. All detectable traces of matrix protein were removed from the samples by a sequential extraction procedure. The purified crystals (n=13 per strain were analyzed qualitatively in the AFM. Surface roughness profile (Ra was measured. Results: The mean (±SD Ra of the crystals of A/J strain (0.58±0.15 nm was lower than the one found for the 129P3/J strain (0.66±0.21 nm but the difference did not reach statistical significance (t=1.187, p=0.247. Crystals of the 129P3/J strain (70.42±6.79 nm were found to be significantly narrower (t=4.013, p=0.0013 than the same parameter measured for the A/J strain (90.42±15.86 nm. Conclusion: enamel crystals of the 129P3/J strain are narrower, which is indicative of slower crystal growth and could interfere in the occurrence of dental fluorosis.

  10. Decay of Sabin inactivated poliovirus vaccine (IPV)-boosted poliovirus antibodies.

    Science.gov (United States)

    Resik, Sonia; Tejeda, Alina; Fonseca, Magile; Sein, Carolyn; Hung, Lai Heng; Martinez, Yenisleidys; Diaz, Manuel; Okayasu, Hiromasa; Sutter, Roland W

    We conducted a follow-on study to a phase I randomized, controlled trial conducted in Cuba, 2012, to assess the persistence of poliovirus antibodies at 21-22 months following booster dose of Sabin-IPV compared to Salk-IPV in adults who had received multiple doses of oral poliovirus vaccine (OPV) during childhood. In 2012, 60 healthy adult males aged 19-23 were randomized to receive one booster dose, of either Sabin-inactivated poliovirus vaccine (Sabin-IPV), adjuvanted Sabin-IPV (aSabin-IPV), or conventional Salk-IPV. In the original study, blood was collected at days 0 (before) and 28 (after vaccination), respectively. In this study, an additional blood sample was collected 21-22 months after vaccination, and tested for neutralizing antibodies to Sabin poliovirus types 1, 2 and 3. We collected sera from 59/60 (98.3%) subjects; 59/59 (100%) remained seropositive to all poliovirus types, 21-22 months after vaccination. The decay curves were very similar among the study groups. Between day 28 and 21-22 months, there was a reduction of ⩾87.4% in median antibody levels for all poliovirus types in all study groups, with no significant differences between the study groups. The decay of poliovirus antibodies over a 21-22-month period was similar regardless of the type of booster vaccine used, suggesting the scientific data of Salk IPV long-term persistence and decay may be broadly applicable to Sabin IPV.

  11. Humanized TLR4/MD-2 mice reveal LPS recognition differentially impacts susceptibility to Yersinia pestis and Salmonella enterica.

    Directory of Open Access Journals (Sweden)

    Adeline M Hajjar

    Full Text Available Although lipopolysaccharide (LPS stimulation through the Toll-like receptor (TLR-4/MD-2 receptor complex activates host defense against Gram-negative bacterial pathogens, how species-specific differences in LPS recognition impact host defense remains undefined. Herein, we establish how temperature dependent shifts in the lipid A of Yersinia pestis LPS that differentially impact recognition by mouse versus human TLR4/MD-2 dictate infection susceptibility. When grown at 37°C, Y. pestis LPS is hypo-acylated and less stimulatory to human compared with murine TLR4/MD-2. By contrast, when grown at reduced temperatures, Y. pestis LPS is more acylated, and stimulates cells equally via human and mouse TLR4/MD-2. To investigate how these temperature dependent shifts in LPS impact infection susceptibility, transgenic mice expressing human rather than mouse TLR4/MD-2 were generated. We found the increased susceptibility to Y. pestis for "humanized" TLR4/MD-2 mice directly paralleled blunted inflammatory cytokine production in response to stimulation with purified LPS. By contrast, for other Gram-negative pathogens with highly acylated lipid A including Salmonella enterica or Escherichia coli, infection susceptibility and the response after stimulation with LPS were indistinguishable between mice expressing human or mouse TLR4/MD-2. Thus, Y. pestis exploits temperature-dependent shifts in LPS acylation to selectively evade recognition by human TLR4/MD-2 uncovered with "humanized" TLR4/MD-2 transgenic mice.

  12. Allergen uptake, activation, and IL-23 production by pulmonary myeloid DCs drives airway hyperresponsiveness in asthma-susceptible mice.

    Directory of Open Access Journals (Sweden)

    Ian P Lewkowich

    Full Text Available Maladaptive, Th2-polarized inflammatory responses are integral to the pathogenesis of allergic asthma. As regulators of T cell activation, dendritic cells (DCs are important mediators of allergic asthma, yet the precise signals which render endogenous DCs "pro-asthmatic", and the extent to which these signals are regulated by the pulmonary environment and host genetics, remains unclear. Comparative phenotypic and functional analysis of pulmonary DC populations in mice susceptible (A/J, or resistant (C3H to experimental asthma, revealed that susceptibility to airway hyperresponsiveness is associated with preferential myeloid DC (mDC allergen uptake, and production of Th17-skewing cytokines (IL-6, IL-23, whereas resistance is associated with increased allergen uptake by plasmacytoid DCs. Surprisingly, adoptive transfer of syngeneic HDM-pulsed bone marrow derived mDCs (BMDCs to the lungs of C3H mice markedly enhanced lung IL-17A production, and rendered them susceptible to allergen-driven airway hyperresponsiveness. Characterization of these BMDCs revealed levels of antigen uptake, and Th17 promoting cytokine production similar to that observed in pulmonary mDCs from susceptible A/J mice. Collectively these data demonstrate that the lung environment present in asthma-resistant mice promotes robust pDC allergen uptake, activation, and limits Th17-skewing cytokine production responsible for driving pathologic T cell responses central to the development of allergen-induced airway hyperresponsiveness.

  13. Environmental factors regulate Paneth cell phenotype and host susceptibility to intestinal inflammation in Irgm1-deficient mice.

    Science.gov (United States)

    Rogala, Allison R; Schoenborn, Alexi A; Fee, Brian E; Cantillana, Viviana A; Joyce, Maria J; Gharaibeh, Raad Z; Roy, Sayanty; Fodor, Anthony A; Sartor, R Balfour; Taylor, Gregory A; Gulati, Ajay S

    2017-12-22

    Crohn's disease (CD) represents a chronic inflammatory disorder of the intestinal tract. Several susceptibility genes have been linked to CD, though their precise role in the pathogenesis of this disorder remains unclear. Immunity-Related GTPase M (IRGM) is an established CD risk allele. We have shown previously that conventionally-raised (CV) mice lacking the IRGM ortholog, Irgm1, exhibit abnormal Paneth cells (PCs) and increased susceptibility to intestinal injury. In the present study, we sought to utilize this model system to determine if environmental conditions impact these phenotypes, as is thought to be the case in human CD. To accomplish this, wild-type and Irgm1-/- mice were re-derived into specific pathogen-free (SPF) and germ-free (GF) conditions. We next assessed how these differential housing environments influenced intestinal injury patterns and epithelial cell morphology and function in wild-type and Irgm1-/- mice. Remarkably, in contrast to CV mice, SPF Irgm1-/- mice showed only a slight increase in susceptibility to dextran sodium sulfate-induced inflammation. SPF Irgm1-/- mice also displayed minimal abnormalities in PC number, morphology, and antimicrobial peptide expression. Goblet cell numbers and epithelial proliferation were also unaffected by Irgm1 in SPF conditions. No microbial differences were observed between wild-type and Irgm1-/- mice, but gut bacterial communities differed profoundly between CV and SPF mice. Specifically, Helicobacter sequences were significantly increased in CV mice; however, inoculating SPF Irgm1-/- mice with H. hepaticus was not sufficient to transmit a pro-inflammatory phenotype. In summary, our findings suggest the impact of Irgm1-deficiency on susceptibility to intestinal inflammation and epithelial function is critically dependent on environmental influences. This work establishes the importance of Irgm1-/- mice as a model to elucidate host-environment interactions that regulate mucosal homeostasis and

  14. Seroepidemiology of Polioviruses among University Students in Northern Italy

    OpenAIRE

    Baldo, Vincenzo; Baldovin, Tatjana; Cocchio, Silvia; Lazzari, Roberta; Saracino, Elena; Bertoncello, Chiara; Buja, Alessandra; Trevisan, Andrea

    2012-01-01

    The widespread use of poliovirus vaccination schemes has led to a marked decline in the incidence of paralytic poliomyelitis worldwide, but wild poliovirus is still endemic in some developing countries, and in 2009 a total of 23 countries reported at least 1 case of poliomyelitis caused by wild-strain polio viruses. A serological survey was thus conducted on the immunological status against polioviruses of 318 young adults, classified by their country of origin. Immunity to poliomyelitis was ...

  15. Defects in early cell recruitment contribute to the increased susceptibility to respiratory Klebsiella pneumoniae infection in diabetic mice.

    Science.gov (United States)

    Martinez, Nuria; Ketheesan, Natkunam; Martens, Gregory W; West, Kim; Lien, Egil; Kornfeld, Hardy

    2016-10-01

    Diabetes is associated with increased susceptibility to Klebsiella pneumoniae and poor prognosis with infection. We demonstrate accelerated mortality in mice with streptozotocin-induced diabetes following tracheal instillation of K. pneumoniae. Diabetic mice recruited fewer granulocytes to the alveolar airspace and had reduced early production of CXCL1, CXCL2, IL-1β and TNF-α following tracheal instillation of K. pneumoniae-lipopolysaccharide. Additionally, TLR2 and TIRAP expression following K. pneumoniae-lipopolysaccharide exposure was decreased in hyperglycemic mice. These findings indicate that impaired innate sensing and failure to rapidly recruit granulocytes to the site of infection is a mechanism for diabetic susceptibility to respiratory K. pneumoniae infection. Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  16. Age-associated variability in susceptibility of Swiss Webster mice to MPV and other excluded murine pathogens.

    Science.gov (United States)

    Grove, Kristina A; Smith, Peter C; Booth, Carmen J; Compton, Susan R

    2012-11-01

    Detection of mouse parvovirus (MPV) and other murine pathogens in research colonies is dependent on the transmissibility of the agents and the sensitivity of sentinels to those agents. Transmissibility is based on several agent-dependent properties including mode of transmission, infectivity, and environmental stability, whereas host susceptibility can vary according to mouse age, strain, and sex. In this study, 4-wk-old, 12-wk-old, and aged Swiss Webster female sentinel mice were compared for their ability to detect infectious agents by using a standardized health surveillance program, to determine whether sentinels should be replaced more frequently to improve the efficiency of detection of infectious agents within a murine colony. Both experimentally and naturally infected mice were used to transmit MPV and other infectious agents from index mice to sentinels. First, Swiss Webster mice were inoculated with MPV, and transmission to 4-, 12-, and 24-wk-old contact and soiled-bedding sentinels was determined. Second, mice naturally infected with 9 infectious agents were obtained from 2 local pet stores, and transmission to 4-wk-old contact sentinels and 4-, 12-, and 44-wk-old soiled-bedding sentinels was determined. For agents that were transmitted via soiled bedding (MPV, mouse hepatitis virus, murine norovirus, Theiler murine encephalomyelitis virus, and pinworms), transmission did not differ in regard to the age of the sentinels. In conclusion, susceptibility to several infectious agents did not differ according to sentinel age in a health-surveillance protocol that used mice older than 12 wk.

  17. Multiple Independent Emergences of Type 2 Vaccine-Derived Polioviruses during a Large Outbreak in Northern Nigeria

    Science.gov (United States)

    Shaw, Jing; Jorba, Jaume; Bukbuk, David; Adu, Festus; Gumede, Nicksy; Pate, Muhammed Ali; Abanida, Emmanuel Ade; Gasasira, Alex; Iber, Jane; Chen, Qi; Vincent, Annelet; Chenoweth, Paul; Henderson, Elizabeth; Wannemuehler, Kathleen; Naeem, Asif; Umami, Rifqiyah Nur; Nishimura, Yorihiro; Shimizu, Hiroyuki; Baba, Marycelin; Adeniji, Adekunle; Williams, A. J.; Kilpatrick, David R.; Oberste, M. Steven; Wassilak, Steven G.; Tomori, Oyewale; Pallansch, Mark A.; Kew, Olen

    2013-01-01

    Since 2005, a large poliomyelitis outbreak associated with type 2 circulating vaccine-derived poliovirus (cVDPV2) has occurred in northern Nigeria, where immunization coverage with trivalent oral poliovirus vaccine (tOPV) has been low. Phylogenetic analysis of P1/capsid region sequences of isolates from each of the 403 cases reported in 2005 to 2011 resolved the outbreak into 23 independent type 2 vaccine-derived poliovirus (VDPV2) emergences, at least 7 of which established circulating lineage groups. Virus from one emergence (lineage group 2005-8; 361 isolates) was estimated to have circulated for over 6 years. The population of the major cVDPV2 lineage group expanded rapidly in early 2009, fell sharply after two tOPV rounds in mid-2009, and gradually expanded again through 2011. The two major determinants of attenuation of the Sabin 2 oral poliovirus vaccine strain (A481 in the 5′-untranslated region [5′-UTR] and VP1-Ile143) had been replaced in all VDPV2 isolates; most A481 5′-UTR replacements occurred by recombination with other enteroviruses. cVDPV2 isolates representing different lineage groups had biological properties indistinguishable from those of wild polioviruses, including efficient growth in neuron-derived HEK293 cells, the capacity to cause paralytic disease in both humans and PVR-Tg21 transgenic mice, loss of the temperature-sensitive phenotype, and the capacity for sustained person-to-person transmission. We estimate from the poliomyelitis case count and the paralytic case-to-infection ratio for type 2 wild poliovirus infections that ∼700,000 cVDPV2 infections have occurred during the outbreak. The detection of multiple concurrent cVDPV2 outbreaks in northern Nigeria highlights the risks of cVDPV emergence accompanying tOPV use at low rates of coverage in developing countries. PMID:23408630

  18. Commensal and probiotic bacteria influence intestinal barrier function and susceptibility to colitis in Nod1-/-; Nod2-/- mice.

    Science.gov (United States)

    Natividad, Jane M M; Petit, Valerie; Huang, Xianxi; de Palma, Giada; Jury, Jennifer; Sanz, Yolanda; Philpott, Dana; Garcia Rodenas, Clara L; McCoy, Kathy D; Verdu, Elena F

    2012-08-01

    The intestinal microbiota regulates key host functions. It is unknown whether modulation of the microbiota can affect a genetically determined host phenotype. Polymorphisms in the Nucleotide oligomerization domain (Nod)-like receptor family confer genetic risk for inflammatory bowel disease (IBD). We investigated whether the intestinal microbiota and the probiotic strain Bifidobacterium breve NCC2950 affect intestinal barrier function and responses to intestinal injury in Nod1(-/-); Nod2(-/-) mice. Specific pathogen-free (SPF) Nod1(-/-); Nod2(-/-) mice and mice gnotobiotically derived with altered Schaedler flora (ASF) biota were used. SPF Nod1(+/-); Nod2(+/-) littermates (generated by crossing SPF Nod1(-/-); Nod2(-/-) and germ-free C57BL/6 mice) and ASF Nod1(+/-); Nod2(+/-) mice were used as controls. SPF mice were gavaged daily with 10(9) -CFU B. breve for 14 days before colitis induction. Denaturing gradient gel electrophoresis (DGGE) and real-time polymerase chain reaction (PCR) were used to assess microbiota composition. Intestinal permeability was assessed by in vitro and in vivo techniques. Expressions of epithelial apical junction proteins, mucin, and antimicrobial proteins were assessed by quantitative reverse-transcription PCR (qRT-PCR) and immunofluorescence. Responses to intestinal injury were investigated using an acute experimental model of colitis. Under SPF conditions, Nod1(-/-); Nod2(-/-) mice had increased paracellular permeability, decreased E-cadherin, and lower colonic antimicrobial RegIII-γ expression compared to Nod1(+/-); Nod2(+/-) littermate controls. These changes were associated with increased susceptibility to colitis. ASF colonization or B. breve supplementation normalized RegIII-γ expression and decreased susceptibility to dextran sodium sulfate (DSS) colitis in Nod1(-/-); Nod2(-/-) mice. The intestinal microbiota influences colitis severity in Nod1(-/-); Nod2(-/-) mice. The results suggest that colonization strategies with defined

  19. Inactivation of poliovirus by chloramine-T.

    Science.gov (United States)

    Gowda, N M; Trieff, N M; Stanton, G J

    1981-01-01

    Since concern has recently been expressed about the presence of genotoxic substances due to chlorination of water and wastewater, chloramine-T (CAT) is proposed as an alternative disinfectant to chlorine. The viricidal properties of chlorine and CAT were compared. Kinetics of inactivation of poliovirus type 2 by chlorine and CAT in chlorine demand-free water were investigated by using a kinetic apparatus. Inactivation of the virus by chlorine and CAT occurred in two steps. The initial linear part of the inactivation curve followed a pseudo-first-order reaction with the virus. An obvious dose-response relationship was demonstrated with CAT. The rate of inactivation of the virus by CAT was faster in acid medium than in alkaline medium. Inactivation kinetic studies were performed at different temperatures, and the kinetic, Arrhenius, and thermodynamic parameters were evaluated. The rate of inactivation of poliovirus type 2 by chlorine was faster than that by CAT under identical conditions. A mechanism for the viral inactivation in acid conditions was proposed which led to a rate equation consistent with the experimental results. The results indicate that CAT may be an effective viricide against poliovirus type 2 in an acid medium. PMID:6271058

  20. The susceptibility to cytotoxic T lymphocyte mediated lysis of chemically induced sarcomas from immunodeficient and normal mice

    DEFF Research Database (Denmark)

    Svane, I M; Engel, A M; Thomsen, Allan Randrup

    1997-01-01

    A panel of sarcomas induced with 3-methylcholanthrene in normal and immunodeficient mice was studied for their capacity to present antigen by the endogenous, MHC class I restricted pathway. Lymphocytic choriomeningitis virus was used to infect cultured tumour cells, and the infected cells were...... tested for susceptibility to cytolysis by virus specific cytotoxic T cells. Tumour cells originating from tumours induced in immunocompetent C.B.-17 mice presented virus antigen more efficiently than tumour cells from immunodeficient SCID mice. No significant difference in virus antigen presentation...... was found between tumours from nude and nu/+ BALB/c mice. The sensitivity of target cells from the individual tumours to cytotoxic T lymphocyte (CTL) mediated lysis correlated negatively with their sensitivity to natural killer (NK) cell mediated lysis. There was a positive correlation between...

  1. Innate and Adaptive Immune Response to Pneumonia Virus of Mice in a Resistant and a Susceptible Mouse Strain

    Directory of Open Access Journals (Sweden)

    Ellen R. T. Watkiss

    2013-01-01

    Full Text Available Respiratory syncytial virus (RSV is the leading cause of infant bronchiolitis. The closely related pneumonia virus of mice (PVM causes a similar immune-mediated disease in mice, which allows an analysis of host factors that lead to severe illness. This project was designed to compare the immune responses to lethal and sublethal doses of PVM strain 15 in Balb/c and C57Bl/6 mice. Balb/c mice responded to PVM infection with an earlier and stronger innate response that failed to control viral replication. Production of inflammatory cyto- and chemokines, as well as infiltration of neutrophils and IFN-γ secreting natural killer cells into the lungs, was more predominant in Balb/c mice. In contrast, C57Bl/6 mice were capable of suppressing both viral replication and innate inflammatory responses. After a sublethal infection, PVM-induced IFN-γ production by splenocytes was stronger early during infection and weaker at late time points in C57Bl/6 mice when compared to Balb/c mice. Furthermore, although the IgG levels were similar and the mucosal IgA titres lower, the virus neutralizing antibody titres were higher in C57Bl/6 mice than in Balb/c mice. Overall, the difference in susceptibility of these two strains appeared to be related not to an inherent T helper bias, but to the capacity of the C57Bl/6 mice to control both viral replication and the immune response elicited by PVM.

  2. High susceptibility to fatty liver disease in two-pore channel 2-deficient mice.

    Science.gov (United States)

    Grimm, Christian; Holdt, Lesca M; Chen, Cheng-Chang; Hassan, Sami; Müller, Christoph; Jörs, Simone; Cuny, Hartmut; Kissing, Sandra; Schröder, Bernd; Butz, Elisabeth; Northoff, Bernd; Castonguay, Jan; Luber, Christian A; Moser, Markus; Spahn, Saskia; Lüllmann-Rauch, Renate; Fendel, Christina; Klugbauer, Norbert; Griesbeck, Oliver; Haas, Albert; Mann, Matthias; Bracher, Franz; Teupser, Daniel; Saftig, Paul; Biel, Martin; Wahl-Schott, Christian

    2014-08-21

    Endolysosomal organelles play a key role in trafficking, breakdown and receptor-mediated recycling of different macromolecules such as low-density lipoprotein (LDL)-cholesterol, epithelial growth factor (EGF) or transferrin. Here we examine the role of two-pore channel (TPC) 2, an endolysosomal cation channel, in these processes. Embryonic mouse fibroblasts and hepatocytes lacking TPC2 display a profound impairment of LDL-cholesterol and EGF/EGF-receptor trafficking. Mechanistically, both defects can be attributed to a dysfunction of the endolysosomal degradation pathway most likely on the level of late endosome to lysosome fusion. Importantly, endolysosomal acidification or lysosomal enzyme function are normal in TPC2-deficient cells. TPC2-deficient mice are highly susceptible to hepatic cholesterol overload and liver damage consistent with non-alcoholic fatty liver hepatitis. These findings indicate reduced metabolic reserve of hepatic cholesterol handling. Our results suggest that TPC2 plays a crucial role in trafficking in the endolysosomal degradation pathway and, thus, is potentially involved in the homoeostatic control of many macromolecules and cell metabolites.

  3. Lung necrosis and neutrophils reflect common pathways of susceptibility to Mycobacterium tuberculosis in genetically diverse, immune-competent mice

    Directory of Open Access Journals (Sweden)

    Muhammad K. K. Niazi

    2015-09-01

    Full Text Available Pulmonary tuberculosis (TB is caused by Mycobacterium tuberculosis in susceptible humans. Here, we infected Diversity Outbred (DO mice with ∼100 bacilli by aerosol to model responses in a highly heterogeneous population. Following infection, ‘supersusceptible’, ‘susceptible’ and ‘resistant’ phenotypes emerged. TB disease (reduced survival, weight loss, high bacterial load correlated strongly with neutrophils, neutrophil chemokines, tumor necrosis factor (TNF and cell death. By contrast, immune cytokines were weak correlates of disease. We next applied statistical and machine learning approaches to our dataset of cytokines and chemokines from lungs and blood. Six molecules from the lung: TNF, CXCL1, CXCL2, CXCL5, interferon-γ (IFN-γ, interleukin 12 (IL-12; and two molecules from blood – IL-2 and TNF – were identified as being important by applying both statistical and machine learning methods. Using molecular features to generate tree classifiers, CXCL1, CXCL2 and CXCL5 distinguished four classes (supersusceptible, susceptible, resistant and non-infected from each other with approximately 77% accuracy using completely independent experimental data. By contrast, models based on other molecules were less accurate. Low to no IFN-γ, IL-12, IL-2 and IL-10 successfully discriminated non-infected mice from infected mice but failed to discriminate disease status amongst supersusceptible, susceptible and resistant M.-tuberculosis-infected DO mice. Additional analyses identified CXCL1 as a promising peripheral biomarker of disease and of CXCL1 production in the lungs. From these results, we conclude that: (1 DO mice respond variably to M. tuberculosis infection and will be useful to identify pathways involving necrosis and neutrophils; (2 data from DO mice is suited for machine learning methods to build, validate and test models with independent data based solely on molecular biomarkers; (3 low levels of immunological cytokines best

  4. Diabetes susceptibility of BALB/cBOM mice treated with streptozotocin. Inhibition by lethal irradiation and restoration by splenic lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Paik, S.G.; Blue, M.L.; Fleischer, N.; Shin, S.

    1982-09-01

    In genetically susceptible strains of mice, repeated injections of a subdiabetogenic dose of streptozotocin induces the development of progressive insulin-dependent hyperglycemia. We showed previously that host T-cell functions play an obligatory etiologic role in this experimental disease by demonstrating that the athymic nude mouse is resistant to diabetes induction unless its T-cell functions are reconstituted by thymus graft. Here we show that lethal irradiation of euthymic (+/nu) mice of BALB/cBOM background causes selective resistance of the mice to the diabetogenic effects of the multiple low doses of streptozotocin without affecting their sensitivity to a high pharmacologic dose of the toxin. We also show that reconstitution of the irradiated mice with splenic lymphocytes causes the restoration of diabetes susceptibility. Lethally irradiated mice thus represent a useful experimental model for analyzing the host functions involved in the development of this disease. These results provide an additional support for the hypothesis that the induction of diabetes in this model system is mediated by an autoimmune amplification mechanism.

  5. The role of Abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans.

    Science.gov (United States)

    Zheng, Ming; Zhang, Haili; Dill, David L; Clark, J David; Tu, Susan; Yablonovitch, Arielle L; Tan, Meng How; Zhang, Rui; Rujescu, Dan; Wu, Manhong; Tessarollo, Lino; Vieira, Wilfred; Gottesman, Michael M; Deng, Suhua; Eberlin, Livia S; Zare, Richard N; Billard, Jean-Martin; Gillet, Jean-Pierre; Li, Jin Billy; Peltz, Gary

    2015-02-01

    We know very little about the genetic factors affecting susceptibility to drug-induced central nervous system (CNS) toxicities, and this has limited our ability to optimally utilize existing drugs or to develop new drugs for CNS disorders. For example, haloperidol is a potent dopamine antagonist that is used to treat psychotic disorders, but 50% of treated patients develop characteristic extrapyramidal symptoms caused by haloperidol-induced toxicity (HIT), which limits its clinical utility. We do not have any information about the genetic factors affecting this drug-induced toxicity. HIT in humans is directly mirrored in a murine genetic model, where inbred mouse strains are differentially susceptible to HIT. Therefore, we genetically analyzed this murine model and performed a translational human genetic association study. A whole genome SNP database and computational genetic mapping were used to analyze the murine genetic model of HIT. Guided by the mouse genetic analysis, we demonstrate that genetic variation within an ABC-drug efflux transporter (Abcb5) affected susceptibility to HIT. In situ hybridization results reveal that Abcb5 is expressed in brain capillaries, and by cerebellar Purkinje cells. We also analyzed chromosome substitution strains, imaged haloperidol abundance in brain tissue sections and directly measured haloperidol (and its metabolite) levels in brain, and characterized Abcb5 knockout mice. Our results demonstrate that Abcb5 is part of the blood-brain barrier; it affects susceptibility to HIT by altering the brain concentration of haloperidol. Moreover, a genetic association study in a haloperidol-treated human cohort indicates that human ABCB5 alleles had a time-dependent effect on susceptibility to individual and combined measures of HIT. Abcb5 alleles are pharmacogenetic factors that affect susceptibility to HIT, but it is likely that additional pharmacogenetic susceptibility factors will be discovered. ABCB5 alleles alter susceptibility

  6. Plaque And Growth Characteristics Of Different Polioviruses Isolated ...

    African Journals Online (AJOL)

    Objective: To determine some virulent trait-related properties of poliovirus isolates from children with acute flaccid paralysis following vaccination with oral polio vaccine (OPV). Design: Six polioviruses earlier characterised into wild, vaccine-derived and OPV-like were studied using the plaque morphology and growth ...

  7. original article evaluation of immunity against poliovirus serotypes ...

    African Journals Online (AJOL)

    Dr Oboro VO

    spread of the virus (13). CONCLUSION. The present study demonstrates 81% herd immunity for the three-poliovirus serotypes among children in five riverine communities in two local government areas of Delta state of Nigeria. Identification of some children without detectable antibodies to one or more poliovirus serotypes, ...

  8. Loss of Myh14 Increases Susceptibility to Noise-Induced Hearing Loss in CBA/CaJ Mice

    Directory of Open Access Journals (Sweden)

    Xiaolong Fu

    2016-01-01

    Full Text Available MYH14 is a member of the myosin family, which has been implicated in many motile processes such as ion-channel gating, organelle translocation, and the cytoskeleton rearrangement. Mutations in MYH14 lead to a DFNA4-type hearing impairment. Further evidence also shows that MYH14 is a candidate noise-induced hearing loss (NIHL susceptible gene. However, the specific roles of MYH14 in auditory function and NIHL are not fully understood. In the present study, we used CRISPR/Cas9 technology to establish a Myh14 knockout mice line in CBA/CaJ background (now referred to as Myh14−/− mice and clarify the role of MYH14 in the cochlea and NIHL. We found that Myh14−/− mice did not exhibit significant hearing loss until five months of age. In addition, Myh14−/− mice were more vulnerable to high intensity noise compared to control mice. More significant outer hair cell loss was observed in Myh14−/− mice than in wild type controls after acoustic trauma. Our findings suggest that Myh14 may play a beneficial role in the protection of the cochlea after acoustic overstimulation in CBA/CaJ mice.

  9. Decay of Sabin inactivated poliovirus vaccine (IPV-boosted poliovirus antibodies

    Directory of Open Access Journals (Sweden)

    Sonia Resik

    2015-01-01

    Conclusion: The decay of poliovirus antibodies over a 21–22-month period was similar regardless of the type of booster vaccine used, suggesting the scientific data of Salk IPV long-term persistence and decay may be broadly applicable to Sabin IPV.

  10. Higher susceptibility of NOD/LtSz-scid Il2rg-/- NSG mice to xenotransplanted lung cancer cell lines

    Directory of Open Access Journals (Sweden)

    Kanaji N

    2014-10-01

    Full Text Available Nobuhiro Kanaji,1 Akira Tadokoro,1 Kentaro Susaki,1 Saki Yokokura,1 Kiyomi Ohmichi,2 Reiji Haba,2 Naoki Watanabe,1 Shuji Bandoh,1 Tomoya Ishii,1 Hiroaki Dobashi,1 Takuya Matsunaga11Department of Internal Medicine, Division of Hematology, Rheumatology and Respiratory Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan; 2Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Kagawa, JapanPurpose: No lung cancer xenograft model using non-obese diabetic (NOD-scid Il2rg-/- mice has been reported. The purpose of this study is to select a suitable mouse strain as a xenogenic host for testing tumorigenicity of lung cancer.Materials and methods: We directly compared the susceptibility of four immunodeficient mouse strains, c-nu, C.B-17 scid, NOD-scid, and NOD/LtSz-scid Il2rg-/- (NSG mice, for tumor formation from xenotransplanted lung cancer cell lines. Various numbers (101–105 cells/head of two lung cancer cell lines, A549 and EBC1, were subcutaneously inoculated and tumor sizes were measured every week up to 12 weeks.Results: When 104 EBC1 cells were inoculated, no tumor formation was observed in BALB/c-nu or C.B-17 scid mice. Tumors developed in two of the five NOD-scid mice (40% and in all the five NSG mice (100%. When 103 EBC1 cells were injected, no tumors developed in any strain other than NSG mice, while tumorigenesis was achieved in all the five NSG mice (100%, P=0.0079 within 9 weeks. NSG mice similarly showed higher susceptibility to xenotransplantation of A549 cells. Tumor formation was observed only in NSG mice after inoculation of 103 or fewer A549 cells (40% vs 0% in 15 NSG mice compared with others, respectively, P=0.0169. We confirmed that the engrafted tumors originated from inoculated human lung cancer cells by immunohistochemical staining with human cytokeratin and vimentin.Conclusion: NSG mice may be the most suitable strain for testing tumorigenicity of lung cancer, especially if only a few cells

  11. A novel multiplex poliovirus binding inhibition assay applicable for large serosurveillance and vaccine studies, without the use of live poliovirus.

    NARCIS (Netherlands)

    Schepp, Rutger M; Berbers, Guy A M; Ferreira, José A; Reimerink, Johan H; van der Klis, Fiona R

    2017-01-01

    Large-scale serosurveillance or vaccine studies for poliovirus using the "gold standard" WHO neutralisation test (NT) are very laborious and time consuming. With the polio eradication at hand and with the removal of live attenuated Sabin strains from the oral poliovirus vaccine (OPV), starting with

  12. Vaccine-induced cellular immune responses differ from innate responses in susceptible and resistant strains of mice infected with Coccidioides posadasii.

    Science.gov (United States)

    Shubitz, Lisa F; Dial, Sharon M; Perrill, Robert; Casement, Rachael; Galgiani, John N

    2008-12-01

    Susceptibility to Coccidioides spp. varies widely in humans and other mammals and also among individuals within a species. Among strains of mice with various susceptibilities, immunohistopathology revealed that C57BL/6 mice were highly susceptible to the disease following intranasal infection, DBA/2n mice were intermediate, and Swiss-Webster mice were innately resistant. Resistant Swiss-Webster mice developed prominent perivascular/peribronchiolar lymphocytic cuffing and well-formed granulomas with few fungal elements and debris in the necrotic center, surrounded by a mantle of macrophages, lymphocytes, and fibrocytes. Susceptible C57BL/6 mice became moribund between 14 and 18 days postinfection, with overwhelming numbers of neutrophils and spherules and very few T cells, the drastic reduction of which was associated with failure and death, while intermediate DBA/2n mice controlled the fungal burden but demonstrated progressive lung inflammation with prominent suppuration, and they deteriorated clinically. Vaccinated C57BL/6 mice had an early and robust lymphocyte response, which included significantly higher Mac2(+), CD3(+), and CD4(+) cell scores on day 18 than those of innately resistant SW mice and DBA/2n mice; they also had prominent perivascular/peribronchiolar lymphocytic infiltrates not present in their unvaccinated counterparts, and they appeared to be resolving lesions by day 56 compared to the other two strains, based on significantly lower disease scores and observably smaller and fewer lesions with few spherules and neutrophils.

  13. Increased susceptibility of vault poly(ADP-ribose) polymerase-deficient mice to carcinogen-induced tumorigenesis.

    Science.gov (United States)

    Raval-Fernandes, Sujna; Kickhoefer, Valerie A; Kitchen, Christina; Rome, Leonard H

    2005-10-01

    Vault poly(ADP-ribose) polymerase (VPARP) and telomerase-associated protein 1 (TEP1) are components of the vault ribonucleoprotein complex. Vaults have been implicated in multidrug resistance of human tumors and are thought to be involved in macromolecular assembly and/or transport. Previous studies showed that VPARP-deficient mice were viable, fertile, and did not display any vault-related or telomerase-related phenotype, whereas disruption of telomerase-associated protein 1 in mice led to reduced stability of the vault RNA and affected its stable association with vaults, although there were no telomerase-related changes. In this study, we evaluated the susceptibility of Vparp-/- and Tep1-/- mice to dimethylhydrazine-induced colon tumorigenesis and urethane-induced lung tumorigenesis. Mice received i.p. injections of either 1 g/kg body weight of urethane twice a week for 2 weeks or 20 mg/kg body weight of dimethylhydrazine once a week for 10 weeks and were analyzed after 10 and 60 weeks, respectively. The colon tumor incidence and multiplicity were significantly higher and colon tumor latency was significantly shorter in Vparp-/- mice compared with wild-type mice. Increased colon tumor incidence, multiplicity, and reduced tumor latency were also seen in Tep1-/- mice, however, these results were statistically not significant. Lung tumor multiplicities were increased in both Vparp-/- and Tep1-/- mice but were not significant. The increase in carcinogen-induced tumors in VPARP-deficient mice is the only phenotype observed to date, and suggests a possible role for VPARP, directly or indirectly, in chemically induced neoplasia.

  14. Inflammatory lesion and parasite load are inversely associated in Leishmania amazonensis infected mice genetically selected according to oral tolerance susceptibility.

    Science.gov (United States)

    Tavares, Daniel; da Conceição Ribeiro, Ricardo; Carlos da Silva, Antonio

    2006-04-01

    Two strains of mice selected according to extreme phenotypes of susceptibility and resistance to oral tolerance (TS and TR mice, respectively) were infected with 1 x 10(7) Leishmania amazonensis promastigotes and studied comparatively. TS mice developed a minor pathology while permitting parasite growth with the presence of increased IL-4, IL-10 and IFN-gamma, and lower NO and IL-2 levels and delayed-type hypersensitivity (DTH). In contrast, in TR mice, footpad swelling was increased but parasite growth was reduced. They produced lower IL-4, IL-10 and IFN-gamma but increased NO, IL-2 levels, DTH, activated spleen macrophages and periarteriolar lymphoid sheaths. The results suggest that the tolerogenic TS mouse profile, with higher IL-10 production, impaired lesion development but also avoided macrophage leishmanicidal activity, maintaining in this manner a silent parasite load. On the other hand, the TR mouse profile contributed to lesion progression with controlled parasite load. To directly address the influence of oral tolerance on infection, mice were gavaged with OVA, and 7 days afterwards were infected and challenged to bystander suppression with OVA in the same footpad. In TR mice gavaged with 25 mg OVA the inflammatory lesion was largely enhanced, while with 5 mg OVA the lesion was diminished. In TS mice the footpad swelling was always lower. However, the bystander effect did not modify the establishment of infection; and similarly to the control non-bystander mice, parasite clearance was maintained in TR and prevented in TS mice. Therefore, a better comprehension of immunoregulation of innate and adaptive immunity in the early stages of infection is necessary for the development of protocols preventing inflammation and contributing to the elimination of parasites.

  15. Immature mice are more susceptible to the detrimental effects of high fat diet on cancellous bone in the distal femur.

    Science.gov (United States)

    Inzana, Jason A; Kung, Ming; Shu, Lei; Hamada, Daisuke; Xing, Lian Ping; Zuscik, Michael J; Awad, Hani A; Mooney, Robert A

    2013-11-01

    With the increasing prevalence of obesity among children and adolescents, it is imperative to understand the implications of early diet-induced obesity on bone health. We hypothesized that cancellous bone of skeletally immature mice is more susceptible to the detrimental effects of a high fat diet (HFD) than mature mice, and that removing excess dietary fat will reverse these adverse effects. Skeletally immature (5weeks old) and mature (20weeks old) male C57BL/6J mice were fed either a HFD (60% kcal fat) or low fat diet (LFD; 10% kcal fat) for 12weeks, at which point, the trabecular bone structure in the distal femoral metaphysis and third lumbar vertebrae were evaluated by micro-computed tomography. The compressive strength of the vertebrae was also measured. In general, the HFD led to deteriorations in cancellous bone structure and compressive biomechanical properties in both age groups. The HFD-fed immature mice had a greater decrease in trabecular bone volume fraction (BVF) in the femoral metaphysis, compared to mature mice (p=0.017 by 2-way ANOVA). In the vertebrae, however, the HFD led to similar reductions in BVF and compressive strength in the two age groups. When mice on the HFD were switched to a LFD (HFD:LFD) for an additional 12weeks, the femoral metaphyseal BVF in immature mice showed no improvements, whereas the mature mice recovered their femoral metaphyseal BVF to that of age-matched lean controls. The vertebral BVF and compressive strength of HFD:LFD mouse bones, following diet correction, were equivalent to those of LFD:LFD mice in both age groups. These data suggest that femoral cancellous metaphyseal bone is more susceptible to the detrimental effects of HFD before skeletal maturity and is less able to recover after correcting the diet. Negative effects of HFD on vertebrae are less severe and can renormalize with LFD:LFD mice after diet correction, in both skeletally immature and mature animals. © 2013. Published by Elsevier Inc. All rights

  16. Datasets in Gene Expression Omnibus used in the study ORD-020969: Genomic effects of androstenedione and sex-specific liver cancer susceptibility in mice

    Data.gov (United States)

    U.S. Environmental Protection Agency — Datasets in Gene Expression Omnibus used in the study ORD-020969: Genomic effects of androstenedione and sex-specific liver cancer susceptibility in mice. This...

  17. Glucagon-Like Peptide-1 Receptor Activation Modulates Pancreatitis-Associated Gene Expression But Does Not Modify the Susceptibility to Experimental Pancreatitis in Mice

    National Research Council Canada - National Science Library

    Jacqueline A. Koehler; Laurie L. Baggio; Benjamin J. Lamont; Safina Ali; Daniel J. Drucker

    2009-01-01

    Glucagon-Like Peptide-1 Receptor Activation Modulates Pancreatitis-Associated Gene Expression But Does Not Modify the Susceptibility to Experimental Pancreatitis in Mice Jacqueline A. Koehler , Laurie L...

  18. Gene expression analysis reveals early changes in several molecular pathways in cerebral malaria-susceptible mice versus cerebral malaria-resistant mice

    Directory of Open Access Journals (Sweden)

    Grau Georges E

    2007-12-01

    Full Text Available Abstract Background Microarray analyses allow the identification and assessment of molecular signatures in whole tissues undergoing pathological processes. To better understand cerebral malaria pathogenesis, we investigated intra-cerebral gene-expression profiles in well-defined genetically cerebral malaria-resistant (CM-R and CM-susceptible (CM-S mice, upon infection by Plasmodium berghei ANKA (PbA. We investigated mouse transcriptional responses at early and late stages of infection by use of cDNA microarrays. Results Through a rigorous statistical approach with multiple testing corrections, we showed that PbA significantly altered brain gene expression in CM-R (BALB/c, and in CM-S (CBA/J and C57BL/6 mice, and that 327 genes discriminated between early and late infection stages, between mouse strains, and between CM-R and CM-S mice. We further identified 104, 56, 84 genes with significant differential expression between CM-R and CM-S mice on days 2, 5, and 7 respectively. The analysis of their functional annotation indicates that genes involved in metabolic energy pathways, the inflammatory response, and the neuroprotection/neurotoxicity balance play a major role in cerebral malaria pathogenesis. In addition, our data suggest that cerebral malaria and Alzheimer's disease may share some common mechanisms of pathogenesis, as illustrated by the accumulation of β-amyloid proteins in brains of CM-S mice, but not of CM-R mice. Conclusion Our microarray analysis highlighted marked changes in several molecular pathways in CM-S compared to CM-R mice, particularly at early stages of infection. This study revealed some promising areas for exploration that may both provide new insight into the knowledge of CM pathogenesis and the development of novel therapeutic strategies.

  19. Role of Micro RNA-205 in Promoting Visceral Adiposity of NZ10 Mice with Polygenic Susceptibility for Type 2 Diabetes.

    Science.gov (United States)

    Adi, Nikhil; Adi, Jennipher; Cesar, Liliana; Kurlansky, Paul; Agatston, Arthur; Webster, Keith A

    2015-07-01

    To characterize diet-dependent miRNA profiles and their targets in the visceral adipose of mice with polygenic susceptibility to type 2 diabetes. Six-week NONcNZO10/LtJ (NZ10) and control SWR/J mice were subjected to high protein-fish oil or control diets for 19 weeks and micro-RNA microarray analyses were implemented on visceral adipose RNA. We found that 27 miRNAs were significantly induced and 10 significantly repressed in the VA of obese NZ10 mice compared with controls. 12 selected regulated miRNAs were confirmed by RT-PCR based on the microarray data and we demonstrated that the expression of these miRNAs remained unaltered in the VA of control SWR mice. To assess the possible functional roles of miRNAs in adipogenesis, we also analyzed their expression in 3T3-L1 cells during growth and differentiation. This revealed that suppression of miRNA-205 alone correlated selectively with increased cell proliferation and lipid formation of adipocytes. Diet and genetics control the expression of obesity-regulated miRNAs in the visceral adipose of NZ10 mice.

  20. Mast cells have no impact on cutaneous leishmaniasis severity and related Th2 differentiation in resistant and susceptible mice.

    Science.gov (United States)

    Paul, Christoph; Wolff, Svenja; Zapf, Thea; Raifer, Hartmann; Feyerabend, Thorsten B; Bollig, Nadine; Camara, Bärbel; Trier, Claudia; Schleicher, Ulrike; Rodewald, Hans-Reimer; Lohoff, Michael

    2016-01-01

    The genus leishmania comprises different protozoan parasites which are causative agents of muco-cutaneous and systemic, potentially lethal diseases. After infection with the species Leishmania major, resistant mice expand Th1 cells which stimulate macrophages for Leishmania destruction. In contrast, susceptible mice generate Th2 cells which deactivate macrophages, leading to systemic spread of the pathogens. Th-cell differentiation is determined within the first days, and Th2 cell differentiation requires IL-4, whereby the initial IL-4 source is often unknown. Mast cells are potential sources of IL-4, and hence their role in murine leishmaniasis has previously been studied in mast cell-deficient Kit mutant mice, although these mice display immunological phenotypes beyond mast cell deficiency. We therefore readdressed this question by infecting Kit-independent mast cell-deficient mice that are Th1 (C57BL/6 Cpa(Cre) ) or Th2 (BALB/c Cpa(Cre) ) prone with L. major. Using different parasite doses and intra- or subcutaneous infection routes, the results demonstrate no role of mast cells on lesion size development, parasite load, immune cell phenotypes expanding in draining lymph nodes, and cytokine production during murine cutaneous leishmaniasis. Thus, other cell types such as ILCs or T cells have to be considered as primary source of Th2-driving IL-4. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Comparison of dynamic expressions of Tim-3 and PD-1 in the brains between toxoplasmic encephalitis-resistant BALB/c and -susceptible C57BL/6 mice.

    Science.gov (United States)

    Wu, Bin; Fu, Xiaoyin; Huang, Bo; Tong, Xinxin; Zheng, Huanqin; Huang, Shiguang; Lu, Fangli

    2014-04-01

    T cells and IFN-γ are essential for controlling the reactivation of toxoplasmic encephalitis (TE), regardless of whether mice are susceptible or resistant to TE. It has been demonstrated that CD8(+) T cells exhausted in chronic Toxoplasma gondii infection result in TE reactivation in C57BL/6 mice. However, this phenomenon had not been reported in genetically TE-resistant BALB/c mice. To explore the immune mechanism of TE in different backgrounds of mice, the dynamic expressions of Tim-3, programmed cell death 1 (PD-1), and their ligands (galectin-9, PD-L1, PD-L2) in brain tissues were compared between TE-resistant BALB/c and -susceptible C57BL/6 mice infected with Prugniaud (Pru, a type II strain) of T. gondii in this study. Compared with infected BALB/c mice, there were remarkable pathological changes with significantly higher histological scores in the brains of C57BL/6 mice at 14, 35, 50, and 70 days postinfection (p.i., P L1 in the brain of C57BL/6 mice than that in BALB/c mice at all the times p.i. (P L1 expressions may contribute to the different immune responses between TE-resistant BALB/c and -susceptible C57BL/6 mice infected with Pru strain of T. gondii.

  2. Human apolipoprotein E4 targeted replacement in mice reveals increased susceptibility to sleep disruption and intermittent hypoxia

    Science.gov (United States)

    Kaushal, Navita; Ramesh, Vijay

    2012-01-01

    Intermittent hypoxia (IH) and sleep fragmentation (SF) are major manifestations of sleep apnea, a frequent condition in aging humans. Sleep perturbations are frequent in Alzheimer's disease (AD) and may underlie the progression of disease. We hypothesized that acute short-term IH, SF, and their combination (IH+SF) may reveal unique susceptibility in sleep integrity in a murine model of AD. The effects of acute IH, SF, and IH+SF on sleep architecture, delta power, sleep latency, and core body temperature were assessed in adult male human ApoE4-targeted replacement mice (hApoE4) and wild-type (WT) controls. Slow wave sleep (SWS) was significantly reduced, and rapid eye movement (REM) sleep was almost abolished during acute exposure to IH alone and IH+SF for 6 h in hApoE4, with milder effects in WT controls. Decreased delta power during SWS did not show postexposure rebound in hApoE4 unlike WT controls. IH and IH+SF induced hypothermia, which was more prominent in hApoE4 than WT controls. Mice subjected to SF also showed sleep deficits but without hypothermia. hApoE4 mice, unlike WT controls, exhibited increased sleep propensity, especially following IH and IH+SF, suggesting limited ability for sleep recovery in hApoE4 mice. These findings substantiate the potential impact of IH and SF in modulating sleep architecture and sleep homeostasis including maintenance of body temperature. Furthermore, the increased susceptibility and limited recovery ability of hApoE4 mice to sleep apnea suggests that early recognition and treatment of the latter in AD patients may restrict the progression and clinical manifestations of this frequent neurodegenerative disorder. PMID:22573105

  3. Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality.

    Science.gov (United States)

    Marchlik, Erica; Thakker, Paresh; Carlson, Thaddeus; Jiang, Zhaozhao; Ryan, Mark; Marusic, Suzana; Goutagny, Nadege; Kuang, Wen; Askew, G Roger; Roberts, Victoria; Benoit, Stephen; Zhou, Tianhui; Ling, Vincent; Pfeifer, Richard; Stedman, Nancy; Fitzgerald, Katherine A; Lin, Lih-Ling; Hall, J Perry

    2010-12-01

    TBK1 is critical for immunity against microbial pathogens that activate TLR4- and TLR3-dependent signaling pathways. To address the role of TBK1 in inflammation, mice were generated that harbor two copies of a mutant Tbk1 allele. This Tbk1(Δ) allele encodes a truncated Tbk1(Δ) protein that is catalytically inactive and expressed at very low levels. Upon LPS stimulation, macrophages from Tbk1(Δ/Δ) mice produce normal levels of proinflammatory cytokines (e.g., TNF-α), but IFN-β and RANTES expression and IRF3 DNA-binding activity are ablated. Three-month-old Tbk1(Δ/Δ) mice exhibit mononuclear and granulomatous cell infiltrates in multiple organs and inflammatory cell infiltrates in their skin, and they harbor a 2-fold greater amount of circulating monocytes than their Tbk1(+/+) and Tbk1(+/Δ) littermates. Skin from 2-week-old Tbk1(Δ/Δ) mice is characterized by reactive changes, including hyperkeratosis, hyperplasia, necrosis, inflammatory cell infiltrates, and edema. In response to LPS challenge, 3-month-old Tbk1(Δ/Δ) mice die more quickly and in greater numbers than their Tbk1(+/+) and Tbk1(+/Δ) counterparts. This lethality is accompanied by an overproduction of several proinflammatory cytokines in the serum of Tbk1(Δ/Δ) mice, including TNF-α, GM-CSF, IL-6, and KC. This overproduction of serum cytokines in Tbk1(Δ/Δ) mice following LPS challenge and their increased susceptibility to LPS-induced lethality may result from the reactions of their larger circulating monocyte compartment and their greater numbers of extravasated immune cells.

  4. Increased susceptibility to diet-induced obesity in histamine-deficient mice

    DEFF Research Database (Denmark)

    Jørgensen, Emilie A; Vogelsang, Thomas W; Knigge, Ulrich

    2006-01-01

    BACKGROUND AND AIM: The neurotransmitter histamine is involved in the regulation of appetite and in the development of age-related obesity in mice. Furthermore, histamine is a mediator of the anorexigenic action of leptin. The aim of the present study was to investigate a possible role of histamine...... in the development of high-fat diet (HFD)-induced obesity. METHODS: Histamine-deficient histidine decarboxylase knock-out (HDC-KO) mice and C57BL/6J wild-type (WT) mice were given either a standard diet (STD) or HFD for 8 weeks. Body weight, 24-hour caloric intake, epididymal adipose tissue size, plasma leptin......-KO mice compared to STD-fed HDC-KO mice was observed, while no such difference was observed in WT mice. CONCLUSION: Based on our results, we conclude that histamine plays a role in the development of HFD-induced obesity....

  5. Susceptibility to obesity and gallbladder stasis produced by a protein- and fat-enriched diet in male mice compared with female mice

    Directory of Open Access Journals (Sweden)

    Takiguchi Soichi

    2007-06-01

    Full Text Available Abstract Background The frequency of Japanese subjects over 20 years old with metabolic syndrome is 45.6% in men but just 16.7% in women. The reason why Japanese male subjects are more susceptible to metabolic syndrome than women is unknown. One possibility is the higher frequency of Japanese male subjects (40–70 years old who had a drinking habit (67%, while that of female subjects was only 25%. In addition, daily fat intake was markedly increased in Japanese subjects (from 9% to 25%, and cholesterol cholelithiasis is one of the most rapidly increasing digestive diseases during the past 50 years. The object of this study is to examine whether a potential sex-related risk factor exists in the manifestation of metabolic syndrome as well as gallstone formation. Methods Gallbladder dysmotility accerelates gallstone formation and gallbladder contraction depends on cholecystokinin (CCK and its receptor (CCK-1R. We developed CCK-1R gene knockout (-/- mice. The effects of the fat- and protein- enriched diet OA-2 on body weight, hyperlipidemia, and frequencies of sludge and gallstone formation were examined, and compared between wild-type and CCK-1R(-/- male and female mice. The OA-2 diet contains slightly higher protein and fat (7.9 % fat and 27.6 % protein compared with a standard diet (CRF-1 (5.6 % fat and 22.6 % protein, but their total energies are similar. After weaning, CRF-1 was provided until 3 months of age in all animals. Administration of an OA-2 diet was started when age-matched CCK-1R(-/- and wild-type male and female mice reached maturity, at 3 months of age. Administration of CRF-1 was continued in the rest of the animals. Mice were sacrificed by guillotine at 6 and 12 months of age and the blood was collected to measure plasma levels of triglyceride and cholesterol. The gallbladder was removed and classified as normal (clear gallbladder, clouded (sludge formation, and/or containing gallstone formations. Results As long as CRF-1 was

  6. Managing the risk of circulating vaccine-derived poliovirus during the endgame: oral poliovirus vaccine needs.

    Science.gov (United States)

    Duintjer Tebbens, Radboud J; Thompson, Kimberly M

    2015-09-24

    The Global Polio Eradication Initiative plans for coordinated cessation of oral poliovirus vaccine (OPV) use, beginning with serotype 2-containing OPV (i.e., OPV2 cessation) followed by the remaining two OPV serotypes (i.e., OPV13 cessation). The risk of circulating vaccine-derived poliovirus (cVDPV) outbreaks after OPV cessation of any serotype depends on the serotype-specific population immunity to transmission prior to its cessation. Based on an existing integrated global model of poliovirus risk management policies, we estimate the serotype-specific OPV doses required to manage population immunity for a strategy of intensive supplemental immunization activities (SIAs) shortly before OPV cessation of each serotype. The strategy seeks to prevent any cVDPV outbreaks after OPV cessation, although actual events remain stochastic. Managing the risks of OPV cessation of any serotype depends on achieving sufficient population immunity to transmission to transmission at OPV cessation. This will require that countries with sub-optimal routine immunization coverage and/or conditions that favor poliovirus transmission conduct SIAs with homotypic OPV shortly before its planned coordinated cessation. The model suggests the need to increase trivalent OPV use in SIAs by approximately 40 % or more during the year before OPV2 cessation and to continue bOPV SIAs between the time of OPV2 cessation and OPV13 cessation. Managing the risks of cVDPVs in the polio endgame will require serotype-specific OPV SIAs in some areas prior to OPV cessation and lead to demands for additional doses of the vaccine in the short term that will affect managers and manufacturers.

  7. The role of Abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans.

    KAUST Repository

    Zheng, Ming

    2015-02-03

    We know very little about the genetic factors affecting susceptibility to drug-induced central nervous system (CNS) toxicities, and this has limited our ability to optimally utilize existing drugs or to develop new drugs for CNS disorders. For example, haloperidol is a potent dopamine antagonist that is used to treat psychotic disorders, but 50% of treated patients develop characteristic extrapyramidal symptoms caused by haloperidol-induced toxicity (HIT), which limits its clinical utility. We do not have any information about the genetic factors affecting this drug-induced toxicity. HIT in humans is directly mirrored in a murine genetic model, where inbred mouse strains are differentially susceptible to HIT. Therefore, we genetically analyzed this murine model and performed a translational human genetic association study.A whole genome SNP database and computational genetic mapping were used to analyze the murine genetic model of HIT. Guided by the mouse genetic analysis, we demonstrate that genetic variation within an ABC-drug efflux transporter (Abcb5) affected susceptibility to HIT. In situ hybridization results reveal that Abcb5 is expressed in brain capillaries, and by cerebellar Purkinje cells. We also analyzed chromosome substitution strains, imaged haloperidol abundance in brain tissue sections and directly measured haloperidol (and its metabolite) levels in brain, and characterized Abcb5 knockout mice. Our results demonstrate that Abcb5 is part of the blood-brain barrier; it affects susceptibility to HIT by altering the brain concentration of haloperidol. Moreover, a genetic association study in a haloperidol-treated human cohort indicates that human ABCB5 alleles had a time-dependent effect on susceptibility to individual and combined measures of HIT. Abcb5 alleles are pharmacogenetic factors that affect susceptibility to HIT, but it is likely that additional pharmacogenetic susceptibility factors will be discovered.ABCB5 alleles alter susceptibility to

  8. The role of Abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans.

    Directory of Open Access Journals (Sweden)

    Ming Zheng

    2015-02-01

    Full Text Available We know very little about the genetic factors affecting susceptibility to drug-induced central nervous system (CNS toxicities, and this has limited our ability to optimally utilize existing drugs or to develop new drugs for CNS disorders. For example, haloperidol is a potent dopamine antagonist that is used to treat psychotic disorders, but 50% of treated patients develop characteristic extrapyramidal symptoms caused by haloperidol-induced toxicity (HIT, which limits its clinical utility. We do not have any information about the genetic factors affecting this drug-induced toxicity. HIT in humans is directly mirrored in a murine genetic model, where inbred mouse strains are differentially susceptible to HIT. Therefore, we genetically analyzed this murine model and performed a translational human genetic association study.A whole genome SNP database and computational genetic mapping were used to analyze the murine genetic model of HIT. Guided by the mouse genetic analysis, we demonstrate that genetic variation within an ABC-drug efflux transporter (Abcb5 affected susceptibility to HIT. In situ hybridization results reveal that Abcb5 is expressed in brain capillaries, and by cerebellar Purkinje cells. We also analyzed chromosome substitution strains, imaged haloperidol abundance in brain tissue sections and directly measured haloperidol (and its metabolite levels in brain, and characterized Abcb5 knockout mice. Our results demonstrate that Abcb5 is part of the blood-brain barrier; it affects susceptibility to HIT by altering the brain concentration of haloperidol. Moreover, a genetic association study in a haloperidol-treated human cohort indicates that human ABCB5 alleles had a time-dependent effect on susceptibility to individual and combined measures of HIT. Abcb5 alleles are pharmacogenetic factors that affect susceptibility to HIT, but it is likely that additional pharmacogenetic susceptibility factors will be discovered.ABCB5 alleles alter

  9. Production of high titer attenuated poliovirus strains on the serum-free PER.C6(®) cell culture platform for the generation of safe and affordable next generation IPV.

    Science.gov (United States)

    Sanders, Barbara P; Oakes, Isabel de los Rios; van Hoek, Vladimir; Liu, Ying; Marissen, Wilfred; Minor, Philip D; Wimmer, Eckard; Schuitemaker, Hanneke; Custers, Jerome H H V; Macadam, Andrew; Cello, Jeronimo; Edo-Matas, Diana

    2015-11-27

    As poliovirus eradication draws closer, alternative Inactivated Poliovirus Vaccines (IPV) are needed to overcome the risks associated with continued use of the Oral Poliovirus Vaccine and of neurovirulent strains used during manufacture of conventional (c) IPV. We have previously demonstrated the susceptibility of the PER.C6(®) cell line to cIPV strains; here we investigated the suspension cell culture platform for growth of attenuated poliovirus strains. We examined attenuated Sabin strain productivity on the PER.C6(®) cell platform compared to the conventional Vero cell platform. The suitability of the suspension cell platform for propagation of rationally-attenuated poliovirus strains (stabilized Sabin type 3 S19 derivatives and genetically attenuated and stabilized MonoCre(X) strains), was also assessed. Yields were quantified by infectious titer determination and D-antigen ELISA using either serotype-specific polyclonal rabbit sera for Sabin strains or monoclonal cIPV-strain-specific antibodies for cIPV, S19 and MonoCre(X) strains. PER.C6(®) cells supported the replication of Sabin strains to yields of infectious titers that were in the range of cIPV strains at 32.5°C. Sabin strains achieved 30-fold higher yields (pIPV vaccines needed for achieving and maintaining poliovirus eradication. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Poliovirus protease 3C(pro) kills cells by apoptosis.

    Science.gov (United States)

    Barco, A; Feduchi, E; Carrasco, L

    2000-01-20

    The tetracycline-based Tet-Off expression system has been used to analyze the effects of poliovirus protease 3C(pro) on human cells. Stable HeLa cell clones that express this poliovirus protease under the control of an inducible, tightly regulated promoter were obtained. Tetracycline removal induces synthesis of 3C protease, followed by drastic morphological alterations and cellular death. Degradation of cellular DNA in nucleosomes and generation of apoptotic bodies are observed from the second day after 3C(pro) induction. The cleavage of poly(ADP-ribose) polymerase, an enzyme involved in DNA repair, occurs after induction of 3C(pro), indicating caspase activation by this poliovirus protease. The 3C(pro)-induced apoptosis is blocked by the caspase inhibitor z-VAD-fmk. Our findings suggest that the protease 3C is responsible for triggering apoptosis in poliovirus-infected cells by a mechanism that involves caspase activation. Copyright 2000 Academic Press.

  11. Working Memory Deficits, Increased Anxiety-Like Traits, and Seizure Susceptibility in BDNF Overexpressing Mice

    Science.gov (United States)

    Papaleo, Francesco; Silverman, Jill L.; Aney, Jordan; Tian, Qingjun; Barkan, Charlotte L.; Chadman, Kathryn K.; Crawley, Jacqueline N.

    2011-01-01

    BDNF regulates components of cognitive processes and has been implicated in psychiatric disorders. Here we report that genetic overexpression of the BDNF mature isoform (BDNF-tg) in female mice impaired working memory functions while sparing components of fear conditioning. BDNF-tg mice also displayed reduced breeding efficiency, higher…

  12. Increased susceptibility to Yersinia enterocolitica Infection of Tff2 deficient mice.

    Science.gov (United States)

    Shah, Aftab A; Mihalj, Martina; Ratkay, Ivana; Lubka-Pathak, Maria; Balogh, Peter; Klingel, Karin; Bohn, Erwin; Blin, Nikolaus; Baus-Loncar, Mirela

    2012-01-01

    TFF2 is one of the members of the trefoil factor family, known for its role in protection of gastrointestinal epithelia upon injury; however, recent studies suggest that TFF2 could also play an important role in the immune system. In the present study Tff2 deficient and wild type mice were infected by Y. enterocolitica which resulted in a lethal outcome in all Tff2 deficient mice, but not in WT animals. Yersinia invaded Peyer's patches more efficiently as shown by high bacterial titers in the KO mice while wild type mice displayed lower titers and a visible bacterial accumulation in the intestine. Bacterial accumulation in Peyer's patches of Tff2 deficient mice was accompanied by increased recruitment of macrophages. While an increased level of MAC-1 positive cells was observed in the spleens of both Tff2 deficient and WT mice at third day post infection, bacterial dissemination to liver, lung and kidneys was observed only in Tff2 knock-out mice. Analysis of the cellular composition of spleen did not reveal any substantial alteration to WT animals, suggesting possible disregulation of hemopoietic cells involved in immune response to Y. enterocolitica. These new data indicate that Tff2 plays an important role in immune response by protecting the organism from consequences of infection and that Tff2 knock-out mice react adversely to bacterial infections, in this case specifically to Y. enterocolitica. Copyright © 2012 S. Karger AG, Basel.

  13. DBA2J db/db mice are susceptible to early albuminuria and glomerulosclerosis that correlate with systemic insulin resistance.

    Science.gov (United States)

    Østergaard, Mette V; Pinto, Vanda; Stevenson, Kirsty; Worm, Jesper; Fink, Lisbeth N; Coward, Richard J M

    2017-02-01

    Diabetic nephropathy (DN) is the leading cause of kidney failure in the world. To understand important mechanisms underlying this condition, and to develop new therapies, good animal models are required. In mouse models of type 1 diabetes, the DBA/2J strain has been shown to be more susceptible to develop kidney disease than other common strains. We hypothesized this would also be the case in type 2 diabetes. We studied db/db and wild-type (wt) DBA/2J mice and compared these with the db/db BLKS/J mouse, which is currently the most widely used type 2 DN model. Mice were analyzed from age 6 to 12 wk for systemic insulin resistance, albuminuria, and glomerular histopathological and ultrastructural changes. Body weight and nonfasted blood glucose were increased by 8 wk in both genders, while systemic insulin resistance commenced by 6 wk in female and 8 wk in male db/db DBA/2J mice. The urinary albumin-to-creatinine ratio (ACR) was closely linked to systemic insulin resistance in both sexes and was increased ~50-fold by 12 wk of age in the db/db DBA/2J cohort. Glomerulosclerosis, foot process effacement, and glomerular basement membrane thickening were observed at 12 wk of age in db/db DBA/2J mice. Compared with db/db BLKS/J mice, db/db DBA/2J mice had significantly increased levels of urinary ACR, but similar glomerular histopathological and ultrastructural changes. The db/db DBA/2J mouse is a robust model of early-stage albuminuric DN, and its levels of albuminuria correlate closely with systemic insulin resistance. This mouse model will be helpful in defining early mechanisms of DN and ultimately the development of novel therapies. Copyright © 2017 the American Physiological Society.

  14. Differential susceptibility of BALB/c, C57BL/6N, and CF1 mice to photoperiod changes

    Directory of Open Access Journals (Sweden)

    Luísa K. Pilz

    2015-09-01

    Full Text Available Objective:Circadian disturbances common to modern lifestyles have been associated with mood disorders. Animal models that mimic such rhythm disturbances are useful in translational research to explore factors contributing to depressive disorders. This study aimed to verify the susceptibility of BALB/c, C57BL/6N, and CF1 mice to photoperiod changes.Methods:Thermochron iButtons implanted in the mouse abdomen were used to characterize temperature rhythms. Mice were maintained under a 12:12 h light-dark (LD cycle for 15 days, followed by a 10:10 h LD cycle for 10 days. Cosinor analysis, Rayleigh z test, periodograms, and Fourier analysis were used to analyze rhythm parameters. Paired Student's t test was used to compare temperature amplitude, period, and power of the first harmonic between normal and shortened cycles.Results:The shortened LD cycle significantly changed temperature acrophases and rhythm amplitude in all mouse strains, but only BALB/c showed altered period.Conclusion:These findings suggest that BALB/c, the preferred strain for stress-induced models of depression, should also be favored for exploring the relationship between circadian rhythms and mood. Temperature rhythm proved to be a useful parameter for characterizing rhythm disruption in mice. Although disruption of temperature rhythm has been successfully documented in untethered mice, an evaluation of desynchronization of other rhythms is warranted.

  15. Poliovirus persistence in human cells in vitro.

    Science.gov (United States)

    Colbère-Garapin, F; Jacques, S; Drillet, A S; Pavio, N; Couderc, T; Blondel, B; Pelletier, I

    2001-01-01

    Poliovirus (PV) can persist in vivo in the intestine of immunocompromised hosts for years. Moreover, immunocompetent individuals who have survived paralytic poliomyelitis sometimes develop the post-poliomyelitis syndrome (PPS), consisting of a variety of symptoms including new muscular atrophies. PPS may be due to PV persistence. We have developed models of PV persistence in neural cells and epidermoid cells. Cell determinants are of crucial importance for the establishment of persistent infections in human neuronal cells, whereas viral determinants play the primary role in human epidermoid HEp-2 cells. The results obtained with these in vitro models show the capacity of PV to persist and reveal a virus and cell co-evolution involving PV-receptor interactions. In addition, they suggest that several mechanisms are used by PV to establish and maintain persistent infections.

  16. Poliovirus vaccination during the endgame: insights from integrated modeling.

    Science.gov (United States)

    Duintjer Tebbens, Radboud J; Thompson, Kimberly M

    2017-06-01

    Managing the polio endgame requires access to sufficient quantities of poliovirus vaccines. After oral poliovirus vaccine (OPV) cessation, outbreaks may occur that require outbreak response using monovalent OPV (mOPV) and/or inactivated poliovirus vaccine. Areas covered: We review the experience and challenges with managing vaccine supplies in the context of the polio endgame. Building on models that explored polio endgame risks and the potential mOPV needs to stop outbreaks from live poliovirus reintroductions, we conceptually explore the potential demands for finished and bulk mOPV doses from a stockpile in the context of limited shelf-life of finished vaccine and time delays to convert bulk to finished vaccine. Our analysis suggests that the required size of the mOPV stockpile varies by serotype, with the highest expected needs for serotype 1 mOPV. Based on realizations of poliovirus risks after OPV cessation, the stockpile required to eliminate the chance of a stock-out appears considerably larger than the currently planned mOPV stockpiles. Expert commentary: The total required stockpile size depends on the acceptable probability of a stock-out, and increases with longer times to finish bulk doses and shorter shelf-lives of finished doses. Successful polio endgame management will require careful attention to poliovirus vaccine supplies.

  17. Rare adverse events associated with oral poliovirus vaccine in Brazil

    Directory of Open Access Journals (Sweden)

    Friedrich F.

    1997-01-01

    Full Text Available Oral poliovirus vaccine (OPV developed by A. Sabin has been effectively used to control poliomyelitis in Brazil, and the last case with the isolation of a wild poliovirus strain occurred in March 1989. Although the vaccine controlled the circulation of wild strains and poliomyelitis cases associated with these strains were not detected during the last eight years, rare cases classified as vaccine-associated paralytic poliomyelitis (VAPP have been detected. Molecular characterization studies of poliovirus strains isolated from VAPP cases and from healthy contacts have confirmed that the isolates are derived from the Sabin vaccine strains and also detected genomic modifications known or suspected to increase neurovirulence such as mutations and recombination. The molecular characterization of polioviruses isolated during the last eight years from paralysis cases classified as Guillain-Barré (GBS syndrome and transverse myelitits (TM, and from facial paralysis (FP cases also confirmed the vaccine origin of the strains and demonstrated mutations known to increase neurovirulence. Analysis of the epidemiologic data of these GBS, TM and FP cases demonstrated that in most of them the last OPV dose was given months or years before the onset of the disease and the isolation of the polioviruses. The temporal association between the isolation of these strains and the GBS, TM and FP suggested that the Sabin vaccine-derived poliovirus strains could also rarely trigger the diseases.

  18. Interleukin 17 receptor signaling is deleterious during Toxoplasma gondii infection in susceptible BL6 mice.

    Science.gov (United States)

    Guiton, Rachel; Vasseur, Virginie; Charron, Sabine; Arias, Marbel Torres; Van Langendonck, Nathalie; Buzoni-Gatel, Dominique; Ryffel, Bernhard; Dimier-Poisson, Isabelle

    2010-08-15

    Th17 cells are involved in host defense against several pathogens. Using interleukin (IL) 17RA-deficient mice, we demonstrated reduced ileitis with diminished neutrophil recruitment and inflammatory lesions in the ileum, in the regional lymph node, in the spleen, and in the liver at day 7 and prolonged survival after Toxoplasma gondii infection. In addition, IL-17A antibody neutralization reduced inflammation and enhanced survival in BL6 mice. Diminished inflammation is associated with augmented interferon (IFN) gamma serum levels and enhanced production of IL-10 and IFN-gamma in cultured splenocytes upon antigen restimulation. Finally, cyst load and inflammation in the brain at 40 days are greater in surviving BL6 mice than in IL-17RA-deficient mice. In conclusion, oral T. gondii infection increases IL-17 expression and contributes to the inflammatory response, and IL-17 neutralization has a partial protective effect against fatal T. gondii-associated inflammation.

  19. Interleukin-6-deficient mice are highly susceptible to Listeria monocytogenes infection: correlation with inefficient neutrophilia.

    OpenAIRE

    Dalrymple, S A; Lucian, L A; Slattery, R; McNeil, T; Aud, D M; Fuchino, S; Lee, F; Murray, R

    1995-01-01

    We have produced interleukin-6 (IL-6)-deficient mice to examine, in vivo, the wide variety of biological activities attributed to this multifunctional cytokine. To investigate the role of IL-6 during infectious disease, IL-6-deficient mice were challenged with sublethal doses of Listeria monocytogenes, a facultative intracellular bacterium. While normal control animals were able to clear the infection, mutant animals exhibited a high mortality rate and showed uncontrolled replication of the b...

  20. Leishmania major-specific B cells are necessary for Th2 cell development and susceptibility to L. major LV39 in BALB/c mice.

    Science.gov (United States)

    Ronet, Catherine; Voigt, Heike; Himmelrich, Hayo; Doucey, Marie-Agnès; Hauyon-La Torre, Yazmin; Revaz-Breton, Mélanie; Tacchini-Cottier, Fabienne; Bron, Claude; Louis, Jacques; Launois, Pascal

    2008-04-01

    B lymphocytes are considered to play a minimal role in host defense against Leishmania major. In this study, the contribution of B cells to susceptibility to infection with different strains of L. major was investigated in BALB/c mice lacking mature B cells due to the disruption of the IgM transmembrane domain (microMT). Whereas BALB/c microMT remained susceptible to infection with L. major IR173 and IR75, they were partially resistant to infection with L. major LV39. Adoptive transfer of naive B cells into BALB/c microMT mice before infection restored susceptibility to infection with L. major LV39, demonstrating a role for B cells in susceptibility to infection with this parasite. In contrast, adoptive transfer of B cells that express an IgM/IgD specific for hen egg lysozyme (HEL), an irrelevant Ag, did not restore disease progression in BALB/c microMT mice infected with L. major LV39. This finding was likely due to the inability of HEL Tg B cells to internalize and present Leishmania Ags to specific T cells. Furthermore, specific Ig did not contribute to disease progression as assessed by transfer of immune serum in BALB/c microMT mice. These data suggest that direct Ag presentation by specific B cells and not Ig effector functions is involved in susceptibility of BALB/c mice to infection with L. major LV39.

  1. Susceptible cytotoxicity to ultraviolet B light in fibroblasts and keratinocytes cultured from autoimmune-prone MRL/Mp-lpr/lpr mice

    Energy Technology Data Exchange (ETDEWEB)

    Furukawa, F.; Lyon, M.B.; Norris, D.A. (Univ. of Colorado School of Medicine, Denver (USA))

    1989-09-01

    The MRL/Mp-lpr/lpr (MRL/l) mouse is an autoimmune model of spontaneous lupus erythematosus (LE), in addition to lupus nephritis. In order to better understand the mechanisms of photosensitivity in LE, in vitro photocytotoxicity was examined by using fibroblasts and keratinocytes cultured from MRL/l mice, control MRL/Mp- +/+ (MRL/n) mice, and normal BALB/c mice. A colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and the acridine orange/ethidium bromide assay were used for determination of cytotoxicity. Fibroblasts cultured from newborn MRL/l mice showed higher susceptibility to single ultraviolet light B (UVB) light irradiation at a dose of 100-500 mJ than those from MRL/n, F1 hybrid of (MRL/l x MRL/n mice), and BALB/c mice. However, the susceptibility to UVB was not observed in young (1-month-old) and adult (4-month-old) MRL/l mice. UVA light irradiation was not cytotoxic. Keratinocytes cultured from MRL mice showed lower cytotoxicity to UVB irradiation than fibroblasts cultured. However, keratinocytes from newborn MRL/l mice showed higher cytotoxicity to 50 mJ UVB irradiation than cells from MRL/n mice. Syngeneic or allogeneic sera augmented UVB-induced cytotoxicity of fibroblasts cultured. UVB irradiation of spleen cells induced no significant difference of cytotoxicity between MRL/l and MRL/n mice. Based on the results of F1 hybrid of (MRL/l x MRL/n) mice, the susceptibility seemed to be associated with autoimmune traits and to be regulated by genetical background.

  2. Impact of tumor necrosis factor receptor p55 deficiency in susceptibility of C57BL/6 mice to infection with Leishmania (Leishmania) amazonensis.

    Science.gov (United States)

    Cargnelutti, Diego Esteban; Salomón, María Cristina; Celedon, Verónica; Cuello-Carrión, Fernando Darío; Gea, Susana; Di Genaro, María Silvia; Scodeller, Eduardo Alberto

    2016-04-01

    Tumor necrosis factor (TNF) is involved in host resistance to several intracellular pathogens. Although the critical role of TNF receptor (TNFR)p55 in Leishmania (Leishmania) major infection has been demonstrated, the impact of TNFRp55 deficiency on L. (L.) amazonensis infection has not been explored. L. (L.) amazonensis-infected TNFRp55(-/-) mice failed to resolve lesions, whereas C57BL/6 wild-type mice completely healed. The susceptibility of the TNFRp55(-/-) mice was characterized by higher lesion size and histopathological damage in comparison with the wild-type mice. A marked increased of the splenic index was observed in the TNFRp55(-/-) mice after 15 weeks infection. These results show that in the absence of TNFRp55, L. (L.) amazonensis-infected knockout mice fail to resolve lesions, whereas wild-type mice completely heal. Copyright © 2014. Published by Elsevier B.V.

  3. Increased Susceptibility of Humanized NSG Mice to Panton-Valentine Leukocidin and Staphylococcus aureus Skin Infection.

    Directory of Open Access Journals (Sweden)

    Ching Wen Tseng

    Full Text Available Staphylococcus aureus is a leading cause of skin and soft-tissue infections worldwide. Mice are the most commonly used animals for modeling human staphylococcal infections. However a supra-physiologic S. aureus inoculum is required to establish gross murine skin pathology. Moreover, many staphylococcal factors, including Panton-Valentine leukocidin (PVL elaborated by community-associated methicillin-resistant S. aureus (CA-MRSA, exhibit selective human tropism and cannot be adequately studied in mice. To overcome these deficiencies, we investigated S. aureus infection in non-obese diabetic (NOD/severe combined immune deficiency (SCID/IL2rγnull (NSG mice engrafted with human CD34+ umbilical cord blood cells. These "humanized" NSG mice require one to two log lower inoculum to induce consistent skin lesions compared with control mice, and exhibit larger cutaneous lesions upon infection with PVL+ versus isogenic PVL- S. aureus. Neutrophils appear important for PVL pathology as adoptive transfer of human neutrophils alone to NSG mice was sufficient to induce dermonecrosis following challenge with PVL+ S. aureus but not PVL- S. aureus. PMX53, a human C5aR inhibitor, blocked PVL-induced cellular cytotoxicity in vitro and reduced the size difference of lesions induced by the PVL+ and PVL- S. aureus, but PMX53 also reduced recruitment of neutrophils and exacerbated the infection. Overall, our findings establish humanized mice as an important translational tool for the study of S. aureus infection and provide strong evidence that PVL is a human virulence factor.

  4. Modeling undetected live poliovirus circulation after apparent interruption of transmission : Implications for surveillance and vaccination

    NARCIS (Netherlands)

    Kalkowska, D.A.; Duintjer Tebbens, R.J.; Pallansch, M.A.; Cochi, S.L.; Wassilak, S.G.F.; Thompson, K.M.

    2015-01-01

    Background Most poliovirus infections occur with no symptoms and this leads to the possibility of silent circulation, which complicates the confirmation of global goals to permanently end poliovirus transmission. Previous simple models based on hypothetical populations assumed perfect detection of

  5. DNA methyltransferase deficiency modifies cancer susceptibility in mice lacking DNA mismatch repair.

    Science.gov (United States)

    Trinh, Binh N; Long, Tiffany I; Nickel, Andrea E; Shibata, Darryl; Laird, Peter W

    2002-05-01

    We have introduced DNA methyltransferase 1 (Dnmt1) mutations into a mouse strain deficient for the Mlh1 protein to study the interaction between DNA mismatch repair deficiency and DNA methylation. Mice harboring hypomorphic Dnmt1 mutations showed diminished RNA expression and DNA hypomethylation but developed normally and were tumor free. When crossed to Mlh1(-/-) homozygosity, they were less likely to develop the intestinal cancers that normally arise in this tumor-predisposed, mismatch repair-deficient background. However, these same mice developed invasive T- and B-cell lymphomas earlier and at a much higher frequency than their Dnmt1 wild-type littermates. Thus, the reduction of Dnmt1 activity has significant but opposing outcomes in the development of two different tumor types. DNA hypomethylation and mismatch repair deficiency interact to exacerbate lymphomagenesis, while hypomethylation protects against intestinal tumors. The increased lymphomagenesis in Dnmt1 hypomorphic, Mlh1(-/-) mice may be due to a combination of several mechanisms, including elevated mutation rates, increased expression of proviral sequences or proto-oncogenes, and/or enhanced genomic instability. We show that CpG island hypermethylation occurs in the normal intestinal mucosa, is increased in intestinal tumors in Mlh1(-/-) mice, and is reduced in the normal mucosa and tumors of Dnmt1 mutant mice, consistent with a role for Dnmt1-mediated CpG island hypermethylation in intestinal tumorigenesis.

  6. In Situ Microscopy Analysis Reveals Local Innate Immune Response Developed around Brucella Infected Cells in Resistant and Susceptible Mice

    Science.gov (United States)

    Copin, Richard; Vitry, Marie-Alice; Hanot Mambres, Delphine; Machelart, Arnaud; De Trez, Carl; Vanderwinden, Jean-Marie; Magez, Stefan; Akira, Shizuo; Ryffel, Bernhard; Carlier, Yves; Letesson, Jean-Jacques; Muraille, Eric

    2012-01-01

    Brucella are facultative intracellular bacteria that chronically infect humans and animals causing brucellosis. Brucella are able to invade and replicate in a broad range of cell lines in vitro, however the cells supporting bacterial growth in vivo are largely unknown. In order to identify these, we used a Brucella melitensis strain stably expressing mCherry fluorescent protein to determine the phenotype of infected cells in spleen and liver, two major sites of B. melitensis growth in mice. In both tissues, the majority of primary infected cells expressed the F4/80 myeloid marker. The peak of infection correlated with granuloma development. These structures were mainly composed of CD11b+ F4/80+ MHC-II+ cells expressing iNOS/NOS2 enzyme. A fraction of these cells also expressed CD11c marker and appeared similar to inflammatory dendritic cells (DCs). Analysis of genetically deficient mice revealed that differentiation of iNOS+ inflammatory DC, granuloma formation and control of bacterial growth were deeply affected by the absence of MyD88, IL-12p35 and IFN-γ molecules. During chronic phase of infection in susceptible mice, we identified a particular subset of DC expressing both CD11c and CD205, serving as a reservoir for the bacteria. Taken together, our results describe the cellular nature of immune effectors involved during Brucella infection and reveal a previously unappreciated role for DC subsets, both as effectors and reservoir cells, in the pathogenesis of brucellosis. PMID:22479178

  7. Low dose chronic Schistosoma mansoni infection increases susceptibility to Mycobacterium bovis BCG infection in mice

    DEFF Research Database (Denmark)

    Elias, D; Akuffo, H; Thors, C

    2005-01-01

    The incidence of mycobacterial diseases is high and the efficacy of Bacillus Calmette Guerin (BCG) is low in most areas of the world where chronic worm infections are common. However, if and how concurrent worm infections could affect immunity to mycobacterial infections has not been elucidated....... In this study we investigated whether infection of mice with Schistosoma mansoni could affect the ability of the animals to control Mycobacterium bovis BCG infection and the immune response to mycobacterial antigens. BALB/c mice subclinically infected with S. mansoni were challenged with M. bovis BCG via...... the intravenous route. The ability of the animals to contain the replication of M. bovis BCG in their organs, lung pathology as well as the in vitro mycobacterial and worm antigen induced immune responses were evaluated. The results showed that S. mansoni coinfected mice had significantly higher levels of BCG...

  8. Comparison of M.I.C.E. and Etest with CLSI agar dilution for antimicrobial susceptibility testing against oxacillin-resistant Staphylococcus spp.

    Science.gov (United States)

    Campana, Eloiza H; Carvalhaes, Cecilia G; Nonato, Bruna; Machado, Antonia M de O; Gales, Ana C

    2014-01-01

    The main objective of this study was to comparatively evaluate the performance of M.I.C.E. and Etest methodologies to that of agar dilution for determining the antimicrobial susceptibility profile of oxacillin-resistant Staphylococcus spp. A total of 100 oxacillin-resistant Staphylococcus spp. isolates were collected from hospitalized patients at a teaching hospital. Antimicrobial susceptibility testing for vancomycin, teicoplanin and linezolid was performed using the reference CLSI agar dilution method (2009), Etest and M.I.C.E. methodologies. The MIC values were interpreted according to CLSI susceptibility breakpoints and compared by regression analysis. In general, the essential agreement (±1-log2) between M.I.C.E. and CLSI agar dilution was 93.0%, 84.0% and 77.0% for linezolid, teicoplanin and vancomycin, respectively. Essential agreement rates between M.I.C.E. and Etest were excellent (>90.0%) for all antibiotics tested. Both strips (M.I.C.E. and Etest) yielded two very major errors for linezolid. Unacceptable minor rates were observed for teicoplanin against CoNS and for vancomycin against S. aureus. According to our results, linezolid and teicoplanin MICs against all staphylococci and S. aureus, respectively, were more accurately predicted by M.I.C.E. strips. However, the Etest showed better performance than M.I.C.E. for predicting vancomycin MICs against all staphylococci. Thus, microbiologists must be aware of the different performance of commercially available gradient strips against staphylococci.

  9. Comparison of M.I.C.E. and Etest with CLSI agar dilution for antimicrobial susceptibility testing against oxacillin-resistant Staphylococcus spp.

    Directory of Open Access Journals (Sweden)

    Eloiza H Campana

    Full Text Available OBJECTIVE: The main objective of this study was to comparatively evaluate the performance of M.I.C.E. and Etest methodologies to that of agar dilution for determining the antimicrobial susceptibility profile of oxacillin-resistant Staphylococcus spp. METHODS: A total of 100 oxacillin-resistant Staphylococcus spp. isolates were collected from hospitalized patients at a teaching hospital. Antimicrobial susceptibility testing for vancomycin, teicoplanin and linezolid was performed using the reference CLSI agar dilution method (2009, Etest and M.I.C.E. methodologies. The MIC values were interpreted according to CLSI susceptibility breakpoints and compared by regression analysis. RESULTS: In general, the essential agreement (±1-log2 between M.I.C.E. and CLSI agar dilution was 93.0%, 84.0% and 77.0% for linezolid, teicoplanin and vancomycin, respectively. Essential agreement rates between M.I.C.E. and Etest were excellent (>90.0% for all antibiotics tested. Both strips (M.I.C.E. and Etest yielded two very major errors for linezolid. Unacceptable minor rates were observed for teicoplanin against CoNS and for vancomycin against S. aureus. CONCLUSIONS: According to our results, linezolid and teicoplanin MICs against all staphylococci and S. aureus, respectively, were more accurately predicted by M.I.C.E. strips. However, the Etest showed better performance than M.I.C.E. for predicting vancomycin MICs against all staphylococci. Thus, microbiologists must be aware of the different performance of commercially available gradient strips against staphylococci.

  10. P2X7 receptor-deficient mice are susceptible to bone cancer pain

    DEFF Research Database (Denmark)

    Hansen, RR; Nielsen, CK; Nasser, A

    2011-01-01

    The purinergic P2X7 receptor is implicated in both neuropathic and inflammatory pain, and has been suggested as a possible target in pain treatment. However, the specific role of the P2X7 receptor in bone cancer pain is unknown. We demonstrated that BALB/cJ P2X7 receptor knockout (P2X7R KO) mice ...

  11. Fluorescent lighting enhances chemically induced papilloma formation and increases susceptibility to tumor challenge in mice.

    Science.gov (United States)

    Wiskemann, A; Sturm, E; Klehr, N W

    1986-01-01

    To study whether fluorescent lighting at work might increase carcinogenesis, hairless mice were exposed to a bank of six 36 W standard fluorescent lamps (neutral-white) every workday for 8 h at an illuminance level of 1,000 lx. For comparison, other mice were exposed to UVB radiation or to simulated solar radiation. In experiment A the animals were irradiated for 6 weeks prior to the application of 7,12-dimethyl-benzanthracene once and--following an interval of 2 days--for 10 weeks after DMBA application. The number of blue nevi and papillomas was enhanced by exposure to all spectra 10 weeks after chemical tumor induction. In experiment B the animals were irradiated for 6 weeks prior to the transplantation of UV-induced fibrosarcoma cells from syngeneic mice into the dorsal and ventral skin. Within the following 4 months fibrosarcoma developed in the dorsal skin exposed to the fluorescent lighting and to the UVB radiation, as well as in the non-irradiated ventral skin of 10-20% of the mice. The results suggest that fluorescent lighting as used in certain work environments may increase carcinogenesis caused by other factors.

  12. Systematic review of mucosal immunity induced by oral and inactivated poliovirus vaccines against virus shedding following oral poliovirus challenge.

    Directory of Open Access Journals (Sweden)

    Thomas R Hird

    Full Text Available Inactivated poliovirus vaccine (IPV may be used in mass vaccination campaigns during the final stages of polio eradication. It is also likely to be adopted by many countries following the coordinated global cessation of vaccination with oral poliovirus vaccine (OPV after eradication. The success of IPV in the control of poliomyelitis outbreaks will depend on the degree of nasopharyngeal and intestinal mucosal immunity induced against poliovirus infection. We performed a systematic review of studies published through May 2011 that recorded the prevalence of poliovirus shedding in stool samples or nasopharyngeal secretions collected 5-30 days after a "challenge" dose of OPV. Studies were combined in a meta-analysis of the odds of shedding among children vaccinated according to IPV, OPV, and combination schedules. We identified 31 studies of shedding in stool and four in nasopharyngeal samples that met the inclusion criteria. Individuals vaccinated with OPV were protected against infection and shedding of poliovirus in stool samples collected after challenge compared with unvaccinated individuals (summary odds ratio [OR] for shedding 0.13 (95% confidence interval [CI] 0.08-0.24. In contrast, IPV provided no protection against shedding compared with unvaccinated individuals (summary OR 0.81 [95% CI 0.59-1.11] or when given in addition to OPV, compared with individuals given OPV alone (summary OR 1.14 [95% CI 0.82-1.58]. There were insufficient studies of nasopharyngeal shedding to draw a conclusion. IPV does not induce sufficient intestinal mucosal immunity to reduce the prevalence of fecal poliovirus shedding after challenge, although there was some evidence that it can reduce the quantity of virus shed. The impact of IPV on poliovirus transmission in countries where fecal-oral spread is common is unknown but is likely to be limited compared with OPV.

  13. Erythrocytic Iron Deficiency Enhances Susceptibility to Plasmodium chabaudi Infection in Mice Carrying a Missense Mutation in Transferrin Receptor 1

    Science.gov (United States)

    Lelliott, Patrick M.; McMorran, Brendan J.; Foote, Simon J.

    2015-01-01

    The treatment of iron deficiency in areas of high malaria transmission is complicated by evidence which suggests that iron deficiency anemia protects against malaria, while iron supplementation increases malaria risk. Iron deficiency anemia results in an array of pathologies, including reduced systemic iron bioavailability and abnormal erythrocyte physiology; however, the mechanisms by which these pathologies influence malaria infection are not well defined. In the present study, the response to malaria infection was examined in a mutant mouse line, TfrcMRI24910, identified during an N-ethyl-N-nitrosourea (ENU) screen. This line carries a missense mutation in the gene for transferrin receptor 1 (TFR1). Heterozygous mice exhibited reduced erythrocyte volume and density, a phenotype consistent with dietary iron deficiency anemia. However, unlike the case in dietary deficiency, the erythrocyte half-life, mean corpuscular hemoglobin concentration, and intraerythrocytic ferritin content were unchanged. Systemic iron bioavailability was also unchanged, indicating that this mutation results in erythrocytic iron deficiency without significantly altering overall iron homeostasis. When infected with the rodent malaria parasite Plasmodium chabaudi adami, mice displayed increased parasitemia and succumbed to infection more quickly than their wild-type littermates. Transfusion of fluorescently labeled erythrocytes into malaria parasite-infected mice demonstrated an erythrocyte-autonomous enhanced survival of parasites within mutant erythrocytes. Together, these results indicate that TFR1 deficiency alters erythrocyte physiology in a way that is similar to dietary iron deficiency anemia, albeit to a lesser degree, and that this promotes intraerythrocytic parasite survival and an increased susceptibility to malaria in mice. These findings may have implications for the management of iron deficiency in the context of malaria. PMID:26303393

  14. Multimodal Fundus Imaging of Sodium Iodate-Treated Mice Informs RPE Susceptibility and Origins of Increased Fundus Autofluorescence.

    Science.gov (United States)

    Zhao, Jin; Kim, Hye Jin; Sparrow, Janet R

    2017-04-01

    By multimodal imaging, and the use of mouse and in vitro models, we have addressed changes in fundus autofluorescence (488 and 790 nm) and observed interactions between the photooxidative stress imposed by RPE bisretinoid lipofuscin and the oxidative impact of systemic sodium iodate (NaIO3). Abca4-/-, wild-type, and Rpe65rd12 mice were given systemic injections of NaIO3 (30 mg/kg). Analysis included noninvasive imaging of fundus autofluorescence (short-wavelength [SW-AF]; near-infrared excitation [NIR-AF]), quantitative fundus AF (qAF; 488 nm); light microscopy, RPE flat-mounts and measurements of outer nuclear layer (ONL) thickness. NaIO3 also was studied by using in vitro assays. In SW-AF and NIR-AF images, fundus mottling was visible 3 and 7 days after NaIO3 injection with changes being more pronounced in Abca4-/- mice that are characterized by an abundance of RPE bisretinoid lipofuscin. In Abca4-/- mice, qAF was elevated 3 and 7 days after NaIO3 administration. In light micrographs and RPE flat-mounts stained to reveal tight junctions (ZO-1) and nuclei, the RPE monolayer was disorganized, and clumping and loss of RPE was visible. ONL thinning was most pronounced in Abca4-/- mice. Treatment of ARPE-19 cells with NaIO3 together with the photooxidation of the bisretinoid A2E by exposure to 430-nm light produced an additive effect whereby loss of cell viability was greater than with either perturbation alone. Elevations in SW-AF intensity can occur due to photoreceptor cell dysfunction as induced secondarily by NaIO3. Photooxidative stress associated with RPE cell bisretinoid lipofuscin may confer increased susceptibility to the oxidant NaIO3.

  15. Susceptibility to Coccidioides species in C57BL/6 mice is associated with expression of a truncated splice variant of Dectin-1 (Clec7a).

    Science.gov (United States)

    del Pilar Jiménez-A, M; Viriyakosol, S; Walls, L; Datta, S K; Kirkland, T; Heinsbroek, S E M; Brown, G; Fierer, J

    2008-06-01

    Coccidioides posadasii spherules stimulate macrophages to make cytokines via TLR-2 and Dectin-1. We used formalin-killed spherules and 1,3-beta-glucan purified from spherules to stimulate elicited peritoneal macrophages and myeloid dendritic cells (mDCs) from susceptible (C57BL/6) and resistant (DBA/2) mouse strains. DBA/2 macrophages produced more TNF-alpha and IL-6 than macrophages from C57BL/6 mice, and the amount of TNF-alpha made was dependent on both TLR2 and Dectin-1. DCs from C57BL/6 mice made more IL-10 and less IL-23p19 and IL-12p70 than did DBA/2 DC. These responses were inhibited by a monoclonal antibody to Dectin-1. DBA/2 mice expressed full-length Dectin-1, whereas C57BL/6 mice spliced out exon 3, which encodes most of the stalk. RAW cells transduced to express the full-length Dectin-1 responded better to FKS than cells expressing truncated Dectin-1. We compared the isoform of Dectin-1 expressed by 34 C57BL/6 X DBA/2 recombinant inbred (BXD RI) lines with their susceptibility to Coccidioides immitis. In 25 of 34 RI lines susceptibility or resistance corresponded to short or full-length isoforms, respectively. These results suggest that alternative splicing of the Dectin-1 gene contributes to susceptibility of C57BL/6 mice to coccidioidomycosis, and affects the cytokine responses of macrophages and mDCs to spherules.

  16. An assessment of the reasons for oral poliovirus vaccine refusals in northern Nigeria.

    Science.gov (United States)

    Michael, Charles A; Ogbuanu, Ikechukwu U; Storms, Aaron D; Ohuabunwo, Chima J; Corkum, Melissa; Ashenafi, Samra; Achari, Panchanan; Biya, Oladayo; Nguku, Patrick; Mahoney, Frank

    2014-11-01

    Accumulation of susceptible children whose caregivers refuse to accept oral poliovirus vaccine (OPV) contributes to the spread of poliovirus in Nigeria. During and immediately following the OPV campaign in October 2012, polio eradication partners conducted a study among households in which the vaccine was refused, using semistructured questionnaires. The selected study districts had a history of persistent OPV refusals in previous campaigns. Polio risk perception was low among study participants. The majority (59%) of participants believed that vaccination was either not necessary or would not be helpful, and 30% thought it might be harmful. Religious beliefs were an important driver in the way people understood disease. Fifty-two percent of 48 respondents reported that illnesses were due to God's will and/or destiny and that only God could protect them against illnesses. Only a minority (14%) of respondents indicated that polio was a significant problem in their community. Caregivers refuse OPV largely because of poor polio risk perception and religious beliefs. Communication strategies should, therefore, aim to increase awareness of polio as a real health threat and educate communities about the safety of the vaccine. In addition, polio eradication partners should collaborate with other agencies and ministries to improve total primary healthcare packages to address identified unmet health and social needs. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  17. World Health Organization regional assessments of the risks of poliovirus outbreaks.

    Science.gov (United States)

    Lowther, Sara A; Roesel, Sigrun; O'Connor, Patrick; Landaverde, Mauricio; Oblapenko, George; Deshevoi, Sergei; Ajay, Goel; Buff, Ann; Safwat, Hala; Salla, Mbaye; Tangermann, Rudi; Khetsuriani, Nino; Martin, Rebecca; Wassilak, Steven

    2013-04-01

    While global polio eradication requires tremendous efforts in countries where wild polioviruses (WPVs) circulate, numerous outbreaks have occurred following WPV importation into previously polio-free countries. Countries that have interrupted endemic WPV transmission should continue to conduct routine risk assessments and implement mitigation activities to maintain their polio-free status as long as wild poliovirus circulates anywhere in the world. This article reviews the methods used by World Health Organization (WHO) regional offices to qualitatively assess risk of WPV outbreaks following an importation. We describe the strengths and weaknesses of various risk assessment approaches, and opportunities to harmonize approaches. These qualitative assessments broadly categorize risk as high, medium, or low using available national information related to susceptibility, the ability to rapidly detect WPV, and other population or program factors that influence transmission, which the regions characterize using polio vaccination coverage, surveillance data, and other indicators (e.g., sanitation), respectively. Data quality and adequacy represent a challenge in all regions. WHO regions differ with respect to the methods, processes, cut-off values, and weighting used, which limits comparisons of risk assessment results among regions. Ongoing evaluation of indicators within regions and further harmonization of methods between regions are needed to effectively plan risk mitigation activities in a setting of finite resources for funding and continued WPV circulation. © 2013 Society for Risk Analysis.

  18. Seroepidemiology of polioviruses among university students in northern Italy.

    Science.gov (United States)

    Baldo, Vincenzo; Baldovin, Tatjana; Cocchio, Silvia; Lazzari, Roberta; Saracino, Elena; Bertoncello, Chiara; Buja, Alessandra; Trevisan, Andrea

    2012-08-01

    The widespread use of poliovirus vaccination schemes has led to a marked decline in the incidence of paralytic poliomyelitis worldwide, but wild poliovirus is still endemic in some developing countries, and in 2009 a total of 23 countries reported at least 1 case of poliomyelitis caused by wild-strain polio viruses. A serological survey was thus conducted on the immunological status against polioviruses of 318 young adults, classified by their country of origin. Immunity to poliomyelitis was assessed by neutralizing antibody titration in tissues cultured on microplates. The rate of seronegativity (≤ 1:8) in the study population was 26.7% for poliovirus type 1, 7.2% for type 2, and 22.6% for type 3. In our sample of 318 individuals, 219 (68.9%) were Italian and 99 (31.1%) were from outside the European Union (EU). The proportion of cases found seropositive to polioviruses 1 and 3 decreased significantly with older age; this age-related decrease was more evident in the Italian group than among the non-EU subjects. Any risk of the wild virus recurring and causing paralytic poliomyelitis must be prevented, keeping Europe polio free by means of appropriate immunological protection, until polio has been conclusively eradicated all over the world. Judging from our findings, it may be worth considering administering a fifth dose of polio vaccine to adolescents.

  19. Pretreatment with Recombinant Flt3 Ligand Partially Protects against Progressive Cutaneous Leishmaniasis in Susceptible BALB/c Mice

    Science.gov (United States)

    Kremer, Inger B.; Gould, Meetha P.; Cooper, Kevin D.; Heinzel, Frederick P.

    2001-01-01

    Dendritic cells are potent antigen-presenting cells that also produce interleukin-12 (IL-12) during innate and adaptive cellular immune responses and that thereby promote the differentiation of gamma interferon (IFN-γ)-producing Th1-type CD4+ T lymphocytes. We hypothesized that expanded dendritic-cell populations in mice pretreated with the hematopoietic cytokine Flt3L would protect against cutaneous Leishmania major infection. Pretreatment of disease-susceptible BALB/c mice with 10 μg of recombinant Flt3L (rFlt3L) for 9 to 10 days before infection increased lymph node IL-12 p40 productive capacity 20-fold compared to that of saline-injected controls. Furthermore, 9 of 22 (40.9%) rFlt3L-pretreated BALB/c mice resolved their cutaneous infections, whereas none of the 22 control BALB/c mice healed. Healed, rFlt3L-pretreated mice did not develop disease following reinfection. Flt3L pretreatment also reduced parasite numbers 1,000-fold in the cutaneous lesions at 2 weeks after infection relative to numbers in lesions of untreated controls. However, Flt3L pretreatment did not significantly alter L. major-induced IFN-γ and IL-4 production in lymph node culture at 1, 2, and 4 weeks after infection. Despite the lack of Th immune deviation, Flt3L ligand-pretreated lymph nodes expressed up to 10-fold higher levels of IL-12 p40 and inducible (type 2) nitric oxide synthase mRNA at 7 days after infection. In contrast, treatment with rFlt3L after infection failed to protect against disease despite comparable expansions of dendritic cells and IL-12 p40 productive capacity in both infected and uninfected BALB/c mice treated with rFlt3L. We conclude that rFlt3L pretreatment before infection with L. major reduces parasite load and promotes healing of cutaneous lesions without stable cytokine deviation towards a dominant Th1 cytokine phenotype. PMID:11159954

  20. Positional cloning reveals strain-dependent expression of Trim16 to alter susceptibility to bleomycin-induced pulmonary fibrosis in mice.

    Directory of Open Access Journals (Sweden)

    Anguel N Stefanov

    Full Text Available Pulmonary fibrosis is a disease of significant morbidity, with no effective therapeutics and an as yet incompletely defined genetic basis. The chemotherapeutic agent bleomycin induces pulmonary fibrosis in susceptible C57BL/6J mice but not in mice of the C3H/HeJ strain, and this differential strain response has been used in prior studies to map bleomycin-induced pulmonary fibrosis susceptibility loci named Blmpf1 and Blmpf2. In this study we isolated the quantitative trait gene underlying Blmpf2 initially by histologically phenotyping the bleomycin-induced lung disease of sublines of congenic mice to reduce the linkage region to 13 genes. Of these genes, Trim16 was identified to have strain-dependent expression in the lung, which we determined was due to sequence variation in the promoter. Over-expression of Trim16 by plasmid injection increased pulmonary fibrosis, and bronchoalveolar lavage levels of both interleukin 12/23-p40 and neutrophils, in bleomycin treated B6.C3H-Blmpf2 subcongenic mice compared to subcongenic mice treated with bleomycin only, which follows the C57BL/6J versus C3H/HeJ strain difference in these traits. In summary we demonstrate that genetic variation in Trim16 leads to its strain-dependent expression, which alters susceptibility to bleomycin-induced pulmonary fibrosis in mice.

  1. The transcription factor NFATp plays a key role in susceptibility to TB in mice.

    Directory of Open Access Journals (Sweden)

    Laura E Via

    Full Text Available In T cells, the transcription factor nuclear factor of activated T cells p (NFATp is a key regulator of the cytokine genes tumor necrosis factor (TNF and interferon-γ (IFN-γ. Here, we show that NFATp-deficient (NFATp(-/- mice have a dramatic and highly significant increase in mortality after Mycobacterium tuberculosis (MTb infection as compared to mortality of control animals after MTb infection. Animals deficient in NFATp have significantly impaired levels of TNF and IFN-γ transcription and protein expression in naïve or total CD4(+ T cells, but display wild-type levels of TNF mRNA or protein from MTb-stimulated dendritic cells (DC. The rapid mortality and disease severity observed in MTb-infected NFATp(-/- mice is associated with dysregulated production of TNF and IFN-γ in the lungs, as well as with increased levels of TNF, in their serum. Furthermore, global blocking of TNF production by injection of a TNF neutralizaing agent at 6 weeks, but not 12 weeks, post-MTb-infection further decreased the survival rate of both wild-type and NFATp(-/- mice, indicating an early role for TNF derived from cells from the monocyte lineage in containment of infection. These results thus demonstrate that NFATp plays a critical role in immune containment of TB disease in vivo, through the NFATp-dependent expression of TNF and IFN-γ in T cells.

  2. Toxicogenomic analysis of susceptibility to inhaled urban particulate matter in mice with chronic lung inflammation

    Directory of Open Access Journals (Sweden)

    Yauk Carole L

    2009-03-01

    Full Text Available Abstract Background Individuals with chronic lung disease are at increased risk of adverse health effects from airborne particulate matter. Characterization of underlying pollutant-phenotype interactions may require comprehensive strategies. Here, a toxicogenomic approach was used to investigate how inflammation modifies the pulmonary response to urban particulate matter. Results Transgenic mice with constitutive pulmonary overexpression of tumour necrosis factor (TNF-α under the control of the surfactant protein C promoter and wildtype littermates (C57BL/6 background were exposed by inhalation for 4 h to particulate matter (0 or 42 mg/m3 EHC-6802 and euthanized 0 or 24 h post-exposure. The low alveolar dose of particles (16 μg did not provoke an inflammatory response in the lungs of wildtype mice, nor exacerbate the chronic inflammation in TNF animals. Real-time PCR confirmed particle-dependent increases of CYP1A1 (30–100%, endothelin-1 (20–40%, and metallothionein-II (20–40% mRNA in wildtype and TNF mice (p Conclusion Our data support the hypothesis that health effects of acute exposure to urban particles are dominated by activation of specific physiological response cascades rather than widespread changes in gene expression.

  3. Increased susceptibility of IDH2-deficient mice to dextran sodium sulfate-induced colitis

    Directory of Open Access Journals (Sweden)

    Hanvit Cha

    2017-10-01

    Full Text Available Inflammatory bowel disease (IBD is a group of chronic, relapsing, immunological, inflammatory disorders of the gastrointestinal tract including ulcerative colitis (UC and Crohn's disease (CD. It has been reported that UC, which is studied using a dextran sodium sulfate (DSS-induced colitis model, is associated with the production of reactive oxygen species (ROS and the apoptosis of intestine epithelial cells (IEC. Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2 has been reported as an essential enzyme in the mitochondrial antioxidant system via generation of NADPH. Therefore, we evaluated the role of IDH2 in DSS-induced colitis using IDH2-deficient (IDH2-/- mice. We observed that DSS-induced colitis in IDH2-/- mice was more severe than that in wild-type IDH2+/+ mice. Our results also suggest that IDH2 deficiency exacerbates PUMA-mediated apoptosis, resulting from NF-κB activation regulated by histone deacetylase (HDAC activity. In addition, DSS-induced colitis is ameliorated by an antioxidant N-acetylcysteine (NAC through attenuation of oxidative stress, resulting from deficiency of the IDH2 gene. In conclusion, deficiency of IDH2 leads to increased mitochondrial ROS levels, which inhibits HDAC activity, and the activation of NF-κB via acetylation is enhanced by attenuated HDAC activity, which causes PUMA-mediated apoptosis of IEC in DSS-induced colitis. The present study supported the rationale for targeting IDH2 as an important cancer chemoprevention strategy, particularly in the prevention of colorectal cancer.

  4. Nutrigenomics of high fat diet induced obesity in mice suggests relationships between susceptibility to fatty liver disease and the proteasome.

    Directory of Open Access Journals (Sweden)

    Helen Waller-Evans

    Full Text Available Nutritional factors play important roles in the etiology of obesity, type 2 diabetes mellitus and their complications through genotype x environment interactions. We have characterised molecular adaptation to high fat diet (HFD feeding in inbred mouse strains widely used in genetic and physiological studies. We carried out physiological tests, plasma lipid assays, obesity measures, liver histology, hepatic lipid measurements and liver genome-wide gene transcription profiling in C57BL/6J and BALB/c mice fed either a control or a high fat diet. The two strains showed marked susceptibility (C57BL/6J and relative resistance (BALB/c to HFD-induced insulin resistance and non alcoholic fatty liver disease (NAFLD. Global gene set enrichment analysis (GSEA of transcriptome data identified consistent patterns of expression of key genes (Srebf1, Stard4, Pnpla2, Ccnd1 and molecular pathways in the two strains, which may underlie homeostatic adaptations to dietary fat. Differential regulation of pathways, including the proteasome, the ubiquitin mediated proteolysis and PPAR signalling in fat fed C57BL/6J and BALB/c suggests that altered expression of underlying diet-responsive genes may be involved in contrasting nutrigenomic predisposition and resistance to insulin resistance and NAFLD in these models. Collectively, these data, which further demonstrate the impact of gene x environment interactions on gene expression regulations, contribute to improved knowledge of natural and pathogenic adaptive genomic regulations and molecular mechanisms associated with genetically determined susceptibility and resistance to metabolic diseases.

  5. Nutrigenomics of high fat diet induced obesity in mice suggests relationships between susceptibility to fatty liver disease and the proteasome.

    Science.gov (United States)

    Waller-Evans, Helen; Hue, Christophe; Fearnside, Jane; Rothwell, Alice R; Lockstone, Helen E; Caldérari, Sophie; Wilder, Steven P; Cazier, Jean-Baptiste; Scott, James; Gauguier, Dominique

    2013-01-01

    Nutritional factors play important roles in the etiology of obesity, type 2 diabetes mellitus and their complications through genotype x environment interactions. We have characterised molecular adaptation to high fat diet (HFD) feeding in inbred mouse strains widely used in genetic and physiological studies. We carried out physiological tests, plasma lipid assays, obesity measures, liver histology, hepatic lipid measurements and liver genome-wide gene transcription profiling in C57BL/6J and BALB/c mice fed either a control or a high fat diet. The two strains showed marked susceptibility (C57BL/6J) and relative resistance (BALB/c) to HFD-induced insulin resistance and non alcoholic fatty liver disease (NAFLD). Global gene set enrichment analysis (GSEA) of transcriptome data identified consistent patterns of expression of key genes (Srebf1, Stard4, Pnpla2, Ccnd1) and molecular pathways in the two strains, which may underlie homeostatic adaptations to dietary fat. Differential regulation of pathways, including the proteasome, the ubiquitin mediated proteolysis and PPAR signalling in fat fed C57BL/6J and BALB/c suggests that altered expression of underlying diet-responsive genes may be involved in contrasting nutrigenomic predisposition and resistance to insulin resistance and NAFLD in these models. Collectively, these data, which further demonstrate the impact of gene x environment interactions on gene expression regulations, contribute to improved knowledge of natural and pathogenic adaptive genomic regulations and molecular mechanisms associated with genetically determined susceptibility and resistance to metabolic diseases.

  6. Poliovirus and echovirus survival in Tetrahymena pyriformis culture in vivo.

    Science.gov (United States)

    Danes, L; Cerva, L

    1984-01-01

    Axenic cultures of Tetrahymena pyriformis, strain I MT IV, grown in a defined medium at room temperature, were used to study interactions of these protozoa with vaccination strain L Sc 2ab of poliovirus type 1, vaccination strain P 712 of poliovirus type 2 and with type 30 echovirus, strain 480/78. T. pyriformis cultures in media containing 10(3.0) TCD50/1 ml of type poliovirus, 10(3.0) TCD50/1 ml of type 2 poliovirus or 10(2.5) TCD50/1 ml echovirus 30 and in virus-free medium did not differ one from another in their growth and die-away kinetics during the 21 days of observation. Two-day T. pyriformis cultures were infected with poliovirus 1 (initial concentration 10(3.2) TCD50/1 ml), and poliovirus 2 and echovirus 30 (initial concentrations 10(3.0) TCD50/1 ml). Viruses were titrated in test tube cultures of BGM cells. The supernatant fluid, standardized sediment and samples of control virus suspension free of protozoa were titrated after 0, 2, 6, 10, 13, 18, 28 and 30 days. Most of the virus in culture was found associated with the sediment, both in the period of active growth and during the die-away phase of T. pyriformis protozoa. The virus in sediment was present at higher titres and its survival time was longer than in virus in liquid phase. Thirteen days after the first contact between T. pyriformis and virus the sediment and supernatant fluid of the old protozoan culture and the T. pyriformis-free control viral suspension were taken and used as inocula for new two-day T. pyriformis cultures.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. Increased seizure susceptibility and other toxicity symptoms following acute sulforaphane treatment in mice.

    Science.gov (United States)

    Socała, Katarzyna; Nieoczym, Dorota; Kowalczuk-Vasilev, Edyta; Wyska, Elżbieta; Wlaź, Piotr

    2017-07-01

    Activation of Nrf2 with sulforaphane has recently gained attention as a new therapeutic approach in the treatment of many diseases, including epilepsy. As a plant-derived compound, sulforaphane is considered to be safe and well-tolerated. It is widely consumed, also by patients suffering from seizure and taking antiepileptic drugs, but no toxicity profile of sulforaphane exists. Since many natural remedies and dietary supplements may increase seizure risk and potentially interact with antiepileptic drugs, the aim of our study was to investigate the acute effects of sulforaphane on seizure thresholds and activity of some first- and second-generation antiepileptic drugs in mice. In addition, some preliminary toxicity profile of sulforaphane in mice after intraperitoneal injection was evaluated. The LD50 value of sulforaphane in mice was estimated at 212.67mg/kg, while the TD50 value - at 191.58mg/kg. In seizure tests, sulforaphane at the highest dose tested (200mg/kg) significantly decreased the thresholds for the onset of the first myoclonic twitch and generalized clonic seizure in the iv PTZ test as well as the threshold for the 6Hz-induced psychomotor seizure. At doses of 10-200mg/kg, sulforaphane did not affect the threshold for the iv PTZ-induced forelimb tonus or the threshold for maximal electroshock-induced hindlimb tonus. Interestingly, sulforaphane (at 100mg/kg) potentiated the anticonvulsant efficacy of carbamazepine in the maximal electroshock seizure test. This interaction could have been pharmacokinetic in nature, as sulforaphane increased concentrations of carbamazepine in both serum and brain tissue. The toxicity study showed that high doses of sulforaphane produced marked sedation (at 150-300mg/kg), hypothermia (at 150-300mg/kg), impairment of motor coordination (at 200-300mg/kg), decrease in skeletal muscle strength (at 250-300mg/kg), and deaths (at 200-300mg/kg). Moreover, blood analysis showed leucopenia in mice injected with sulforaphane at 200mg

  8. Effect of Fidaxomicin versus Vancomycin on Susceptibility to Intestinal Colonization with Vancomycin-Resistant Enterococci and Klebsiella pneumoniae in Mice.

    Science.gov (United States)

    Deshpande, Abhishek; Hurless, Kelly; Cadnum, Jennifer L; Chesnel, Laurent; Gao, Lihong; Chan, Luisa; Kundrapu, Sirisha; Polinkovsky, Alexander; Donskey, Curtis J

    2016-07-01

    The use of oral vancomycin or metronidazole for treatment of Clostridium difficile infection (CDI) may promote colonization by health care-associated pathogens due to disruption of the intestinal microbiota. Because the macrocyclic antibiotic fidaxomicin causes less alteration of the intestinal microbiota than vancomycin, we hypothesized that it would not lead to a loss of colonization resistance to vancomycin-resistant enterococci (VRE) and extended-spectrum-β-lactamase-producing Klebsiella pneumoniae (ESBL-Kp). Mice (8 per group) received orogastric saline, vancomycin, or fidaxomicin daily for 5 days at doses resulting in stool concentrations in mice similar to those measured in humans. The mice were challenged with 10(5) CFU of orogastric VRE or ESBL-Kp on day 2 of treatment and concentrations of the pathogens in stool were monitored. The impact of drug exposure on the microbiome was measured by cultures, real-time PCR for selected anaerobic bacteria, and deep sequencing. In comparison to saline controls, oral vancomycin promoted establishment of high-density colonization by VRE and ESBL-Kp in stool (8 to 10 log10 CFU/g; P 0.5). Vancomycin treatment resulted in significant reductions in enterococci, Bacteroides spp., and Clostridium leptum, whereas the population of aerobic and facultative Gram-negative bacilli increased; deep-sequencing analysis demonstrated suppression of Firmicutes and expansion of Proteobacteria during vancomycin treatment. Fidaxomicin did not cause significant alteration of the microbiota. In summary, in contrast to vancomycin, fidaxomicin treatment caused minimal disruption of the intestinal microbiota and did not render the microbiota susceptible to VRE and ESBL-Kp colonization. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  9. Neto2-null mice have impaired GABAergic inhibition and are susceptible to seizures

    Directory of Open Access Journals (Sweden)

    Vivek eMahadevan

    2015-09-01

    Full Text Available Neto2 is a transmembrane protein that interacts with the neuron-specific K+-Cl- cotransporter (KCC2 in the CNS. Efficient KCC2 transport is essential for setting the neuronal Cl- gradient, which is required for fast GABAergic inhibition. Neto2 is required to maintain the normal abundance of KCC2 in neurons, and increases KCC2 function by binding to the active oligomeric form of this cotransporter. In the present study we characterized GABAergic inhibition and KCC2-mediated neuronal chloride homeostasis in pyramidal neurons from adult hippocampal slices. Using gramicidin perforated patch clamp recordings we found that the reversal potential for GABA (EGABA was significantly depolarized. We also observed that surface levels of KCC2 and phosphorylation of KCC2 serine 940 (Ser940 were reduced in Neto2-/- neurons compared to wild-type controls. To examine GABAergic inhibition we recorded spontaneous inhibitory postsynaptic currents (sIPSCs and found that Neto2-/- neurons had significant reductions in both their amplitude and frequency. Based on the critical role of Neto2 in regulating GABAergic inhibition we rationalized that Neto2-null mice would be prone to seizure activity. We found that Neto2-null mice demonstrated a decrease in the latency to pentylenetetrazole (PTZ-induced seizures and an increase in seizure severity.

  10. 100 years poliovirus: from discovery to eradication. A meeting report.

    Science.gov (United States)

    Skern, Tim

    2010-09-01

    Just over hundred years ago, Karl Landsteiner and Erwin Popper identified a virus, later termed poliovirus, as the causative agent of poliomyelitis. This groundbreaking discovery simultaneously provided the basis for the measures that today prevent the outbreaks of the terrible epidemics caused by poliovirus. In 1988, the WHO started its eradication program to eliminate the virus from the planet. The symposium celebrated the discovery of poliovirus and discussed our current state of knowledge of poliovirus biology. Prospects for the eradication program were evaluated, with particular emphasis being placed on why certain countries still have not succeeding in interrupting wild-type transmission of poliovirus. Discussion also centred on the role of inactivated poliovirus vaccines in the eradication program and the maintenance of a poliovirus-free world, whenever this goal should be achieved.

  11. Genetic analysis and characterization of wild poliovirus type 1 during sustained transmission in a population with >95% vaccine coverage, Israel 2013.

    Science.gov (United States)

    Shulman, Lester M; Martin, Javier; Sofer, Danit; Burns, Cara C; Manor, Yossi; Hindiyeh, Musa; Gavrilin, Eugene; Wilton, Thomas; Moran-Gilad, Jacob; Gamzo, Ronni; Mendelson, Ella; Grotto, Itamar

    2015-04-01

    Israel has >95% polio vaccine coverage with the last 9 birth cohorts immunized exclusively with inactivated polio vaccine (IPV). Using acute flaccid paralysis and routine, monthly countrywide environmental surveillance, no wild poliovirus circulation was detected between 1989 and February 2013, after which wild type 1 polioviruses South Asia genotype (WPV1-SOAS) have persistently circulated in southern Israel and intermittently in other areas without any paralytic cases as determined by intensified surveillance of environmental and human samples. We aimed to characterize antigenic and neurovirulence properties of WPV1-SOAS silently circulating in a highly vaccinated population. WPV1-SOAS capsid genes from environmental and stool surveillance isolates were sequenced, their neurovirulence was determined using transgenic mouse expressing the human poliovirus receptor (Tg21-PVR) mice, and their antigenicity was characterized by in vitro neutralization using human sera, epitope-specific monoclonal murine anti-oral poliovirus vaccine (OPV) antibodies, and sera from IPV-immunized rats and mice. WPV1 amino acid sequences in neutralizing epitopes varied from Sabin 1 and Mahoney, with little variation among WPV1 isolates. Neutralization by monoclonal antibodies against 3 of 4 OPV epitopes was lost. Three-fold lower geometric mean titers (Z = -4.018; P SOAS isolates were neurovirulent (50% intramuscular paralytic dose in Tg21-PVR mice: log10(7.0)). IPV-immunized mice were protected against WPV1-induced paralysis. Phenotypic and antigenic profile changes of WPV1-SOAS may have contributed to the intense silent transmission, whereas the reduced neurovirulence may have contributed to the absence of paralytic cases in the background of high population immunity. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  12. Characterization of Poliovirus Neutralization Escape Mutants of Single-Domain Antibody Fragments (VHHs)

    Science.gov (United States)

    Schotte, Lise; Thys, Bert; Strauss, Mike; Filman, David J.; Rombaut, Bart

    2015-01-01

    To complete the eradication of poliovirus and to protect unvaccinated people subsequently, the development of one or more antiviral drugs will be necessary. A set of five single-domain antibody fragments (variable parts of the heavy chain of a heavy-chain antibody [VHHs]) with an in vitro neutralizing activity against poliovirus type 1 was developed previously (B. Thys, L. Schotte, S. Muyldermans, U. Wernery, G. Hassanzadeh-Ghassabeh, and B. Rombaut, Antiviral Res 87:257–264, 2010, http://dx.doi.org/10.1016/j.antiviral.2010.05.012), and their mechanisms of action have been studied (L. Schotte, M. Strauss, B. Thys, H. Halewyck, D. J. Filman, M. Bostina, J. M. Hogle, and B. Rombaut, J Virol 88:4403–4413, 2014, http://dx.doi.org/10.1128/JVI.03402-13). In this study, neutralization escape mutants were selected for each VHH. Sequencing of the P1 region of the genome showed that amino acid substitutions are found in the four viral proteins of the capsid and that they are located both in proximity to the binding sites of the VHHs and in regions further away from the canyon and hidden beneath the surface. Characterization of the mutants demonstrated that they have single-cycle replication kinetics that are similar to those of their parental strain and that they are all drug (VHH) independent. Their resistant phenotypes are stable, as they do not regain full susceptibility to the VHH after passage over HeLa cells in the absence of VHH. They are all at least as stable as the parental strain against heat inactivation at 44°C, and three of them are even significantly (P < 0.05) more resistant to heat inactivation. The resistant variants all still can be neutralized by at least two other VHHs and retain full susceptibility to pirodavir and 35-1F4. PMID:26014941

  13. Biochemical association between essential trace elements and susceptibility to Leishmania major in BALB/c and C57BL/6 mice

    Directory of Open Access Journals (Sweden)

    Marzyeh Amini

    Full Text Available Several enzymes that contribute to immune system responses require zinc and copper as trace elements for their activity. We examined zinc and copper levels in two susceptible Balb/c mouse lines and resistant C57bl/6 mice infected with Leishmania major MRHO/IR/75/ER, a prevalent strain that causes cutaneous leishmaniasis in Iran. Serum Zn and Cu were determined by flame atomic absorption spectrophotometry. Higher Cu levels were found in infected C57bl/6 mice and higher Zn levels were found in infected Balb/c mice. Also, Cu/Zn ratios were increased in both the Balb/c and the C57bl/6 mice. We conclude that concentrations of essential trace elements vary during cutaneous leishmaniasis infection and that this variation is associated with susceptibility/resistance to Leishmania major in Balb/c and C57bl/6 mice. We detected Zn deficiency in the plasma of infected Balb/c mice; possibly, therapeutic administration of Zn would be useful for treating this form of leishmaniasis. Increases in Cu level might increase resistance to leishmaniasis. Based on our findings, the Cu/Zn ratio could be a useful marker for the pathophysiology of leishmaniasis.

  14. Health facility-based survey of poliovirus antibody prevalence ...

    African Journals Online (AJOL)

    Background: High level of Poliovirus protective antibodies, must at all times be sustained in a community if poliomyelitis eradication is to be achieved. For some time now children have been vaccinated against poliomyelitis through various means in Northern Nigeria without authorities taking steps to evaluate the ...

  15. original article evaluation of immunity against poliovirus serotypes ...

    African Journals Online (AJOL)

    Dr Oboro VO

    polioviruses to block the infection. This study was therefore conducted to determine the proportion of infants with protective levels of serum neutralizing antibodies after at least two doses of OPV among children within the age at greatest risk of poliomyelitis in the riverine areas. (known as hard-to-reach areas because of the.

  16. Circulating Vaccine Derived Poliovirus and the polio eradication ...

    African Journals Online (AJOL)

    No Abstract. Key words: Polio, polio eradication, vaccine derived poliovirus, Oral polio vaccine, inactivated polio vaccine, surveillance. Full Text: EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT. Article Metrics. Metrics Loading ... Metrics powered by PLOS ALM.

  17. Development of novel inactivated poliovirus vaccines: Breaking away from convention

    NARCIS (Netherlands)

    Sanders, B.P.

    2015-01-01

    Infection with poliovirus (a small, non-enveloped Picornavirus) can result in poliomyelitis, hallmarked by symptoms of paralysis which is caused by viral destruction of motor neurons. Circulating humoral neutralizing antibodies can effectively protect against the disease, an immune response which

  18. Increment of late sodium currents in the left atrial myocytes and its potential contribution to increased susceptibility of atrial fibrillation in castrated male mice.

    Science.gov (United States)

    Zhang, Yang; Wang, Hui-Min; Wang, Ying-Zhe; Zhang, Yi-Yuan; Jin, Xue-Xin; Zhao, Yue; Wang, Jin; Sun, Yi-Lin; Xue, Gen-Long; Li, Peng-Hui; Huang, Qi-He; Yang, Bao-Feng; Pan, Zhen-Wei

    2017-07-01

    The incidence of atrial fibrillation (AF) is correlated with decreased levels of testosterone in elderly men. Late sodium current may exert a role in AF pathogenesis. The purpose of this study was to explore the effect of testosterone deficiency on AF susceptibility and the therapeutic effect of late sodium current inhibitors in mice. Male ICR mice (5 weeks old) were castrated to establish a testosterone deficiency model. One month after castration, dihydrotestosterone 5 mg/kg was administered subcutaneously for 2 months. Serum total testosterone level was assessed by enzyme-linked immunosorbent assay. High-frequency electrical stimulation was used to induce atrial arrhythmias. Whole-cell patch-clamp technique was used to for single-cell electrophysiologic study. Serum dihydrotestosterone levels of castration mice declined significantly but recovered with administration of exogenous dihydrotestosterone. In comparison with sham mice, the number of AF episodes significantly increased by 13.5-fold, AF rate increased by 3.75-fold, and AF duration prolonged in castrated mice. Dihydrotestosterone administration alleviated the occurrence of AF. Action potential duration at both 50% and 90% repolarization were markedly increased in castrated mice compared to sham controls. The late sodium current was enhanced in castrated male mice. These alterations were alleviated by treatment with dihydrotestosterone. Systemic application of the INa-L inhibitors ranolazine, eleclazine, and GS967 inhibited the occurrence of AF in castrated mice. Testosterone deficiency contributed to the increased late sodium current, prolonged action potential repolarization, and increased susceptibility to AF. Blocking of late sodium current is beneficial against the occurrence of AF in castrated mice. Copyright © 2017. Published by Elsevier Inc.

  19. Mutation at the Evi1 locus in Junbo mice causes susceptibility to otitis media.

    Directory of Open Access Journals (Sweden)

    Nicholas Parkinson

    2006-10-01

    Full Text Available Otitis media (OM, inflammation of the middle ear, remains the most common cause of hearing impairment in children. It is also the most common cause of surgery in children in the developed world. There is evidence from studies of the human population and mouse models that there is a significant genetic component predisposing to OM, yet nothing is known about the underlying genetic pathways involved in humans. We identified an N-ethyl-N-nitrosourea-induced dominant mouse mutant Junbo with hearing loss due to chronic suppurative OM and otorrhea. This develops from acute OM that arises spontaneously in the postnatal period, with the age of onset and early severity dependent on the microbiological status of the mice and their air quality. We have identified the causal mutation, a missense change in the C-terminal zinc finger region of the transcription factor Evi1. This protein is expressed in middle ear basal epithelial cells, fibroblasts, and neutrophil leukocytes at postnatal day 13 and 21 when inflammatory changes are underway. The identification and characterization of the Junbo mutant elaborates a novel role for Evi1 in mammalian disease and implicates a new pathway in genetic predisposition to OM.

  20. Normal radial migration and lamination are maintained in dyslexia-susceptibility candidate gene homolog Kiaa0319 knockout mice.

    Science.gov (United States)

    Martinez-Garay, Isabel; Guidi, Luiz G; Holloway, Zoe G; Bailey, Melissa A G; Lyngholm, Daniel; Schneider, Tomasz; Donnison, Timothy; Butt, Simon J B; Monaco, Anthony P; Molnár, Zoltán; Velayos-Baeza, Antonio

    2017-04-01

    Developmental dyslexia is a common disorder with a strong genetic component, but the underlying molecular mechanisms are still unknown. Several candidate dyslexia-susceptibility genes, including KIAA0319, DYX1C1, and DCDC2, have been identified in humans. RNA interference experiments targeting these genes in rat embryos have shown impairments in neuronal migration, suggesting that defects in radial cortical migration could be involved in the disease mechanism of dyslexia. Here we present the first characterisation of a Kiaa0319 knockout mouse line. Animals lacking KIAA0319 protein do not show anatomical abnormalities in any of the layered structures of the brain. Neurogenesis and radial migration of cortical projection neurons are not altered, and the intrinsic electrophysiological properties of Kiaa0319-deficient neurons do not differ from those of wild-type neurons. Kiaa0319 overexpression in cortex delays radial migration, but does not affect final neuronal position. However, knockout animals show subtle differences suggesting possible alterations in anxiety-related behaviour and in sensorimotor gating. Our results do not reveal a migration disorder in the mouse model, adding to the body of evidence available for Dcdc2 and Dyx1c1 that, unlike in the rat in utero knockdown models, the dyslexia-susceptibility candidate mouse homolog genes do not play an evident role in neuronal migration. However, KIAA0319 protein expression seems to be restricted to the brain, not only in early developmental stages but also in adult mice, indicative of a role of this protein in brain function. The constitutive and conditional knockout lines reported here will be useful tools for further functional analyses of Kiaa0319.

  1. Susceptibility quantitative trait loci for pathogenic leucocytosis in SCG/Kj mice, a spontaneously occurring crescentic glomerulonephritis and vasculitis model

    Science.gov (United States)

    Hamano, Y; Abe, M; Matsuoka, S; Zhang, D; Kondo, Y; Kagami, Y; Ishigami, A; Maruyama, N; Tsuruta, Y; Yumura, W; Suzuki, K

    2014-01-01

    The spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mouse, a model of human crescentic glomerulonephritis (CrGN) and systemic vasculitis, is characterized by the production of myeloperoxidase-specific anti-neutrophil cytoplasmic autoantibody (MPO-ANCA) and marked leucocytosis. This study was performed to identify the specific populations of leucocytes associated with CrGN and susceptibility loci for pathogenic leucocytosis. Four hundred and twenty female (C57BL/6 × SCG/Kj) F2 intercross mice were subjected to serial flow cytometry examination of the peripheral blood (PB). Kidney granulocytes and monocytes were examined histopathologically. Linkage analyses were performed with 109 polymorphic microsatellite markers. Correlation studies revealed that increase of the granulocytes, F4/80+ cells, CD3+CD4−CD8− T cells and dendritic cells (DCs) in peripheral blood (PB) were associated significantly with glomerulonephritis, crescent formation and vasculitis. In kidney sections, F4/80low cells were observed in crescent, while F4/80high cells were around the Bowman's capsules and in the interstitium. Numbers of F4/80+ cells in crescents correlated significantly with F4/80+ cell numbers in PB, but not with numbers of F4/80+ cells in the interstitium. Genome-wide quantitative trait locus (QTL) mapping revealed three SCG/Kj-derived non-Fas QTLs for leucocytosis, two on chromosome 1 and one on chromosome 17. QTLs on chromosome 1 affected DCs, granulocytes and F4/80+ cells, but QTL on chromosome 17 affected DCs and granulocytes. We found CrGN-associated leucocytes and susceptibility QTLs with their positional candidate genes. F4/80+ cells in crescents are considered as recruited inflammatory macrophages. The results provide information for leucocytes to be targeted and genetic elements in CrGN and vasculitis. PMID:24654803

  2. Neutralization epitope patterns of poliovirus strains isolated from paralytic cases.

    Science.gov (United States)

    Crainic, R; Blondel, B; Aubert-Combiescu, A; Beytout, D; Couillin, P; Candrea, A; Boué, A; Horaud, F

    1984-01-01

    Monoclonal antibodies were used in previous work to define neutralization epitopes (NE) of poliovirus during its natural variation upon interhuman passages. Two kind of NE were found: constant (K) epitopes, present on practically all poliovirus strains of the same serotype, and variable (V) epitopes, which were strain-specific either for wild-laboratory strains (Mahoney, MEF1, and Saukett) (VW epitopes), or for attenuated Sabin strains (VS epitopes), or for attenuated Sabin strains (VS epitopes). In the present paper we analyzed the NE formulae of poliovirus strains of each of the three serotypes isolated from paralytic cases that have occurred after mass vaccination with oral poliovaccine (Sabin). Type 1 isolates from both the central nervous system and stools showed the existence of the four VW epitopes characteristic for Mahoney virus. However, in some cases, variation of the K epitope formula was noticed. As concerns the paralytic cases where type 2 poliovirus was isolated, the situation was more complex due to the existence of three different VS epitopes. Various patterns of VS epitopes were encountered, making difficult the definition of the strains origin. Most of the type 3 strains isolated from paralytic cases contained one or both VS epitopes, some of them having an identical NE formula to the Sabin type 3 vaccine virus. These data showed that the use of strain-specific neutralizing monoclonal antibodies for the characterization of strain origin is more complex than generally agreed. The multitude of NE coexisting on the same virus particle and their variation during viral replication in the human intestine call for cautious interpretation of the results obtained in poliovirus intratypic differentiation by neutralizing monoclonal antibodies.

  3. Lower susceptibility of female mice to acetaminophen hepatotoxicity: Role of mitochondrial glutathione, oxidant stress and c-jun N-terminal kinase

    Energy Technology Data Exchange (ETDEWEB)

    Du, Kuo; Williams, C. David; McGill, Mitchell R.; Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu

    2014-11-15

    Acetaminophen (APAP) overdose causes severe hepatotoxicity in animals and humans. However, the mechanisms underlying the gender differences in susceptibility to APAP overdose in mice have not been clarified. In our study, APAP (300 mg/kg) caused severe liver injury in male mice but 69–77% lower injury in females. No gender difference in metabolic activation of APAP was found. Hepatic glutathione (GSH) was rapidly depleted in both genders, while GSH recovery in female mice was 2.6 fold higher in the mitochondria at 4 h, and 2.5 and 3.3 fold higher in the total liver at 4 h and 6 h, respectively. This faster recovery of GSH, which correlated with greater induction of glutamate-cysteine ligase, attenuated mitochondrial oxidative stress in female mice, as suggested by a lower GSSG/GSH ratio at 6 h (3.8% in males vs. 1.4% in females) and minimal centrilobular nitrotyrosine staining. While c-jun N-terminal kinase (JNK) activation was similar at 2 and 4 h post-APAP, it was 3.1 fold lower at 6 h in female mice. However, female mice were still protected by the JNK inhibitor SP600125. 17β-Estradiol pretreatment moderately decreased liver injury and oxidative stress in male mice without affecting GSH recovery. Conclusion: The lower susceptibility of female mice is achieved by the improved detoxification of reactive oxygen due to accelerated recovery of mitochondrial GSH levels, which attenuates late JNK activation and liver injury. However, even the reduced injury in female mice was still dependent on JNK. While 17β-estradiol partially protects male mice, it does not affect hepatic GSH recovery. - Highlights: • Female mice are less susceptible to acetaminophen overdose than males. • GSH depletion and protein adduct formation are similar in both genders. • Recovery of hepatic GSH levels is faster in females and correlates with Gclc. • Reduced oxidant stress in females leads to reduced JNK activation. • JNK activation and mitochondrial translocation are critical

  4. Monoclonal antibodies to polioviruses; comparison of intratypic strain differentiation of poliovirus type 1 using monoclonal antibodies versus cross-absorbed antisera.

    NARCIS (Netherlands)

    A.D.M.E. Osterhaus (Albert); A.L. van Wezel; T.G. Hazendonk; F.G.C.M. Uytdehaag (Fons); J.A.A.M. van Asten (Jack); G. van Steenis (Bert)

    1983-01-01

    textabstractA panel of 10 monoclonal antibodies raised to 3 different poliovirus type 1 strains was tested in a micro-enzyme-linked immunosorbent assay and in a micro-neutralization test against 87 poliovirus type 1 strains. The results, evaluated in a newly developed system for intratypic strain

  5. Deficits in learning and memory in mice with a mutation of the candidate dyslexia susceptibility gene Dyx1c1.

    Science.gov (United States)

    Rendall, Amanda R; Tarkar, Aarti; Contreras-Mora, Hector M; LoTurco, Joseph J; Fitch, R Holly

    2017-09-01

    Dyslexia is a learning disability characterized by difficulty learning to read and write. The underlying biological and genetic etiology remains poorly understood. One candidate gene, dyslexia susceptibility 1 candidate 1 (DYX1C1), has been shown to be associated with deficits in short-term memory in dyslexic populations. The purpose of the current study was to examine the behavioral phenotype of a mouse model with a homozygous conditional (forebrain) knockout of the rodent homolog Dyx1c1. Twelve Dyx1c1 conditional homozygous knockouts, 7 Dyx1c1 conditional heterozygous knockouts and 6 wild-type controls were behaviorally assessed. Mice with the homozygous Dyx1c1 knockout showed deficits on memory and learning, but not on auditory or motor tasks. These findings affirm existing evidence that DYX1C1 may play an underlying role in the development of neural systems important to learning and memory, and disruption of this function could contribute to the learning deficits seen in individuals with dyslexia. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Influence of exposure patterns of nitrogen dioxide and modifications by ozone on susceptibility to bacterial infectious disease in mice

    Energy Technology Data Exchange (ETDEWEB)

    Graham, J.A.; Gardner, D.E.; Blommer, E.J.; House, D.E.; Menache, M.G.

    1987-01-01

    The nitrogen dioxide (NO/sub 2/) diurnal cycle found in urban communities usually consists of a low basal concentration upon which are superimposed higher-concentration peaks or spikes of short duration. Various components of the environmental-exposure mode were examined to assess effects of urban exposure profiles on susceptibility to infectious pulmonary disease. Mice were exposed to NO/sub 2/ peaks of 4.5 ppm for 1, 3.5, or 7 h, challenged with Streptococcus sp. either immediately or 18 h postexposure, and then observed for mortality. When the streptococcal challenges were immediately after NO/sub 2/ exposure, the mortality rate was directly related to the length of peak exposure, whether or not a basal exposure was used, and all peak lengths significantly increased mortality. When the challenge was delayed for 18 h after the peak exposure, spiked exposure, of 3.5 and 7 h increased mortality to the same degree. If a 1-h peak exposure to 4.5 ppm was superimposed twice daily upon a continuous basal NO/sub 2/ concentration of 1.5 ppm, there was a suggestive trend toward increased mortality near the end of the second week of exposure when challenge occurred immediately after the morning spike.

  7. Mannosyl-Recognizing Receptors Induce an M1-Like Phenotype in Macrophages of Susceptible Mice but an M2-Like Phenotype in Mice Resistant to a Fungal Infection

    Science.gov (United States)

    Feriotti, Claudia; Loures, Flávio V.; Frank de Araújo, Eliseu; da Costa, Tania Alves; Calich, Vera L. G.

    2013-01-01

    In addition to alpha1,3 glucan, mannan and mannan-linked proteins are expressed in the outer layer of Paracoccidioides brasiliensis yeasts. The recognition of mannosyl residues by multiple pathogen recognition receptors, such as the mannose receptor (MR), complement receptor 3 (CR3) and toll-like receptor 4 (TLR4) on macrophage membranes can influence macrophage activation and the mechanisms of innate immunity against fungal pathogens. The aim of this study was to clarify the role of these receptors in the interaction between P. brasiliensis and macrophages from resistant (A/J) and susceptible (B10.A) mice. Therefore, the phagocytic, fungicidal and secretory abilities of macrophages were evaluated in the presence of mannan and antibodies against MR, CR3 and TLR4. We verified that mannan increased and anti-MR antibody decreased the killing ability and nitric oxide production of macrophages. The specific blockade of MR, CR3 and TLR4 by monoclonal antibodies impaired fungal recognition and modulated the production of cytokines. Mannan or P. brasiliensis induced decreased expression of MR and TLR2 on A/J macrophages, whereas CR3, TLR4 and TLR2 were reduced on B10.A cells. Importantly, both mannan and P. brasiliensis induced the production of IL-12 by B10.A macrophages, whereas TGF-β, TNF-α and IL-6 were produced by A/J cells. In addition, B10.A macrophages exhibited a prevalent expression of inducible NO-synthase and SOCS3 (suppressor of cytokine signaling-3), indicating a pro-inflammatory, “M1-like” differentiation. In contrast, the elevated expression of arginase-1, found in inflammatory zone-1 (FIZZ1), YM1 (CHI313, chitinase-like lectin), and SOCS1, typical markers of alternatively activated macrophages, indicates a prevalent “M2-like” differentiation of A/J macrophages. In conclusion, our data reveal that several mannosyl-recognizing receptors coordinate the apparently paradoxical innate response to paracoccidioidomycosis, in which resistance is initially

  8. National choices related to inactivated poliovirus vaccine, innovation and the endgame of global polio eradication.

    Science.gov (United States)

    Thompson, Kimberly M; Duintjer Tebbens, Radboud J

    2014-02-01

    Achieving the goal of a world free of poliomyelitis still requires significant effort. Although polio immunization represents a mature area, the polio endgame will require new tools and strategies, particularly as national and global health leaders coordinate the cessation of all three serotypes of oral poliovirus vaccine and increasingly adopt inactivated poliovirus vaccine (IPV). Poliovirus epidemiology and the global options for managing polioviruses continue to evolve, along with our understanding and appreciation of the resources needed and the risks that require management. Based on insights from modeling, we offer some perspective on the current status of plans and opportunities to achieve and maintain a world free of wild polioviruses and to successfully implement oral poliovirus vaccine cessation. IPV costs and potential wastage will represent an important consideration for national policy makers. Innovations may reduce future IPV costs, but the world urgently needs lower-cost IPV options.

  9. Reduced Leukocyte Infiltration in Absence of Eosinophils Correlates with Decreased Tissue Damage and Disease Susceptibility in ΔdblGATA Mice during Murine Neurocysticercosis.

    Directory of Open Access Journals (Sweden)

    Pramod K Mishra

    2016-06-01

    Full Text Available Neurocysticercosis (NCC is one of the most common helminth parasitic diseases of the central nervous system (CNS and the leading cause of acquired epilepsy worldwide. NCC is caused by the presence of the metacestode larvae of the tapeworm Taenia solium within brain tissues. NCC patients exhibit a long asymptomatic phase followed by a phase of symptoms including increased intra-cranial pressure and seizures. While the asymptomatic phase is attributed to the immunosuppressive capabilities of viable T. solium parasites, release of antigens by dying organisms induce strong immune responses and associated symptoms. Previous studies in T. solium-infected pigs have shown that the inflammatory response consists of various leukocyte populations including eosinophils, macrophages, and T cells among others. Because the role of eosinophils within the brain has not been investigated during NCC, we examined parasite burden, disease susceptibility and the composition of the inflammatory reaction in the brains of infected wild type (WT and eosinophil-deficient mice (ΔdblGATA using a murine model of NCC in which mice were infected intracranially with Mesocestoides corti, a cestode parasite related to T. solium. In WT mice, we observed a time-dependent induction of eosinophil recruitment in infected mice, contrasting with an overall reduced leukocyte infiltration in ΔdblGATA brains. Although, ΔdblGATA mice exhibited an increased parasite burden, reduced tissue damage and less disease susceptibility was observed when compared to infected WT mice. Cellular infiltrates in infected ΔdblGATA mice were comprised of more mast cells, and αβ T cells, which correlated with an abundant CD8+ T cell response and reduced CD4+ Th1 and Th2 responses. Thus, our data suggest that enhanced inflammatory response in WT mice appears detrimental and associates with increased disease susceptibility, despite the reduced parasite burden in the CNS. Overall reduced leukocyte

  10. 2,3,7,8-tetrachlorodibenzo-p-dioxin slows the progression of experimental cutaneous Leishmaniasis in susceptible BALB/c and SCID mice.

    Science.gov (United States)

    DeKrey, Gregory K; Teagarden, Riane E; Lenberg, Jerica L; Titus, Richard G

    2013-01-01

    In a model of experimental cutaneous leishmaniasis, pre-exposure of Leishmania major-resistant mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor agonist, causes suppression of the protective anti-parasite T helper 1 response while paradoxically also reducing parasite burdens in those animals. In this study, we examined if TCDD exposure could also reduce parasite burdens in L. major-susceptible BALB/c mice. In the highest dose group (160 µg/Kg), TCDD treatment caused a significant reduction of parasite burdens by 10-fold after three weeks while also causing a significant lymphoid atrophy indicating suppression of the non-protective T helper 2 response. A dose-dependent delay of foot lesion progression was also observed such that lesion size in the highest dose group was less than half that of controls after 35 days of infection. Importantly, although TCDD exposure initially reduced disease severity and prolonged the course of disease by as much as three fold in some animals, this effect was transitory and TCDD did not induce resistance to L. major infection. Because TCDD exposure reduced L. major burdens in both resistant and susceptible mice, we hypothesized that TCDD reduces L. major burdens in mice by a mechanism that does not involve adaptive immunity. To test this, severe combined immunodeficient (SCID) mice were used. In mice infected with a moderate number of L. major (10,000), TCDD treatment caused a time- and dose-dependent decrease of parasite burdens by nearly 100-fold after six weeks in the highest dose group (200 µg/Kg). A significant and dose-dependent delay of foot lesion progression was also observed in these animals. These results indicate that TCDD exposure can reduce the severity of leishmanial disease in mice independent of adaptive immunity.

  11. 2,3,7,8-tetrachlorodibenzo-p-dioxin slows the progression of experimental cutaneous Leishmaniasis in susceptible BALB/c and SCID mice.

    Directory of Open Access Journals (Sweden)

    Gregory K DeKrey

    Full Text Available In a model of experimental cutaneous leishmaniasis, pre-exposure of Leishmania major-resistant mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, an aryl hydrocarbon receptor agonist, causes suppression of the protective anti-parasite T helper 1 response while paradoxically also reducing parasite burdens in those animals. In this study, we examined if TCDD exposure could also reduce parasite burdens in L. major-susceptible BALB/c mice. In the highest dose group (160 µg/Kg, TCDD treatment caused a significant reduction of parasite burdens by 10-fold after three weeks while also causing a significant lymphoid atrophy indicating suppression of the non-protective T helper 2 response. A dose-dependent delay of foot lesion progression was also observed such that lesion size in the highest dose group was less than half that of controls after 35 days of infection. Importantly, although TCDD exposure initially reduced disease severity and prolonged the course of disease by as much as three fold in some animals, this effect was transitory and TCDD did not induce resistance to L. major infection. Because TCDD exposure reduced L. major burdens in both resistant and susceptible mice, we hypothesized that TCDD reduces L. major burdens in mice by a mechanism that does not involve adaptive immunity. To test this, severe combined immunodeficient (SCID mice were used. In mice infected with a moderate number of L. major (10,000, TCDD treatment caused a time- and dose-dependent decrease of parasite burdens by nearly 100-fold after six weeks in the highest dose group (200 µg/Kg. A significant and dose-dependent delay of foot lesion progression was also observed in these animals. These results indicate that TCDD exposure can reduce the severity of leishmanial disease in mice independent of adaptive immunity.

  12. Candidate chromosome 1 disease susceptibility genes for Sjogren’s syndrome xerostomia are narrowed by novel NOD.B10 congenic mice

    Science.gov (United States)

    Mongini, Patricia K. A.; Kramer, Jill M.; Ishikawa, Tomo-o; Herschman, Harvey; Esposito, Donna

    2014-01-01

    Sjogren’s syndrome (SS) is characterized by salivary gland leukocytic infiltrates and impaired salivation (xerostomia). Cox-2 (Ptgs2) is located on chromosome 1 within the span of the Aec2 region. In an attempt to demonstrate that COX-2 drives antibody-dependent hyposalivation, NOD.B10 congenic mice bearing a Cox-2flox gene were generated. A congenic line with non-NOD alleles in Cox-2-flanking genes failed manifest xerostomia. Further backcrossing yielded disease-susceptible NOD.B10 Cox-2flox lines; fine genetic mapping determined that critical Aec2 genes lie within a 1.56 to 2.17 Mb span of DNA downstream of Cox-2. Bioinformatics analysis revealed that susceptible and non-susceptible lines exhibit non-synonymous coding SNPs in 8 protein-encoding genes of this region, thereby better delineating candidate Aec2 alleles needed for SS xerostomia. PMID:24685748

  13. A defect in the synthesis of Interferon-γ by the T cells of Complement-C5 deficient mice leads to enhanced susceptibility for tuberculosis

    Science.gov (United States)

    Mashruwala, Mary Anne; Smith, Amanda K.; Lindsey, Devin R.; Moczygemba, Margaret; Wetsel, Rick A.; Klein, John R.; Actor, Jeffrey K.; Jagannath, Chinnaswamy

    2012-01-01

    Interferon-γ (IFNγ) plays a major role during host defense against Mycobacterium tuberculosis (Mtb). T cells produce IFNγ in response to IL-12 and IL-18 secreted from Mtb infected macrophages. IFNγ in turn, induces nitric oxide secretion in macrophages that kills Mtb. IFNγ knock-out mice are thus hyper-susceptible to tuberculosis. We reported earlier that Complement C5 deficient (C5-/-) congenic mice are more susceptible to tuberculosis and showed reduced IL-12 synthesis in their macrophages. Using C5-/- congenic mice that carry a deletion in the C5 gene and the wild type C5+/+ mice, we demonstrate here that, the C5-/-derived CD3+ T cells, have an additional defect in the synthesis of IFNγ. C5-/- T cells produced lower levels of IFNγ upon stimulation by antigen presenting cells (APCs) infected with Mtb or when stimulated directly with a combination of IL-12 and IL-18. The latter was in part due to a reduced phosphorylation of STAT-4 following IL-12/IL-18 stimulation. Addition of C5a peptide to IL-12/IL-18 partially restored STAT4 phosphorylation and IFNγ synthesis in C5-/- T cells indicating that IL-12/IL-18 mediated signaling within CD3+ T cells involves C5a peptide. Finally, C5-/- T cells derived from M.bovis BCG or Mtb infected mice showed a reduced expression of T-bet (T-box expressed in T cells) transcription factor, which correlated well with a reduced T cell secretion of IFNγ. Since T-bet mediated IFNγ synthesis facilitates Th1 expansion, C5-/- mouse derived T cells appear to have an intrinsic defect in the production of IFNγ, which is related to C5 deficiency and this may explain their increased susceptibility to infection with Mtb and BCG. PMID:22154007

  14. Interleukin-17A-Deficient Mice Are Highly Susceptible to Toxoplasma gondii Infection Due to Excessively Induced T. gondii HSP70 and Interferon Gamma Production.

    Science.gov (United States)

    Moroda, Masataka; Takamoto, Masaya; Iwakura, Yoichiro; Nakayama, Jun; Aosai, Fumie

    2017-12-01

    Interleukin17A (IL-17A) is known to be involved in the host defense against pathogens and the pathogenesis of autoimmune diseases. Previously, we showed that excessive amounts of interferon gamma (IFN-γ) play an important role in the pathogenesis of the lethal effects of Toxoplasma gondii by inducing anaphylactic responses. In the study described in this report, we examined the effects of IL-17A deficiency on murine host defense against oral T. gondii infection. IL-17A-deficient C57BL/6 (B6) mice exhibited higher rates of mortality than wild-type (WT) mice during the acute phase of T. gondii infection. CD4+ T cells in the mesenteric lymph nodes (mLNs) and ileum of T. gondii-infected IL-17A-deficient mice produced higher levels of IFN-γ than did those of WT mice. In addition, the level of T. gondii HSP70 (T.gHSP70) expression was also significantly increased in the ileum, mLNs, liver, and spleen of infected IL-17A-deficient mice compared with that in WT mice. These elevated levels of expression of T.gHSP70 and IFN-γ in infected IL-17A-deficient mice were presumably linked to the IL-17A defect since they decreased to WT levels after treatment with recombinant IL-17A. Furthermore, IL-17A-deficient mice were highly susceptible to the anaphylactic effect of T.gHSP70, and the survival of IL-17A-deficient mice during the acute phase was improved by treatment with an anti-T.gHSP70 monoclonal antibody. These results suggest that IL-17A plays an important role in host survival against T. gondii infection by protecting the host from an anaphylactic reaction via the downregulation of T.gHSP70 and IFN-γ production. Copyright © 2017 American Society for Microbiology.

  15. Phenotypic characterization in mice of thymus target cells susceptible to productive infection by the radiation leukemia virus

    Energy Technology Data Exchange (ETDEWEB)

    Boniver, J. (Univ. of Liege, Belgium); Decleve, A.; Honsik, C.; Libermann, M.; Kaplan, H.S.

    1981-11-01

    The spread of virus repliction was studied by electron microscopy in the thymuses of inbred C57BL/Ka mice after intrathymic inoculation of the radiation leukemia virus (RadLV). The first type C-budding virus particles appeared in scarce blast cells of the subcapsular zone. Most of these blast cells were ''X-cells,'' i.e., the thymus lymphoid cells most actively engaged in DNA synthesis. Virus replication spread to the entire cortical blast cell population and, from day 7 on, to the small cortical lymphocytes. The first virus-producing cells were derived from a very few target cells (approx. =0.001-0.003% of thymocytes) susceptible to RadLV infection. For determination of the phenotypes of these target cells, various thymocyte subpopulations obtained through a battery of cell separation methods were tested for their ability to support the replication of RadLV/VL/sub 3/ virus in short-term culture. Most of these target cells were sensitive to the lytic effect of hydrocortisone and migrated in the fastest fraction of a 1Xg sedimentation gradient, together with the majority of (/sup 3/H)thymidine-incorporating blast cells. They exhibited an intermediate density and expressed H-2 and Thy 1.2 cell surface antigens, although they were not found preferentially among the high Thy 1.2 population to which most of the cortical blast cells belonged. The spread of RadLV within the thymus and the surface phenotype characteristics of target cells indicate that these cells correspond to a thymocyte subset at the earliest stage of thymic lymphopoiesis and may be transitional between the prothymocytes and the subcapsular blast cell population.

  16. Influence of exposure patterns of nitrogen dioxide and modifications by ozone on susceptibility to bacterial infectious disease in mice

    Energy Technology Data Exchange (ETDEWEB)

    Graham, J.A.; Gardner, D.E.; Blommer, E.J.; House, D.E.; Menache, M.G.; Miller, F.J.

    1987-01-01

    The nitrogen dioxide (NO/sub 2/) diurnal cycle found in urban communities usually consists of a low basal concentration upon which are superimposed higher concentration peaks or spikes of short duration. Various components of this environmental exposure mode were examined to assess effects of urban exposure profiles on susceptibility to infectious pulmonary disease. Mice were exposed to NO/sub 2/ peaks of 4.5 ppm for 1, 3.5, or 7 h, challenged with Streptococcus sp. either immediately or 18 h postexposure, and then observed for mortality. When the streptococcal challenges were immediately after NO/sub 2/ exposure, the mortality rate was directly related to the length of peak exposure, whether or not a basal exposure was used, and all peak lengths significantly increased mortality. When the challenge was delayed for 18 h after the peak exposure, spiked exposures of 3.5 and 7 h increased mortality to the same degree. If a 1-h peak exposure to 4.5 ppm was superimposed twice daily upon a continuous basal NO/sub 2/ concentration of 1.5 ppm, there was a suggestive trend toward increased mortality near the end of the second week of exposure when challenge occurred immediately after the morning spike. Studies were also conducted to examine interactions with ozone (O/sub 3/) and NO/sub 2/, since urban air typically contains both of these oxidants. Using various combinations of basal and spiked exposure levels of NO/sub 2/ and O/sub 3/, synergistic results were obtained for streptococcal-induced mortality.

  17. Susceptibility of Anopheles quadrimaculatus (Diptera: Culicidae) to subperiodic Brugia malayi and Brugia pahangi (Nematoda: Filarioidea) adapted to nude mice and jirds.

    Science.gov (United States)

    Nayar, J K; Knight, J W; Vickery, A C

    1990-05-01

    Anopheles quadrimaculatus and Aedes aegypti (Black-eyed Liverpool strain) were fed on jirds and nude mice (jird-jird infection, jird-mouse infection, and mouse-jird infection) infected with subperiodic Brugia malayi and B. pahangi. Microfilariae of B. malayi from jird-mouse and mouse-jird infections developed normally in An. quadrimaculatus, whereas those from jird-jird infections did not develop. Microfilariae of both species from jirds and nude mice developed normally in Ae. aegypti and those of B. pahangi developed normally in An. quadrimaculatus. It is suggested that microfilariae from nude mice are modified physiologically, immunologically, or both so that they can develop in refractory An. quadrimaculatus, thus indicating that susceptibility and refractoriness of An. quadrimaculatus to B. malayi also is influenced by factors relating to the vertebrate host in addition to mosquito genetic factors.

  18. Candidate genes on murine chromosome 8 are associated with susceptibility to Staphylococcus aureus infection in mice and are involved with Staphylococcus aureus septicemia in humans.

    Directory of Open Access Journals (Sweden)

    Qin Yan

    Full Text Available We previously showed that chromosome 8 of A/J mice was associated with susceptibility to S. aureus infection. However, the specific genes responsible for this susceptibility are unknown. Chromosome substitution strain 8 (CSS8 mice, which have chromosome 8 from A/J but an otherwise C57BL/6J genome, were used to identify the genetic determinants of susceptibility to S. aureus on chromosome 8. Quantitative trait loci (QTL mapping of S. aureus-infected N2 backcross mice (F1 [C8A] × C57BL/6J identified a locus 83180780-88103009 (GRCm38/mm10 on A/J chromosome 8 that was linked to S. aureus susceptibility. All genes on the QTL (n~ 102 were further analyzed by three different strategies: 1 different expression in susceptible (A/J and resistant (C57BL/6J mice only in response to S. aureus, 2 consistently different expression in both uninfected and infected states between the two strains, and 3 damaging non-synonymous SNPs in either strain. Eleven candidate genes from the QTL region were significantly differently expressed in patients with S. aureus infection vs healthy human subjects. Four of these 11 genes also exhibited significantly different expression in S. aureus-challenged human neutrophils: Ier2, Crif1, Cd97 and Lyl1. CD97 ligand binding was evaluated within peritoneal neutrophils from A/J and C57BL/6J. CD97 from A/J had stronger CD55 but weaker integrin α5β1 ligand binding as compared with C57BL/6J. Because CD55/CD97 binding regulates immune cell activation and cytokine production, and integrin α5β1 is a membrane receptor for fibronectin, which is also bound by S. aureus, strain-specific differences could contribute to susceptibility to S. aureus. Down-regulation of Crif1 with siRNA was associated with increased host cell apoptosis among both naïve and S. aureus-infected bone marrow-derived macrophages. Specific genes in A/J chromosome 8, including Cd97 and Crif1, may play important roles in host defense against S. aureus.

  19. Estimating the extent of vaccine-derived poliovirus infection.

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    Alison Wringe

    Full Text Available BACKGROUND: Eight outbreaks of paralytic polio attributable to circulating vaccine-derived poliovirus (cVDPV have highlighted the risks associated with oral poliovirus vaccine (OPV use in areas of low vaccination coverage and poor hygiene. As the Polio Eradication Initiative enters its final stages, it is important to consider the extent to which these viruses spread under different conditions, so that appropriate strategies can be devised to prevent or respond to future cVDPV outbreaks. METHODS AND FINDINGS: This paper examines epidemiological (temporal, geographic, age, vaccine history, social group, ascertainment, and virological (type, genetic diversity, virulence parameters in order to infer the numbers of individuals likely to have been infected in each of these cVDPV outbreaks, and in association with single acute flaccid paralysis (AFP cases attributable to VDPVs. Although only 114 virologically-confirmed paralytic cases were identified in the eight cVDPV outbreaks, it is likely that a minimum of hundreds of thousands, and more likely several million individuals were infected during these events, and that many thousands more have been infected by VDPV lineages within outbreaks which have escaped detection. CONCLUSIONS: Our estimates of the extent of cVDPV circulation suggest widespread transmission in some countries, as might be expected from endemic wild poliovirus transmission in these same settings. These methods for inferring extent of infection will be useful in the context of identifying future surveillance needs, planning for OPV cessation and preparing outbreak response plans.

  20. Impaired long-term memory retention and working memory in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia.

    Science.gov (United States)

    Takao, Keizo; Toyama, Keiko; Nakanishi, Kazuo; Hattori, Satoko; Takamura, Hironori; Takeda, Masatoshi; Miyakawa, Tsuyoshi; Hashimoto, Ryota

    2008-10-22

    Schizophrenia is a complex genetic disorder caused by multiple genetic and environmental factors. The dystrobrevin-binding protein 1 (DTNBP1: dysbindin-1) gene is a major susceptibility gene for schizophrenia. Genetic variations in DTNBP1 are associated with cognitive functions, general cognitive ability and memory function, and clinical features of patients with schizophrenia including negative symptoms and cognitive decline. Since reduced expression of dysbindin-1 has been observed in postmortem brains of patients with schizophrenia, the sandy (sdy) mouse, which has a deletion in the Dtnbp1 gene and expresses no dysbindin-1 protein, could be an animal model of schizophrenia. To address this issue, we have carried out a comprehensive behavioral analysis of the sdy mouse in this study. In a rotarod test, sdy mice did not exhibit motor learning whilst the wild type mice did. In a Barnes circular maze test both sdy mice and wild type mice learned to selectively locate the escape hole during the course of the training period and in the probe trial conducted 24 hours after last training. However, sdy mice did not locate the correct hole in the retention probe tests 7 days after the last training trial, whereas wild type mice did, indicating impaired long-term memory retention. A T-maze forced alternation task, a task of working memory, revealed no effect of training in sdy mice despite the obvious effect of training in wild type mice, suggesting a working memory deficit. Sdy mouse showed impaired long-term memory retention and working memory. Since genetic variation in DTNBP1 is associated with both schizophrenia and memory function, and memory function is compromised in patients with schizophrenia, the sdy mouse may represent a useful animal model to investigate the mechanisms of memory dysfunction in the disorder.

  1. Impaired long-term memory retention and working memory in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia

    Directory of Open Access Journals (Sweden)

    Takao Keizo

    2008-10-01

    Full Text Available Abstract Background Schizophrenia is a complex genetic disorder caused by multiple genetic and environmental factors. The dystrobrevin-binding protein 1 (DTNBP1: dysbindin-1 gene is a major susceptibility gene for schizophrenia. Genetic variations in DTNBP1 are associated with cognitive functions, general cognitive ability and memory function, and clinical features of patients with schizophrenia including negative symptoms and cognitive decline. Since reduced expression of dysbindin-1 has been observed in postmortem brains of patients with schizophrenia, the sandy (sdy mouse, which has a deletion in the Dtnbp1 gene and expresses no dysbindin-1 protein, could be an animal model of schizophrenia. To address this issue, we have carried out a comprehensive behavioral analysis of the sdy mouse in this study. Results In a rotarod test, sdy mice did not exhibit motor learning whilst the wild type mice did. In a Barnes circular maze test both sdy mice and wild type mice learned to selectively locate the escape hole during the course of the training period and in the probe trial conducted 24 hours after last training. However, sdy mice did not locate the correct hole in the retention probe tests 7 days after the last training trial, whereas wild type mice did, indicating impaired long-term memory retention. A T-maze forced alternation task, a task of working memory, revealed no effect of training in sdy mice despite the obvious effect of training in wild type mice, suggesting a working memory deficit. Conclusion Sdy mouse showed impaired long-term memory retention and working memory. Since genetic variation in DTNBP1 is associated with both schizophrenia and memory function, and memory function is compromised in patients with schizophrenia, the sdy mouse may represent a useful animal model to investigate the mechanisms of memory dysfunction in the disorder.

  2. Sorveglianza della circolazione ambientale dei poliovirus nel Lazio

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    A.M. Patti

    2003-05-01

    Full Text Available Ancora oggi in tutto il mondo il vaccino antipolio più utilizzato è l’OPV costituito da virus viventi attenuati che vengono eliminati per un periodo di tempo variabile dal soggetto vaccinato. L’immissione di virus vaccinali nell’ambiente è stata in passato, e lo è tuttora nelle zone endemiche, estremamente importante per assicurare e la competizione con il poliovirus selvaggio e una immunità di gregge. Nei paesi polio-free, ed in futuro in tutto il mondo, la circolazione di virus vaccinali potrebbe viceversa diventare un punto critico in grado di inficiare i risultati dell’eradicazione. Infatti i virus vaccino derivati, replicando, retromutano verso la neurovirulenza e/o accumulano mutazioni che alla fine conferiscono loro caratteristiche del tutto diverse dai ceppi parentali; inoltre possono anche ricombinarsi con il selvaggio o con altri enterovirus assumendo caratteristiche di virulenza e di trasmissibilità interumana che emergono con lo scoppio di focolai epidemici. Obiettivo del presente progetto è stata la valutazione della circolazione dei poliovirus e degli eventuali virus vaccino derivati in matrici ambientali nella regione Lazio nel periodo 1996-2002. Metodo: sono stati analizzati 26 campioni di liquami e 36 campioni di acque superficiali contaminate da liquami. Le particelle virali sono state concentrate mediante ultra filtrazione tangenziale (10.000 NMWR – Millipore. I concentrati sono stati seminati su cellule BGM ed L20B. I virus isolati sono stati identificati con antisieri specifici (RIUM e sui poliovirus, presso l’ISS, sono stati effettuati la differenziazione intratipica, il sequenziamento della regione VPI/2A, il sequenziamento della regione 5’ NCR e la regione codificante la polimerasi virale. Risultati e conclusioni: sono stati isolati complessivamente 6 poliovirus di cui 4 da acque superficiali. I virus erano tutti Sabin-kike e retromutati ma non ricombinanti. I dati ottenuti sottolineano l

  3. The differential interferon responses of two strains of Stat1-deficient mice do not alter susceptibility to HSV-1 and VSV in vivo.

    Science.gov (United States)

    Katzenell, Sarah; Chen, Yufei; Parker, Zachary M; Leib, David A

    2014-02-01

    Stat1 is a pivotal transcription factor for generation of the interferon (IFN)-dependent antiviral response. Two Stat1 knockout mouse lines have been previously generated, one deleted the N-terminal domain (ΔNTD) and one in the DNA-binding domain (ΔDBD). These widely-used strains are assumed interchangeable, and both are highly susceptible to various pathogens. In this study, primary cells derived from ΔNTD mice were shown to be significantly more responsive to IFN, and established an antiviral state with greater efficiency than cells derived from ΔDBD mice, following infection with vesicular stomatitis virus and herpes simplex virus type-1. Also, while mice from both strains succumbed rapidly and equally to virus infection, ΔDBD mice supported significantly higher replication in brains and livers than ΔNTD mice. Endpoint-type experimental comparisons of these mouse strains are therefore misleading in failing to indicate important differences in virus replication and innate response. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. A novel role for APOBEC3: Susceptibility to sexual transmission of murine acquired immunodeficiency virus (mAIDS is aggravated in APOBEC3 deficient mice

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    Jones Philip H

    2012-06-01

    Full Text Available Abstract Background APOBEC3 proteins are host factors that restrict infection by retroviruses like HIV, MMTV, and MLV and are variably expressed in hematopoietic and non-hematopoietic cells, such as macrophages, lymphocytes, dendritic, and epithelia cells. Previously, we showed that APOBEC3 expressed in mammary epithelia cells function to limit milk-borne transmission of the beta-retrovirus, mouse mammary tumor virus. In this present study, we used APOBEC3 knockout mice and their wild type counterpart to query the role of APOBEC3 in sexual transmission of LP-BM5 MLV – the etiological agent of murine AIDs (mAIDs. Results We show that mouse APOBEC3 is expressed in murine genital tract tissues and gametes and that genital tract tissue of APOBEC3-deficient mice are more susceptible to infection by LP-BM5 virus. APOBEC3 expressed in genital tract tissues most likely plays a role in decreasing virus transmission via the sexual route, since mice deficient in APOBEC3 gene have higher genitalia and seminal plasma virus load and sexually transmit the virus more efficiently to their partners compared to APOBEC3+ mice. Moreover, we show that female mice sexually infected with LP-BM5 virus transmit the virus to their off-spring in APOBEC3-dependent manner. Conclusion Our data indicate that genital tissue intrinsic APOBEC3 restricts genital tract infection and limits sexual transmission of LP-BM5 virus.

  5. Investigation of an outbreak of type 3 wild poliovirus in Cote d'Ivoire ...

    African Journals Online (AJOL)

    This can occur when routine immunization coverage is low, polio supplementary immunization activities are done with only the poliovirus vaccine against the circulating poliovirus, people live in precarious socio-economic conditions and AFP surveillance is poorly performed. Côte d'Ivoire experienced this outbreak as many ...

  6. Anti-poliovirus activity of medicinal plants selected from the Nigerian ...

    African Journals Online (AJOL)

    Evuel

    results support the traditional use of S. siamea and Z. candida as antiviral agents and suggest that they could provide a possible source for anti-poliovirus drug discovery and development. Key words: Anti-poliovirus activity, traditional medicine, MTT colorimetric assay. INTRODUCTION. From the early times, plants have ...

  7. Poliovirus-specific memory immunity in seronegative elderly people does not protect against virus excretion.

    NARCIS (Netherlands)

    Abbink, Frithjofna; Buisman, Anne M; Doornbos, Gerda; Woldman, Jan; Kimman, Tjeerd G; Conyn- van Spaendonck, Marina A E

    2005-01-01

    BACKGROUND: Dutch people born between 1925 and 1945 were ineligible for vaccination with the inactivated poliovirus vaccine (IPV) introduced in 1957 and may have escaped natural infection because of reduced poliovirus circulation. We examined whether people with low or undetectable antibody levels

  8. Homologous prime-boost strategy with TgPI-1 improves the immune response and protects highly susceptible mice against chronic Toxoplasma gondii infection.

    Science.gov (United States)

    Sánchez, Vanesa R; Fenoy, Ignacio M; Picchio, Mariano S; Soto, Ariadna S; Arcon, Nadia; Goldman, Alejandra; Martin, Valentina

    2015-10-01

    Subunit-based vaccines are safer than live or attenuated pathogen vaccines, although they are generally weak immunogens. Thus, proper combination of immunization strategies and adjuvants are needed to increase their efficacy. We have previously protected C3H/HeN mice from Toxoplasma gondii infection by immunization with the serine protease inhibitor-1 (TgPI-1) in combination with alum. In this work, we explore an original vaccination protocol that combines administration of recombinant TgPI-1 by intradermal and intranasal routes in order to enhance protection in the highly susceptible C57BL/6 strain. Mice primed intradermally with rTgPI-1 plus alum and boosted intranasally with rTgPI-1 plus CpG-ODN elicited a strong specific Th1/Th2 humoral response, along with a mucosal immune response characterized by specific-IgA in intestinal lavages. A positive cellular response of mesentheric lymph node cells and Th1/Th2 cytokine secretion in the ileon were also detected. When immunized mice were challenged with the cystogenic Me49 T. gondii strain, they displayed up to 62% reduction in brain parasite burden. Moreover, adoptive transfer of mesenteric lymph node cells from vaccinated to naïve mice induced significant protection against infection. These results demonstrate that this strategy that combines the administration of TgPI-1 by two different routes, intradermal priming and intranasal boost, improves protective immunity against T. gondii chronic infection in highly susceptible mice. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Evidence of presence of poliovirus genomic sequences in cerebrospinal fluid from patients with postpolio syndrome.

    Science.gov (United States)

    Leparc-Goffart, I; Julien, J; Fuchs, F; Janatova, I; Aymard, M; Kopecka, H

    1996-01-01

    The postpolio syndrome (PPS) is characterized by new neuromuscular symptoms occurring 30 to 40 years after the acute episode of poliomyelitis paralysis. The presence of the poliovirus RNA genome in the cerebrospinal fluid from 10 patients with PPS and from 23 control patients was sought by using reverse transcription and a PCR specific for polioviruses and/or other enteroviruses. Poliovirus-specific genomic sequences in the 5' untranslated region and in the capsid region (VP1) were detected by reverse transcription PCR in 5 of 10 patients with PPS but in none of the control patients. Sequencing confirmed the presence of mutated poliovirus sequences. This finding suggests persistent viral infection in the central nervous system related to the presence of poliovirus genomes. PMID:8818905

  10. Impact of inactivated poliovirus vaccine on mucosal immunity: implications for the polio eradication endgame.

    Science.gov (United States)

    Parker, Edward Pk; Molodecky, Natalie A; Pons-Salort, Margarita; O'Reilly, Kathleen M; Grassly, Nicholas C

    2015-01-01

    The polio eradication endgame aims to bring transmission of all polioviruses to a halt. To achieve this aim, it is essential to block viral replication in individuals via induction of a robust mucosal immune response. Although it has long been recognized that inactivated poliovirus vaccine (IPV) is incapable of inducing a strong mucosal response on its own, it has recently become clear that IPV may boost immunity in the intestinal mucosa among individuals previously immunized with oral poliovirus vaccine. Indeed, mucosal protection appears to be stronger following a booster dose of IPV than oral poliovirus vaccine, especially in older children. Here, we review the available evidence regarding the impact of IPV on mucosal immunity, and consider the implications of this evidence for the polio eradication endgame. We conclude that the implementation of IPV in both routine and supplementary immunization activities has the potential to play a key role in halting poliovirus transmission, and thereby hasten the eradication of polio.

  11. STUDY OF IMMUNITY TO POLIOVIRUSES ON CERTAIN "SILENT" TERRITORIES OF RUSSIA

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    N. I. Romanenkova

    2011-01-01

    Full Text Available Abstract. The degree of immunity to polioviruses of three serotypes among children of different ages was analysed on certain "controlled" and "silent" territories of Russia in different periods of Polio Eradication Initiative. It was shown that the levels of immunity of children’s population to polioviruses on "controlled" and "silent" territories had no significant difference. It was stated that on the phase which preceded the certification for the absence of circulation of wild polioviruses, when the National Immunisation Days were conducted in the country, the percentage of eronegative children to polioviruses of different serotypes was low on all the territories of Russia. After Russia as a part of the WHO European region was certified as a polio free country and mass immunisation was stopped thepercentage of seronegative children increased, especially to poliovirus of serotype 3, both on the "controlled" and on the "silent" territories.

  12. An economic analysis of poliovirus risk management policy options for 2013-2052.

    Science.gov (United States)

    Duintjer Tebbens, Radboud J; Pallansch, Mark A; Cochi, Stephen L; Wassilak, Steven G F; Thompson, Kimberly M

    2015-09-24

    The Global Polio Eradication Initiative plans for coordinated cessation of oral poliovirus vaccine (OPV) after interrupting all wild poliovirus (WPV) transmission, but many questions remain related to long-term poliovirus risk management policies. We used an integrated dynamic poliovirus transmission and stochastic risk model to simulate possible futures and estimate the health and economic outcomes of maintaining the 2013 status quo of continued OPV use in most developing countries compared with OPV cessation policies with various assumptions about global inactivated poliovirus vaccine (IPV) adoption. Continued OPV use after global WPV eradication leads to continued high costs and/or high cases. Global OPV cessation comes with a high probability of at least one outbreak, which aggressive outbreak response can successfully control in most instances. A low but non-zero probability exists of uncontrolled outbreaks following a poliovirus reintroduction long after OPV cessation in a population in which IPV-alone cannot prevent poliovirus transmission. We estimate global incremental net benefits during 2013-2052 of approximately $16 billion (US$2013) for OPV cessation with at least one IPV routine immunization dose in all countries until 2024 compared to continued OPV use, although significant uncertainty remains associated with the frequency of exportations between populations and the implementation of long term risk management policies. Global OPV cessation offers the possibility of large future health and economic benefits compared to continued OPV use. Long-term poliovirus risk management interventions matter (e.g., IPV use duration, outbreak response, containment, continued surveillance, stockpile size and contents, vaccine production site requirements, potential antiviral drugs, and potential safer vaccines) and require careful consideration. Risk management activities can help to ensure a low risk of uncontrolled outbreaks and preserve or further increase the

  13. Patients with Primary Immunodeficiencies Are a Reservoir of Poliovirus and a Risk to Polio Eradication

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    Asghar Aghamohammadi

    2017-06-01

    Full Text Available Immunodeficiency-associated vaccine-derived polioviruses (iVDPVs have been isolated from primary immunodeficiency (PID patients exposed to oral poliovirus vaccine (OPV. Patients may excrete poliovirus strains for months or years; the excreted viruses are frequently highly divergent from the parental OPV and have been shown to be as neurovirulent as wild virus. Thus, these patients represent a potential reservoir for transmission of neurovirulent polioviruses in the post-eradication era. In support of WHO recommendations to better estimate the prevalence of poliovirus excreters among PIDs and characterize genetic evolution of these strains, 635 patients including 570 with primary antibody deficiencies and 65 combined immunodeficiencies were studied from 13 OPV-using countries. Two stool samples were collected over 4 days, tested for enterovirus, and the poliovirus positive samples were sequenced. Thirteen patients (2% excreted polioviruses, most for less than 2 months following identification of infection. Five (0.8% were classified as iVDPVs (only in combined immunodeficiencies and mostly poliovirus serotype 2. Non-polio enteroviruses were detected in 30 patients (4.7%. Patients with combined immunodeficiencies had increased risk of delayed poliovirus clearance compared to primary antibody deficiencies. Usually, iVDPV was detected in subjects with combined immunodeficiencies in a short period of time after OPV exposure, most for less than 6 months. Surveillance for poliovirus excretion among PID patients should be reinforced until polio eradication is certified and the use of OPV is stopped. Survival rates among PID patients are improving in lower and middle income countries, and iVDPV excreters are identified more frequently. Antivirals or enhanced immunotherapies presently in development represent the only potential means to manage the treatment of prolonged excreters and the risk they present to the polio endgame.

  14. Mice with a targeted deletion of the type 2 deiodinase are insulin resistant and susceptible to diet induced obesity.

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    Alessandro Marsili

    Full Text Available The type 2 iodothyronine deiodinase (D2 converts the pro-hormone thyroxine into T3 within target tissues. D2 is essential for a full thermogenic response of brown adipose tissue (BAT, and mice with a disrupted Dio2 gene (D2KO have an impaired response to cold. BAT is also activated by overfeeding.After 6-weeks of HFD feeding D2KO mice gained 5.6% more body weight and had 28% more adipose tissue. Oxygen consumption (V0(2 was not different between genotypes, but D2KO mice had an increased respiratory exchange ratio (RER, suggesting preferential use of carbohydrates. Consistent with this, serum free fatty acids and β-hydroxybutyrate were lower in D2KO mice on a HFD, while hepatic triglycerides were increased and glycogen content decreased. Neither genotype showed glucose intolerance, but D2KO mice had significantly higher insulin levels during GTT independent of diet. Accordingly, during ITT testing D2KO mice had a significantly reduced glucose uptake, consistent with insulin resistance. Gene expression levels in liver, muscle, and brown and white adipose tissue showed no differences that could account for the increased weight gain in D2KO mice. However, D2KO mice have higher PEPCK mRNA in liver suggesting increased gluconeogenesis, which could also contribute to their apparent insulin resistance.We conclude that the loss of the Dio2 gene has significant metabolic consequences. D2KO mice gain more weight on a HFD, suggesting a role for D2 in protection from diet-induced obesity. Further, D2KO mice appear to have a greater reliance on carbohydrates as a fuel source, and limited ability to mobilize and to burn fat. This results in increased fat storage in adipose tissue, hepatic steatosis, and depletion of liver glycogen in spite of increased gluconeogenesis. D2KO mice are also less responsive to insulin, independent of diet-induced obesity.

  15. The absence of GH signaling affects the susceptibility to high-fat diet-induced hypothalamic inflammation in male mice

    DEFF Research Database (Denmark)

    Baquedano, Eva; Ruiz-Lopez, Ana M; Sustarsic, Elahu G

    2014-01-01

    GH is important in metabolic control, and mice with disruption of the gene encoding the GH receptor (GHR) and GH binding protein (GHR-/- mice) are dwarf with low serum IGF-1 and insulin levels, high GH levels, and increased longevity, despite their obesity and altered lipid and metabolic profiles...

  16. Deficiency of immunity to poliovirus type 3: a lurking danger?

    Science.gov (United States)

    Reinheimer, Claudia; Friedrichs, Imke; Rabenau, Holger F; Doerr, Hans W

    2012-01-26

    Europe was certified to be polio-free in 2002 by the WHO. However, wild polioviruses remain endemic in India, Pakistan, Afghanistan, and Nigeria, occasionally causing polio outbreaks, as in Tajikistan in 2010. Therefore, effective surveillance measures and vaccination campaigns remain important. To determine the poliovirus immune status of a German study population, we retrospectively evaluated the seroprevalence of neutralizing antibodies (NA) to the poliovirus types 1, 2 and 3 (PV1, 2, 3) in serum samples collected from 1,632 patients admitted the University Hospital of Frankfurt am Main, Germany, in 2001, 2005 and 2010. Testing was done by using a standardized microneutralization assay. Level of immunity to PV1 ranged between 84.2% (95%CI: 80.3-87.5), 90.4% (88.3-92.3) and 87.5% (85.4-88.8) in 2001, 2005 and 2010. For PV2, we found 90.8% (87.5-90.6), 91.3% (89.3-93.1) and 89.8% (88.7-90.9), in the same period. Seroprevalence to PV3 was 76.6% (72.2-80.6), 69.8% (66.6-72.8) and 72.9% (67.8-77.5) in 2001 and 2005 and 2010, respectively. In 2005 and 2010 significant lower levels of immunity to PV3 in comparison to PV1 and 2 were observed. Since 2001, immunity to PV3 is gradually, but not significantly decreasing. Immunity to PV3 is insufficient in our cohort. Due to increasing globalization and worldwide tourism, the danger of polio-outbreaks is not averted - even not in developed countries, such as Germany. Therefore, vaccination remains necessary.

  17. Deficiency of immunity to poliovirus type 3: a lurking danger?

    Directory of Open Access Journals (Sweden)

    Reinheimer Claudia

    2012-01-01

    Full Text Available Abstract Background Europe was certified to be polio-free in 2002 by the WHO. However, wild polioviruses remain endemic in India, Pakistan, Afghanistan, and Nigeria, occasionally causing polio outbreaks, as in Tajikistan in 2010. Therefore, effective surveillance measures and vaccination campaigns remain important. To determine the poliovirus immune status of a German study population, we retrospectively evaluated the seroprevalence of neutralizing antibodies (NA to the poliovirus types 1, 2 and 3 (PV1, 2, 3 in serum samples collected from 1,632 patients admitted the University Hospital of Frankfurt am Main, Germany, in 2001, 2005 and 2010. Methods Testing was done by using a standardized microneutralization assay. Results Level of immunity to PV1 ranged between 84.2% (95%CI: 80.3-87.5, 90.4% (88.3-92.3 and 87.5% (85.4-88.8 in 2001, 2005 and 2010. For PV2, we found 90.8% (87.5-90.6, 91.3% (89.3-93.1 and 89.8% (88.7-90.9, in the same period. Seroprevalence to PV3 was 76.6% (72.2-80.6, 69.8% (66.6-72.8 and 72.9% (67.8-77.5 in 2001 and 2005 and 2010, respectively. In 2005 and 2010 significant lower levels of immunity to PV3 in comparison to PV1 and 2 were observed. Since 2001, immunity to PV3 is gradually, but not significantly decreasing. Conclusion Immunity to PV3 is insufficient in our cohort. Due to increasing globalization and worldwide tourism, the danger of polio-outbreaks is not averted - even not in developed countries, such as Germany. Therefore, vaccination remains necessary.

  18. A comparison of the pulmonary defenses against streptococcal infection in rats and mice following O3 exposure: Differences in disease susceptibility and neutrophil recruitment

    Energy Technology Data Exchange (ETDEWEB)

    Gilmour, M.I.; Selgrade, M.K. (Univ. of North Carolina, Chapel Hill (United States))

    1993-12-01

    Ozone (O3) exposure reduces alveolar macrophage (AM) phagocytosis in mice and increases their susceptibility to Streptococcus zooepidemicus. O3 exposure also decreases AM phagocytosis in rats but does not result in mortality to infection. To investigate the mechanism of disease protection in rats, antibacterial defenses of two strains of mice and F344 rats were compared. O3 exposure (3 hr, 0.4 or 0.8 ppm) and infection with S. zooepidemicus resulted in a dose-dependent proliferation of bacteria in the lungs of mice and high mortality. Polymorphonuclear leukocytes (PMNs) were observed in severely affected individuals 2 or more days postinfection and did not alter the fatal infection. In contrast, microbial inactivation was only impaired in O3-exposed rat lungs during the first 48 hr after infection. In these animals PMNs could be isolated from bronchoalveolar lavage fluid between 6 and 48 hr postinfection with the peak response occurring at 24 hr. Pretreatment with anti-PMN serum eliminated the neutrophil influx and impaired further the bactericidal activity in ozone-exposed rats. The results suggest that inhaled streptococci are cleared normally from the mouse lung by AMs. Following exposure to O3, AM phagocytosis is reduced and the mice develop a fatal infection. The persistence of bacteria in the lungs of O3-exposed rats triggers a transient influx of PMNs whose appearance corresponds with elimination of the bacteria. Differences in antimicrobial defenses between various experimental species and humans need to be better understood in order to predict effects of air pollutants on susceptibility to infection in man.

  19. Temporal profile of magnetic resonance angiography and decreased ratio of regulatory T cells after immunological adjuvant administration to mice lacking RNF213, a susceptibility gene for moyamoya disease.

    Science.gov (United States)

    Kanoke, Atsushi; Fujimura, Miki; Niizuma, Kuniyasu; Fujimura, Taku; Kakizaki, Aya; Ito, Akira; Sakata, Hiroyuki; Sato-Maeda, Mika; Kure, Shigeo; Tominaga, Teiji

    2016-07-01

    Moyamoya disease (MMD) is a chronic, occlusive cerebrovascular disease with an unknown etiology and is characterized by an abnormal vascular network at the base of the brain. Recent studies identified the RNF213 gene (RNF213) as an important susceptibility gene for MMD; however, the mechanisms underlying the RNF213 abnormality related to MMD have not yet been elucidated. We previously reported that Rnf213-deficient mice and Rnf213 p. R4828K knock-in mice did not spontaneously develop MMD, indicating the importance of secondary insults in addition to genetic factors in the pathogenesis of MMD. The most influential secondary insult is considered to be an immunological reaction because RNF213 is predominantly expressed in immunological tissues. Therefore, we herein attempted to evaluate the role of an immunological stimulation as a supplementary insult to the target disruption of RNF213 in the pathophysiology of MMD. Rnf213-deficient mice were treated with strong immunological adjuvants including muramyl dipeptide (MDP)-Lys (L18), and then underwent time-sequential magnetic resonance angiography (MRA) up to 40 weeks of age. The results obtained did not reveal any characteristic finding of MMD, and no significant difference was observed in MRA findings or the anatomy of the circle of Willis between Rnf213-deficient mice and wild-type mice after the administration of MDP-Lys (L18). The ratio of regulatory T cells after the administration of MDP-Lys (L18) was significantly decreased in Rnf213-deficient mice (p<0.01), suggesting the potential role of the RNF213 abnormality in the differentiation of regulatory T cells. Although the mechanisms underlying the development of MMD currently remain unclear, the RNF213 abnormality may compromise immunological self-tolerance, thereby contributing to the development of MMD. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Aging Increases Susceptibility to High Fat Diet-Induced Metabolic Syndrome in C57BL/6 Mice: Improvement in Glycemic and Lipid Profile after Antioxidant Therapy

    Directory of Open Access Journals (Sweden)

    Valéria Nunes-Souza

    2016-01-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD has been considered a novel component of the metabolic syndrome (MetS, with the oxidative stress participating in its progression. This study aimed to evaluate the metabolic profile in young and old mice with MetS, and the effects of apocynin and tempol on glycemic and lipid parameters. Young and old C57BL/6 mice with high fat diet- (HFD- induced MetS received apocynin and tempol 50 mg·kg−1/day in their drinking water for 10 weeks. After HFD, the young group showed elevated fasting glucose, worsened lipid profile in plasma, steatosis, and hepatic lipid peroxidation. Nevertheless, the old group presented significant increase in fasting insulin levels, insulin resistance, plasma and hepatic lipid peroxidation, and pronounced steatosis. The hepatic superoxide dismutase and catalase activity did not differ between the groups. Tempol and apocynin seemed to prevent hepatic lipid deposition in both groups. Furthermore, apocynin improved glucose tolerance and insulin sensitivity in old mice. In summary, old mice are more susceptible to HFD-induced metabolic changes than their young counterparts. Also, the antioxidant therapy improved insulin sensitivity and glucose tolerance, and in addition, apocynin seemed to prevent the HFD-induced hepatic fat deposition, suggesting an important role of oxidative stress in the induction of NAFLD.

  1. Aging Increases Susceptibility to High Fat Diet-Induced Metabolic Syndrome in C57BL/6 Mice: Improvement in Glycemic and Lipid Profile after Antioxidant Therapy.

    Science.gov (United States)

    Nunes-Souza, Valéria; César-Gomes, Cheila Juliana; Da Fonseca, Lucas José Sá; Guedes, Glaucevane Da Silva; Smaniotto, Salete; Rabelo, Luíza Antas

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) has been considered a novel component of the metabolic syndrome (MetS), with the oxidative stress participating in its progression. This study aimed to evaluate the metabolic profile in young and old mice with MetS, and the effects of apocynin and tempol on glycemic and lipid parameters. Young and old C57BL/6 mice with high fat diet- (HFD-) induced MetS received apocynin and tempol 50 mg·kg(-1)/day in their drinking water for 10 weeks. After HFD, the young group showed elevated fasting glucose, worsened lipid profile in plasma, steatosis, and hepatic lipid peroxidation. Nevertheless, the old group presented significant increase in fasting insulin levels, insulin resistance, plasma and hepatic lipid peroxidation, and pronounced steatosis. The hepatic superoxide dismutase and catalase activity did not differ between the groups. Tempol and apocynin seemed to prevent hepatic lipid deposition in both groups. Furthermore, apocynin improved glucose tolerance and insulin sensitivity in old mice. In summary, old mice are more susceptible to HFD-induced metabolic changes than their young counterparts. Also, the antioxidant therapy improved insulin sensitivity and glucose tolerance, and in addition, apocynin seemed to prevent the HFD-induced hepatic fat deposition, suggesting an important role of oxidative stress in the induction of NAFLD.

  2. Chromatin organization as a possible factor in the control of susceptibility to radiation-induced AML in mice

    Science.gov (United States)

    Maranon, David G.

    The studies described in this dissertation involve the use and comparison of two mouse strains: one sensitive (CBA/CaJ) and another resistant (C57BL/6J) to radiation-induced acute myeloid leukemia (AML). The purpose of these studies was to identify factors that may account for the large difference in the susceptibility of these strains to radiation-induced AML. The present study was initiated to determine whether the distances between breakpoint clusters on chromosome 2 are in closer proximity in the bone marrow cells of the CBA/CaJ mouse strain than in the C57BL/6J strain. Bacterial artificial chromosomes (BACs) were selected as markers of the central portion of the proximal and distal deletion breakpoint clusters as well as mdr on chromosome 2, where the preponderance of breaks occurs. Distance measurements were made by three dimensional fluorescent in situ hybridization (3DFISH) image analysis of hundreds of cells using Metamorph and ImageJ for data collection and Autoquant software for deconvolution and reconstruction of the three dimensional cell nuclei. Comparing bone marrow cells of CBA/CaJ and C57BL/6J mice, no differences were found between the proximity of the two regions represented for the selected markers compared in both murine strains. For the markers chosen the distribution of the distances showed similarities between the same cell types from both mouse strains; namely, fibroblasts, whole bone marrow (WBM), and hematopoietic stem cells (HSC). However, there was not found a change in the distance distributions toward the closer distances expected between the clusters in HSC and WBM compared with fibroblasts in both mouse strains. There was; however, a tissue-dependent distance distribution between the markers Specifically, the average distances of the clusters in fibroblasts (2.55 um for CBA/CaJ and 3.09 um for C57BL/6) were larger than the distance in blood cells (1.74 um in BM and 1.53 um in HSC for CBA/CaJ; and 1.79 um in BM and 1.77 um in HSC for

  3. Achieving high seroprevalence against polioviruses in Sri Lanka--results from a serological survey, 2014.

    Science.gov (United States)

    Gamage, Deepa; Palihawadana, Paba; Mach, Ondrej; Weldon, William C; Oberste, Steven M; Sutter, Roland W

    2015-12-01

    The immunization program in Sri Lanka consistently reaches >90% coverage with oral poliovirus vaccines (OPV), and no polio supplementary vaccination campaigns have been conducted since 2003. We evaluated serological protection against polioviruses in children. A cross-sectional community-based survey was performed in three districts of Sri Lanka (Colombo, Badulla, and Killinochi). Randomly selected children in four age groups (9-11 months, 3-4 years, 7-9 years, and 15 years) were tested for poliovirus neutralizing antibodies. All 400 enrolled children completed the study. The proportion of seropositive children for poliovirus Type 1 and Type 2 was >95% for all age groups; for poliovirus Type 3 it was 95%, 90%, 77%, and 75% in the respective age groups. The vaccination coverage in our sample based on vaccination cards or parental recall was >90% in all age groups. Most Sri Lankan children are serologically protected against polioviruses through routine immunization only. This seroprevalence survey provided baseline data prior to the anticipated addition of inactivated poliovirus vaccine (IPV) into the Sri Lankan immunization program and the switch from trivalent OPV (tOPV) to bivalent OPV (bOPV). Copyright © 2015 Ministry of Health, Saudi Arabia. Published by Elsevier Ltd. All rights reserved.

  4. Murine Cytomegalovirus Downregulates Interleukin-17 in Mice with Retrovirus-induced Immunosuppression that are Susceptible to Experimental Cytomegalovirus Retinitis

    Science.gov (United States)

    Blalock, Emily L.; Chien, Hsin; Dix, Richard D.

    2013-01-01

    Interleukin-17 (IL-17), a proinflammatory cytokine produced by CD4+ Th17 cells, has been associated with the pathogenesis of several autoimmune diseases including uveitis. The fate of IL-17 during HIV/AIDS, however, remains unclear, and a possible role for IL-17 in the pathogenesis of AIDS-related diseases has not been investigated. Toward these ends, we performed studies using a well-established animal model of experimental murine cytomegalovirus (MCMV) retinitis that develops in C57/BL6 mice with retrovirus-induced immunosuppression (MAIDS). After establishing baseline levels for IL-17 production in whole splenic cells of healthy mice, we observed a significant increase in IL-17 mRNA levels in whole splenic cells of mice with MAIDS of 4-weeks (MAIDS-4), 8-weeks (MAIDS-8), and 10-weeks (MAIDS-10) duration. In contrast, enriched populations of splenic CD4+ T cells, splenic macrophages, and splenic neutrophils exhibited a reproducible decrease in levels of IL-17 mRNA during MAIDS progression. To explore a possible role for IL-17 during the pathogenesis of MAIDS-related MCMV retinitis, we first demonstrated constitutive IL-17 expression in retinal photoreceptor cells of uninfected eyes of healthy mice. Subsequent studies, however, revealed a significant decrease in intraocular levels of IL-17 mRNA and protein in MCMV-infected eyes of MAIDS-10 mice during retinitis development. That MCMV infection might cause a remarkable downregulation of IL-17 production was supported further by the finding that systemic MCMV infection of healthy, MAIDS-4, or MAIDS-10 mice also significantly decreased IL-17 mRNA production by whole splenic CD4+ T cells. Based on additional studies using IL-10 −/− mice infected systemically with MCMV and IL-10 −/− mice with MAIDS infected intraocularly with MCMV, we propose that MCMV infection downregulates IL-17 production via stimulation of suppressor of cytokine signaling (SOCS)-3 and interleukin-10. PMID:23415673

  5. Seroprevalencia de anticuerpos contra el poliovirus 1 en niños mexicanos Seroprevalence of antibodies against poliovirus type 1 in Mexican children

    Directory of Open Access Journals (Sweden)

    Juan Ruiz-Gómez

    2007-01-01

    Full Text Available OBJETIVO: Analizar la frecuencia y distribución de la prevalencia de anticuerpos contra el virus de la poliomielitis tipo 1 en niños menores de 10 años en México, además de contribuir a la evaluación del programa de vacunación. MATERIAL Y MÉTODOS: Se estudió la presencia de anticuerpos contra el poliovirus tipo 1 en una muestra de la Encuesta Nacional de Salud 2000. Los sueros se recolectaron entre noviembre de 1999 y junio de 2000 a nivel nacional. La muestra constó de 6 270 niños de uno a nueve años de edad y se utilizó la técnica de neutralización. RESULTADOS: La seropositividad fue de 99.3% (IC95%99.1-99.7. Se identificaron como factores de riesgo de susceptibilidad el analfabetismo (RM= 1.5, p= 0.002 y el bajo ingreso familiar (RM= 1.4, p= 0.0487 y como factor protector el acceso a la seguridad social (RM= 0.41, p=0.04. CONCLUSIONES: Las actividades del programa de vacunación que han llevado a cabo las instituciones de salud han dado resultados en el control y eliminación de la enfermedad. Sin embargo, los programas de vacunación no deben interrumpirse, incluso si se ha registrado 99.3% de seropositividad; no puede soslayarse que al convertir el 0.7% restante, se calcula que hay 190 000 niños susceptibles de contraer la enfermedad. Estos niños se localizan sobre todo en el sur del país.OBJECTIVE: To analyze the frequency and distribution of the prevalence of antibodies against the poliomyelitis type 1 virus in children 1-9 years old in Mexico. MATERIAL AND METHODS: Antibodies against poliovirus type 1 (neutralization method were studied in 6 270 sera selected from the 24 232 sera from children one to nine years old, collected by the 2000 National Health Survey (ENSA 2000 that was conducted from November 1999 to June 2000. RESULTS: Overall seroprevalence was 99.3% (95%CI: 99.1-99.7. Using bivariate analysis, absence of antibodies was shown to be associated with illiteracy (OR= 1.5, p=0.002 and low household income (OR= 1

  6. Transgenerational inheritance of enhanced susceptibility to radiation-induced medulloblastoma in newborn Ptch1⁺/⁻ mice after paternal irradiation.

    Science.gov (United States)

    Paris, Lorena; Giardullo, Paola; Leonardi, Simona; Tanno, Barbara; Meschini, Roberta; Cordelli, Eugenia; Benassi, Barbara; Longobardi, Maria Grazia; Izzotti, Alberto; Pulliero, Alessandra; Mancuso, Mariateresa; Pacchierotti, Francesca

    2015-11-03

    The hypothesis of transgenerational induction of increased cancer susceptibility after paternal radiation exposure has long been controversial because of inconsistent results and the lack of a mechanistic interpretation. Here, exploiting Ptch1 heterozygous knockout mice, susceptible to spontaneous and radiation-induced medulloblastoma, we show that exposure of paternal germ cells to 1 Gy X-rays, at the spermatogonial stage, increased by a considerable 1.4-fold the offspring susceptibility to medulloblastoma induced by neonatal irradiation. This effect gained further biological significance thanks to a number of supporting data on the immunohistochemical characterization of the target tissue and preneoplastic lesions (PNLs). These results altogether pointed to increased proliferation of cerebellar granule cell precursors and PNLs cells, which favoured the development of frank tumours. The LOH analysis of tumor DNA showed Ptch1 biallelic loss in all tumor samples, suggesting that mechanisms other than interstitial deletions, typical of radiation-induced medulloblastoma, did not account for the observed increased cancer risk. This data was supported by comet analysis showing no differences in DNA damage induction and repair in cerebellar cells as a function of paternal irradiation. Finally, we provide biological plausibility to our results offering evidence of a possible epigenetic mechanism of inheritance based on radiation-induced changes of the microRNA profile of paternal sperm.

  7. GENOMIC IDENTIFICATION OF POTENTIAL RISK FACTORS DURING ACETAMINOPHEN-INDUCED LIVER DISEASE IN SUSCEPTIBLE AND RESISTANT STRAINS OF MICE

    Science.gov (United States)

    Drug-induced liver disease (DILD) continues to cause significant morbidity and mortality and impair new drug development. Mounting evidence suggests that DILD is a complex, multifactorial disease in which no one factor is likely to be an absolute indicator of susceptibility. As a...

  8. Susceptibility to lethal cerebral malaria is regulated by epistatic interaction between chromosome 4 (Berr6) and chromosome 1 (Berr7) loci in mice.

    Science.gov (United States)

    Torre, S; van Bruggen, R; Kennedy, J M; Berghout, J; Bongfen, S E; Langat, P; Lathrop, M; Vidal, S M; Gros, P

    2013-06-01

    In humans, cerebral malaria is a rare but often lethal complication of infection with Plasmodium parasites, the occurrence of which is influenced by complex genetic factors of the host. We used a mouse model of experimental cerebral malaria (ECM) with Plasmodium berghei ANKA to study genetic factors regulating appearance of neurological symptoms and associated lethality. In a genome-wide screen of N-ethyl-N-nitrosourea-mutagenized mice derived from C57BL/6J (B6) and 129S1/SvImJ (129) mouse strains, we detected a strong interaction between the genetic backgrounds of these strains, which modulates ECM resistance. We have mapped a major gene locus to central chromosome 4 (log of the odds (LOD) 6.7; 79.6-97.3 Mb), which we designate Berr8. [corrected]. B6 alleles at Berr6 are associated with resistance, and are inherited in a co-dominant fashion. In mice heterozygous for Berr6 B6/129 alleles, resistance to ECM is strongly modulated by a second locus, Berr7, that maps to the proximal portion of chromosome 1 (LOD 4.03; 41.4 Mb). 129 alleles at Berr7 are associated with ECM resistance in a dosage-dependent fashion. Results are discussed in view of the possible role of this two-locus system in susceptibility to unrelated inflammatory conditions in mice and humans.

  9. MyD88-, but not Nod1- and/or Nod2-deficient mice, show increased susceptibility to polymicrobial sepsis due to impaired local inflammatory response.

    Directory of Open Access Journals (Sweden)

    Fabiane Sônego

    Full Text Available Pathogen recognition and triggering of the inflammatory response following infection in mammals depend mainly on Toll-like and Nod-like receptors. Here, we evaluated the role of Nod1, Nod2 and MyD88-dependent signaling in the chemokine production and neutrophil recruitment to the infectious site during sepsis induced by cecal ligation and puncture (CLP in C57Bl/6 mice. We demonstrate that Nod1 and Nod2 are not involved in the release of chemokines and recruitment of neutrophils to the infectious site during CLP-induced septic peritonitis because these events were similar in wild-type, Nod1-, Nod2-, Nod1/Nod2- and Rip2-deficient mice. Consequently, the local and systemic bacterial loads were not altered. Accordingly, neither Nod1 nor Nod2 was involved in the production of the circulating cytokines and in the accumulation of leukocytes in the lungs. By contrast, we showed that MyD88-dependent signaling is crucial for the establishment of the local inflammatory response during CLP-induced sepsis. MyD88-deficient mice were susceptible to sepsis because of an impaired local production of chemokines and defective neutrophil recruitment to the infection site. Altogether, these data show that Nod1, Nod2 and Rip2 are not required for local chemokine production and neutrophil recruitment during CLP-induced sepsis, and they reinforce the importance of MyD88-dependent signaling for initiation of a protective host response.

  10. Pathogenesis of Lassa fever virus infection: I. Susceptibility of mice to recombinant Lassa Gp/LCMV chimeric virus.

    Science.gov (United States)

    Lee, Andrew M; Cruite, Justin; Welch, Megan J; Sullivan, Brian; Oldstone, Michael B A

    2013-08-01

    Lassa virus (LASV) is a BSL-4 restricted agent. To allow study of infection by LASV under BSL-2 conditions, we generated a recombinant virus in which the LASV glycoprotein (Gp) was placed on the backbone of lymphocytic choriomeningitis virus (LCMV) Cl13 nucleoprotein, Z and polymerase genes (rLCMV Cl13/LASV Gp). The recombinant virus displayed high tropism for dendritic cells following in vitro or in vivo infection. Inoculation of immunocompetent adults resulted in an acute infection, generation of virus-specific CD8(+) T cells and clearance of the infection. Inoculation of newborn mice with rLCMV Cl13/LASV Gp resulted in a life-long persistent infection. Interestingly, adoptive transfer of rLCMV Cl13/LASV Gp immune memory cells into such persistently infected mice failed to purge virus but, in contrast, cleared virus from mice persistently infected with wt LCMV Cl13. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Leukotriene C4 increases the susceptibility of adult mice to Shiga toxin-producing Escherichia coli infection.

    Science.gov (United States)

    Cabrera, Gabriel; Fernández-Brando, Romina J; Mejías, María Pilar; Ramos, María Victoria; Abrey-Recalde, María Jimena; Vanzulli, Silvia; Vermeulen, Mónica; Palermo, Marina S

    2015-12-01

    Shiga toxin-producing Escherichia coli (STEC) is a food-borne pathogen that causes hemorrhagic colitis. Under some circumstances, Shiga toxin (Stx) produced within the intestinal tract enters the bloodstream, leading to systemic complications that may cause the potentially fatal hemolytic-uremic syndrome (HUS). Despite STEC human infection is characterized by acute inflammation of the colonic mucosa, little is known regarding the role of proinflammatory mediators like cysteine leukotrienes (cysLTs) in this pathology. Thus, the aim of this work was to analyze whether leukotriene C4 (LTC4) influences STEC pathogenesis in mice. We report that exogenous LTC4 pretreatment severely affected the outcome of STEC gastrointestinal infection. LTC4-pretreated (LTC4+) and STEC-infected (STEC+) mice showed an increased intestinal damage by histological studies, and a decreased survival compared to LTC4-non-pretreated (LTC4-) and STEC+ mice. LTC4+/STEC+ mice that died after the infection displayed neutrophilia and high urea levels, indicating that the cause of death was related to Stx2-toxicity. Despite the differences observed in the survival between LTC4+ and LTC4- mice after STEC infection, both groups showed the same survival after Stx2-intravenous inoculation. In addition, LTC4 pretreatment increased the permeability of mucosal intestinal barrier, as assessed by FITC-dextran absorption experiments. Altogether these results suggest that LTC4 detrimental effect on STEC infection is related to the increased passage of pathogenic factors to the bloodstream. Finally, we showed that STEC infection per se increases the endogenous LTC4 levels in the gut, suggesting that this inflammatory mediator plays a role in the pathogenicity of STEC infection in mice, mainly by disrupting the mucosal epithelial barrier. Copyright © 2015 Elsevier GmbH. All rights reserved.

  12. Increased susceptibility to collagen-induced arthritis in female mice carrying congenic Cia40/Pregq2 fragments

    DEFF Research Database (Denmark)

    Liljander, Maria; Andersson, Åsa Inga Maria; Holmdahl, Rikard

    2008-01-01

    of the B10.Q strain. The major polymorphic candidate genes for the effects on CIA are Cd79b, Abca8a, and Map2k6. The congenic fragment also contains polymorphic genes that affect reproductive behavior and reproductive success. The Sox9 gene, known to influence sex reversal, is a candidate gene...... effects on onset, incidence, severity, and anti-CII antibody titers were observed in female mice carrying a heterozygous congenic Cia40/Pregq2 fragment of NFR/N origin, containing one or more polymorphic genes. Congenic male mice did not show increased incidence of CIA, but males carrying a heterozygous...

  13. Antibodies to poliovirus detected by immunoradiometric assay with a monoclonal antibody

    Energy Technology Data Exchange (ETDEWEB)

    Spitz, M.; Fossati, C.A.; Schild, G.C.; Spitz, L.; Brasher, M. (National Inst. for Biological Standards and Control, London (UK))

    1982-10-01

    An immunoradiometric assay (IRMA) for the assay of antibodies to poliovirus antigens is described. Dilutions of the test sera or whole (finger prick) blood samples were incubated with the poliovirus antigen bound to a solid phase and the specific antibody was detected by the addition of a mouse anti-human IgG monoclonal antibody (McAb), which was itself revealed by iodinated sheep IgG antimouse F(ab). The authors have shown that this technique is suitable for the estimation of IgG anti-poliovirus antibodies induced in children following polio vaccine. The present study shows that SPRIA provides a simple and inexpensive method for serological studies with poliovirus particularly for use in large-scale surveys.

  14. Poliovirus immunity in newly resettled adult refugees in Idaho, United States of America.

    Science.gov (United States)

    Roscoe, Clay; Gilles, Ryan; Reed, Alex J; Messerschmidt, Matt; Kinney, Rebecca

    2015-06-12

    In the United States, vaccines have eliminated wild poliovirus (WPV) infection, though resettling refugees may lack immunity and importation of WPV remains a concern. A cross-sectional survey was performed to determine the prevalence of poliovirus immunity in adult refugees resettling in Boise, Idaho, U.S.A.; immunity was evaluated using two definitions: serotypes 1, 2 and 3 positive, or serotypes 1 and 3 positive. This survey evaluated 795 adult refugees between August 2010 and November 2012. Poliovirus immunity in adults >18 years was 55.3% for serotypes 1, 2 and 3 combined, and 60% for serotypes 1 and 3 only. This study demonstrated a WPV immunity rate of refugee population in the United States, reinforcing the need to ensure poliovirus immunity in all newly arrived adult refugees, either by expanding pre-departure immunization or by screening for immunity at resettlement and vaccinating when indicated. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Increased susceptibility to fundus camera-delivered light-induced retinal degeneration in mice deficient in oxidative stress response proteins.

    Science.gov (United States)

    Ding, Yi; Aredo, Bogale; Zhong, Xin; Zhao, Cynthia X; Ufret-Vincenty, Rafael L

    2017-06-01

    Oxidative stress is an important contributor to the pathogenesis of many retinal diseases including age-related macular degeneration and retinal dystrophies. Light-induced retinal degeneration (LIRD) can serve as a model in which to study the response of the retina to stress. Of note, many genetic mutant mice are in a C57BL/6 J background and are thus resistant to the usual LIRD models. We recently developed a new model of fundus camera-delivered light-induced retinal degeneration (FCD-LIRD) which is effective in strains of mice expressing the light-resistant variant of RPE65 (450Met), including C57BL/6 J. In this work we investigated whether FCD-LIRD would be useful as a model in which to test the effect of genetic mutations on the response of the retina to stress. Furthermore, we tested whether oxidative stress plays an important role in the setting of this new FCD-LIRD model. FCD-LIRD was applied to C57BL/6 J mice and to mice simultaneously deficient in three proteins that are important in the response of the retina to oxidative stress (SOD1, DJ-1 and Parkin). Using fundus photography, we found that retinal damage was dramatically increased in the SOD1/DJ-1/Parkin deficient mice compared to C57BL/6 J. Outer retinal OCT volume and RPE cell morphology analysis in ZO-1-stained flat mounts added support to these findings. Gene expression analysis confirmed a strong oxidative stress response after FCD-LIRD, which was differentially altered in the SOD1/DJ1/Parkin deficient mice. We conclude that FCD-LIRD is useful to study the effect of genetic mutations on the response of the retina to light stress in light-resistant strains of mice. Furthermore, oxidative stress seems to be an important component of FCD-LIRD. Finally, we have established protocols to quantify the effect of FCD-LIRD on the retina and RPE which will be useful for future studies. Further dissection of the mechanisms by which the retina responds to light-induced oxidative stress may result in new

  16. DNA repair in the c-myc proto-oncogene locus: Possible involvement in susceptibility or resistance to plasmacytoma induction in BALB/c mice

    Energy Technology Data Exchange (ETDEWEB)

    Beecham, E.J.; Mushinski, J.F.; Shacter, E.; Potter, M.; Bohr, V.A. (Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, MD (USA))

    1991-06-01

    This report describes an unexpected difference in the efficiency of removal of UV-induced DNA damage in the c-myc locus in splenic B lymphoblasts from two inbred strains of mice. In cells from plasmacytoma-resistant DBA/2N mice, 35% of UV-induced damage in the regulatory and 5{prime} flank of c-myc is removed by 12 h. However, in cells from plasmacytoma-susceptible BALB/cAn mice, damage is not removed from this region. In the protein-encoding region and 3{prime} flank of c-myc as well as in two dihydrofolate reductase gene fragments, UV damage is repaired with similar efficiency in B lymphoblasts from both strains of mice. Furthermore, in the protein-encoding portion and 3{prime} flank of c-myc, damage is selectively removed from only the transcribed strand. No repair is detected in the nontranscribed strand. In contrast, DNA repair in the 5{prime} flank of c-myc is not strand specific; in DNA from DBA/2N cells, UV damage is rapidly removed from both the transcribed and nontranscribed strands. In BALB/cAn cells no repair was detected in either strand in the 5'flank, consistent with the results with double-stranded, nick-translated probes to this region of c-myc. In addition to the repair studies, we have detected post-UV-damage formation: in most of the genes studied, we find that additional T4 endonuclease-sensitive sites are formed in the DNA 2 h after irradiation. Our findings provide new insights into the details of gene-specific and strand-specific DNA repair and suggest that there may be close links between DNA repair and B-cell neoplastic development.

  17. A RT-PCR method for selective amplification and phenotypic characterization of all three serotypes of Sabin-related polioviruses from viral mixtures

    Directory of Open Access Journals (Sweden)

    Eliane Veiga da Costa

    2012-08-01

    Full Text Available Outbreaks caused by vaccine-derived polioviruses are challenging the final eradication of paralytic poliomyelitis. Therefore, the surveillance of the acute flaccid paralysis cases based on poliovirus isolation and characterization remains an essential activity. Due to the use of trivalent oral poliovirus vaccine (OPV, mixtures containing more than one serotype of Sabin-related polioviruses are frequently isolated from clinical samples. Because each poliovirus isolate needs to be individually analyzed, we designed polymerase chain reaction primers that can selectively distinguish and amplify a genomic segment of the three Sabin-related poliovirus serotypes present in mixtures, thus, optimizing the diagnosis and providing prompt information to support epidemiologic actions.

  18. Postpolio syndrome: poliovirus persistence is involved in the pathogenesis.

    Science.gov (United States)

    Julien, J; Leparc-Goffart, I; Lina, B; Fuchs, F; Foray, S; Janatova, I; Aymard, M; Kopecka, H

    1999-06-01

    The pathogenesis of the postpolio syndrome (PPS) remains unclear. In this study we looked for poliovirus (PV) persistence in the CSF of 20 patients with PPS, in a control group including 20 patients with unrelated neurological diseases, and in 7 patients with stable poliomyelitis sequelae. CSF samples and sera were examined using reverse transcriptase-polymerase chain reaction (RT-PCR) for the detection of PV or other enterovirus genomes; this assay allows the detection from as little as 1 fg viral RNA. Sequencing of amplified products from 5 patients was performed. PV genomic sequences were detected in the CSF of 11 of 20 patients with PPS and in none of the control group. Sequencing in the 5' untranslated region confirmed the presence of mutated PV sequences. These findings suggest that PPS is related to the persistence of PV in the central nervous system.

  19. Use of Doehlert matrices for study of poliovirus-1 adsorption.

    Science.gov (United States)

    Quignon, F; Huyard, A; Schwartzbrod, L; Thomas, F

    1997-10-01

    Experiments designed according to Doehlert matrices were carried out to study poliovirus-1 adsorption to Na-montmorillonite in a complex aqueous environment. Salt concentration and valence, virus load, clay concentration, and organic matter concentration were included in the design as selected parameters for possible or known involvement in viral adsorption in environmental waters. Use of this experimental design not only allowed to detect and quantify direct influence of the tested parameters upon the viral response, but also to reveal the influence of interactions between these tested factors. Thus, beyond the reassessment of the higher efficiency of multivalent cations on virus adsorption, as opposed to monovalent ones, detection was enabled of a tannic acid/aluminium specific interaction that seemed to be responsible for the nonavailability of these elements for interaction with viruses. Such a statistical tool allows for a gain in experimental accuracy beyond technical improvements and is particularly suited for low-cost study of multifactorial phenomena.

  20. Poliovirus Studies during the Endgame of the Polio Eradication Program.

    Science.gov (United States)

    Arita, Minetaro

    2017-01-24

    Since the beginning of Global Polio Eradication Initiative in 1988, poliomyelitis cases caused by wild poliovirus (PV) have been drastically reduced, with only 74 cases reported in 2 endemic countries in 2015. The current limited PV transmission suggests that we are in the endgame of the polio eradication program. However, specific challenges have emerged in the endgame, including tight budget, switching of the vaccines, and changes in biorisk management of PV. To overcome these challenges, several PV studies have been implemented in the eradication program. Some of the responses to the emerging challenges in the polio endgame might be valuable in other infectious diseases eradication programs. Here, I will review challenges that confront the polio eradication program and current research to address these challenges.

  1. Poliovirus proteinase 2A induces cleavage of eucaryotic initiation factor 4F polypeptide p220.

    Science.gov (United States)

    Kräusslich, H G; Nicklin, M J; Toyoda, H; Etchison, D; Wimmer, E

    1987-01-01

    Poliovirus infection of HeLa cells induces rapid shutoff of host protein synthesis, whereas translation of poliovirus RNA is not inhibited. It is presumed that shutoff is the result of proteolytic cleavage of component p220 of eucaryotic initiation factor 4F. To study whether poliovirus proteinase 2A is involved in this cleavage, we translated synthetic RNAs that contained the coding region for poliovirus-specific polypeptides P1 and 2A in vitro and assayed for cleavage of p220. We report here that cleavage of p220 occurred in all cases when active proteinase 2A was translated and that disruption of the coding sequence of 2A by linker insertion or deletion prevented processing of p220 in vitro. Activity of 2A was determined by its ability to cleave at the P1-P2 site of a segment of the poliovirus polyprotein. We also constructed a plasmid in which the 3'-most 500 nucleotides of the nontranslated region of encephalomyocarditis virus were linked to the coding sequence for poliovirus polypeptide 2A. Translation of the RNA transcript of this clone was very efficient and yielded a fusion protein that included 2A; this polypeptide also induced cleavage of p220. In vitro translation in the presence of antibodies against 2A specifically inhibited processing of p220, whereas incubation of in vitro translation products with antibodies against 2A after translation was completed did not prevent proteolysis of p220. Images PMID:3039165

  2. Air pollution-mediated susceptibility to inflammation and insulin resistance: influence of CCR2 pathways in mice.

    Science.gov (United States)

    Liu, Cuiqing; Xu, Xiaohua; Bai, Yuntao; Wang, Tse-Yao; Rao, Xiaoquan; Wang, Aixia; Sun, Lixian; Ying, Zhekang; Gushchina, Liubov; Maiseyeu, Andrei; Morishita, Masako; Sun, Qinghua; Harkema, Jack R; Rajagopalan, Sanjay

    2014-01-01

    Epidemiologic and experimental studies support an association between PM2.5 exposure and insulin resistance (IR). Innate immune cell activation has been suggested to play a role in the pathogenesis of these effects. We sought to evaluate the role of CC-chemokine receptor 2 (CCR2) in PM2.5-mediated inflammation and IR. Wild-type C57BL/6 and CCR2-/- male mice were fed a high-fat diet and exposed to either concentrated ambient PM2.5 or filtered air for 17 weeks via a whole-body exposure system. We evaluated glucose tolerance and insulin sensitivity. At euthanasia, blood, spleen, and visceral adipose tissue (VAT) were collected, and inflammatory cells were measured using flow cytometry. We used standard immunoblots, immunohistochemical methods, and quantitative PCR (polymerase chain reaction) to assess pathways of interest involving insulin signaling, inflammation, and lipid and glucose metabolism in various organs. Vascular function was assessed using myography. PM2.5 exposure resulted in whole-body IR and increased hepatic lipid accumulation in the liver, which was attenuated in CCR2-/- mice by inhibiting SREBP1c-mediated transcriptional programming, decreasing fatty acid uptake, and suppressing p38 MAPK activity. Abnormal phosphorylation levels of AKT, AMPK in VAT, and adipose tissue macrophage content in wild-type mice were not present in CCR2-/- mice. However, the impaired whole-body glucose tolerance and reduced GLUT-4 in skeletal muscle in response to PM2.5 was not corrected by CCR2 deficiency. PM2.5 mediates IR by regulating VAT inflammation, hepatic lipid metabolism, and glucose utilization in skeletal muscle via both CCR2-dependent and -independent pathways. These findings provide new mechanistic links between air pollution and metabolic abnormalities underlying IR.

  3. 17-β Estradiol reduces atherosclerosis without exacerbating lupus in ovariectomized systemic lupus erythematosus-susceptible LDLr−/− mice

    Science.gov (United States)

    Shelton, KA; Cline, JM; Cann, JA

    2013-01-01

    Objective To test the hypothesis that estrogen treatment in a radiation chimera mouse model of systemic lupus erythematosus (SLE) and atherosclerosis will increase SLE-associated atherosclerosis by increasing autoantibody production and inflammation. Methods We used a radiation chimera mouse model in which bone marrow from the polygenic B6.Sle1.2.3 model of SLE was transferred to the low density lipoprotein receptor knock out (LDLr−/−) model of atherosclerosis on a C57BL/6 background (Sle/LDLr−/−). Ovariectomized chimeric mice were treated for 10 weeks with either 5.6 ug/day of 17β-estradiol or placebo; outcomes included atherosclerosis plaque size, anti-dsDNA autoantibody production and renal pathology. Results Mean atherosclerosis plaque size was 67.4 ± 7.6% smaller in the estrogen treated group (patherosclerosis lesion size and either the renal histology score or UP:UC ratio in Sle/LDLr−/− mice. Conclusion These results indicate that 17β-estradiol is atheroprotective within the context of murine SLE independent of changes in serum cholesterol concentration, autoantibody concentration, or renal pathology. The SLE phenotype in Sle/LDLr−/− mice is not exacerbated by exogenous 17β-estradiol administration, and the reduced UP:UC ratio suggests a protective effect against lupus nephritis. PMID:23395521

  4. 17-β Estradiol reduces atherosclerosis without exacerbating lupus in ovariectomized systemic lupus erythematosus-susceptible LDLr(-/-) mice.

    Science.gov (United States)

    Shelton, K A; Cline, J M; Cann, J A

    2013-04-01

    To test the hypothesis that estrogen treatment in a radiation chimera mouse model of systemic lupus erythematosus (SLE) and atherosclerosis will increase SLE-associated atherosclerosis by increasing autoantibody production and inflammation. We used a radiation chimera mouse model in which bone marrow from the polygenic B6.Sle1.2.3 model of SLE was transferred to the low density lipoprotein receptor knock out (LDLr(-/-)) model of atherosclerosis on a C57BL/6 background (Sle/LDLr(-/-)). Ovariectomized chimeric mice were treated for 10 weeks with either 5.6 μg/day of 17β-estradiol or placebo; outcomes included atherosclerosis plaque size, anti-dsDNA autoantibody production and renal pathology. Mean atherosclerosis plaque size was 67.4 ± 7.6% smaller in the estrogen treated group (p atherosclerosis lesion size and either the renal histology score or UP:UC ratio in Sle/LDLr(-/-) mice. These results indicate that 17β-estradiol is atheroprotective within the context of murine SLE independent of changes in serum cholesterol concentration, autoantibody concentration, or renal pathology. The SLE phenotype in Sle/LDLr(-/-) mice is not exacerbated by exogenous 17β-estradiol administration, and the reduced UP:UC ratio suggests a protective effect against lupus nephritis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  5. RNAseq expression analysis of resistant and susceptible mice after influenza A virus infection identifies novel genes associated with virus replication and important for host resistance to infection.

    Science.gov (United States)

    Wilk, Esther; Pandey, Ashutosh K; Leist, Sarah Rebecca; Hatesuer, Bastian; Preusse, Matthias; Pommerenke, Claudia; Wang, Junxi; Schughart, Klaus

    2015-09-02

    The host response to influenza A infections is strongly influenced by host genetic factors. Animal models of genetically diverse mouse strains are well suited to identify host genes involved in severe pathology, viral replication and immune responses. Here, we have utilized a dual RNAseq approach that allowed us to investigate both viral and host gene expression in the same individual mouse after H1N1 infection. We performed a detailed expression analysis to identify (i) correlations between changes in expression of host and virus genes, (ii) host genes involved in viral replication, and (iii) genes showing differential expression between two mouse strains that strongly differ in resistance to influenza infections. These genes may be key players involved in regulating the differences in pathogenesis and host defense mechanisms after influenza A infections. Expression levels of influenza segments correlated well with the viral load and may thus be used as surrogates for conventional viral load measurements. Furthermore, we investigated the functional role of two genes, Reg3g and Irf7, in knock-out mice and found that deletion of the Irf7 gene renders the host highly susceptible to H1N1 infection. Using RNAseq analysis we identified novel genes important for viral replication or the host defense. This study adds further important knowledge to host-pathogen-interactions and suggests additional candidates that are crucial for host susceptibility or survival during influenza A infections.

  6. Serologic response to inactivated poliovirus vaccine: a randomized clinical trial comparing 2 vaccination schedules in Puerto Rico.

    Science.gov (United States)

    Dayan, Gustavo H; Thorley, Margaret; Yamamura, Yasuhiro; Rodríguez, Nayra; McLaughlin, Steve; Torres, Lourdes M; Seda, Antonio; Carbia, Marcia; Alexander, Lorraine N; Caceres, Victor; Pallansch, Mark A

    2007-01-01

    The World Health Organization (WHO) recommends the discontinuation of oral poliovirus vaccine after eradication of wild poliovirus. Studies assessing inactivated poliovirus vaccine (IPV) immunogenicity in tropical countries, using the WHO Expanded Programme on Immunization (EPI) schedule, have been limited. We conducted a randomized clinical trial in Ponce, Puerto Rico. Infants were assigned to 1 of 2 study arms: those in the EPI arm received IPV at 6, 10, and 14 weeks of age, and those in the US arm received IPV at 2, 4, and 6 months of age. Neutralizing antibody titers against poliovirus types 1, 2, and 3 were tested on serum specimens obtained before administration of the first dose of IPV and 28-45 days after administration of the last dose of IPV. Seroconversion rates for the EPI (n=225) and US (n=230) arms, respectively, were 85.8% and 99.6% for poliovirus type 1 (P<.001), 86.2% and 100% for poliovirus type 2 (P<.001), and 96.9% and 99.1% for poliovirus type 3 (P=.08). Seroconversion rates were lower among infants in the EPI arm who had high maternal antibody levels for all 3 poliovirus types (P<.001). The EPI schedule resulted in lower seroconversion rates for poliovirus types 1 and 2. These results are relevant for tropical countries planning to use IPV in a posteradication environment.

  7. Genetic Susceptibility to Chronic Hepatitis Is Inherited Codominantly in Helicobacter hepaticus-Infected AB6F1 and B6AF1 Hybrid Male Mice, and Progression to Hepatocellular Carcinoma Is Linked to Hepatic Expression of Lipogenic Genes and Immune Function-Associated Networks▿ †

    OpenAIRE

    García, Alexis; Ihrig, Melanie M.; Rebecca C Fry; Feng, Yan; Xu, Sandy; Boutin, Samuel R.; Rogers, Arlin B.; Muthupalani, Suresh; Samson, Leona D.; Fox, James G.

    2008-01-01

    Helicobacter hepaticus causes hepatitis in susceptible strains of mice. Previous studies indicated that A/JCr mice are susceptible and C57BL/6NCr mice are resistant to H. hepaticus-induced hepatitis. We used F1 hybrid mice derived from A/J and C57BL/6 matings to investigate their phenotype and determine their hepatic gene expression profile in response to H. hepaticus infection. F1 hybrid mice, as well as parental A/J and C57BL/6 mice, were divided equally into control and H. hepaticus-infect...

  8. The Intrauterine and Nursing Period Is a Window of Susceptibility for Development of Obesity and Intestinal Tumorigenesis by a High Fat Diet in Min/+ Mice as Adults

    Science.gov (United States)

    Ngo, Ha Thi; Hetland, Ragna Bogen; Steffensen, Inger-Lise

    2015-01-01

    We studied how obesogenic conditions during various life periods affected obesity and intestinal tumorigenesis in adult C57BL/6J-Min (multiple intestinal neoplasia)/+ mice. The mice were given a 10% fat diet throughout life (negative control) or a 45% fat diet in utero, during nursing, during both in utero and nursing, during adult life, or during their whole life-span, and terminated at 11 weeks for tumorigenesis (Min/+) or 23 weeks for obesogenic effect (wild-type). Body weight at 11 weeks was increased after a 45% fat diet during nursing, during both in utero and nursing, and throughout life, but had normalized at 23 weeks. In the glucose tolerance test, the early exposure to a 45% fat diet in utero, during nursing, or during both in utero and nursing, did not affect blood glucose, whereas a 45% fat diet given to adults or throughout life did. However, a 45% fat diet during nursing or during in utero and nursing increased the number of small intestinal tumors. So did exposures to a 45% fat diet in adult life or throughout life, but without increasing the tumor numbers further. The intrauterine and nursing period is a window of susceptibility for dietary fat-induced obesity and intestinal tumor development. PMID:25874125

  9. Host Susceptibility to Brucella abortus Infection Is More Pronounced in IFN-γ knockout than IL-12/β2-Microglobulin Double-Deficient Mice

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    Ana Paula M. S. Brandão

    2012-01-01

    Full Text Available Brucella abortus is a facultative intracellular bacterial pathogen that causes abortion in domestic animals and undulant fever in humans. IFN-γ, IL-12, and CD8+ T lymphocytes are important components of host immune responses against B. abortus. Herein, IFN-γ and IL-12/β2-microglobulin (β2-m knockout mice were used to determine whether CD8+ T cells and IL-12-dependent IFN-γ deficiency would be more critical to control B. abortus infection compared to the lack of endogenous IFN-γ. At 1 week after infection, IFN-γ KO and IL-12/β2-m KO mice showed increased numbers of bacterial load in spleens; however, at 3 weeks postinfection (p.i., only IFN-γ KO succumbed to Brucella. All IFN-γ KO had died at 16 days p.i. whereas death within the IL-12/β2-m KO group was delayed and occurred at 32 days until 47 days postinfection. Susceptibility of IL-12/β2-m KO animals to Brucella was associated to undetectable levels of IFN-γ in mouse splenocytes and inability of these cells to lyse Brucella-infected macrophages. However, the lack of endogenous IFN-γ was found to be more important to control brucellosis than CD8+ T cells and IL-12-dependent IFN-γ deficiencies.

  10. The Intrauterine and Nursing Period Is a Window of Susceptibility for Development of Obesity and Intestinal Tumorigenesis by a High Fat Diet in Min/+ Mice as Adults

    Directory of Open Access Journals (Sweden)

    Ha Thi Ngo

    2015-01-01

    Full Text Available We studied how obesogenic conditions during various life periods affected obesity and intestinal tumorigenesis in adult C57BL/6J-Min (multiple intestinal neoplasia/+ mice. The mice were given a 10% fat diet throughout life (negative control or a 45% fat diet in utero, during nursing, during both in utero and nursing, during adult life, or during their whole life-span, and terminated at 11 weeks for tumorigenesis (Min/+ or 23 weeks for obesogenic effect (wild-type. Body weight at 11 weeks was increased after a 45% fat diet during nursing, during both in utero and nursing, and throughout life, but had normalized at 23 weeks. In the glucose tolerance test, the early exposure to a 45% fat diet in utero, during nursing, or during both in utero and nursing, did not affect blood glucose, whereas a 45% fat diet given to adults or throughout life did. However, a 45% fat diet during nursing or during in utero and nursing increased the number of small intestinal tumors. So did exposures to a 45% fat diet in adult life or throughout life, but without increasing the tumor numbers further. The intrauterine and nursing period is a window of susceptibility for dietary fat-induced obesity and intestinal tumor development.

  11. Enhanced susceptibility of ovaries from obese mice to 7,12-dimethylbenz[a]anthracene-induced DNA damage

    Energy Technology Data Exchange (ETDEWEB)

    Ganesan, Shanthi, E-mail: shanthig@iastate.edu; Nteeba, Jackson, E-mail: nteeba@iastate.edu; Keating, Aileen F., E-mail: akeating@iastate.edu

    2014-12-01

    7,12-Dimethylbenz[a]anthracene (DMBA) depletes ovarian follicles and induces DNA damage in extra-ovarian tissues, thus, we investigated ovarian DMBA-induced DNA damage. Additionally, since obesity is associated with increased offspring birth defect incidence, we hypothesized that a DMBA-induced DNA damage response (DDR) is compromised in ovaries from obese females. Wild type (lean) non agouti (a/a) and KK.Cg-Ay/J heterozygote (obese) mice were dosed with sesame oil or DMBA (1 mg/kg; intraperitoneal injection) at 18 weeks of age, for 14 days. Total ovarian RNA and protein were isolated and abundance of Ataxia telangiectasia mutated (Atm), X-ray repair complementing defective repair in Chinese hamster cells 6 (Xrcc6), breast cancer type 1 (Brca1), Rad 51 homolog (Rad51), poly [ADP-ribose] polymerase 1 (Parp1) and protein kinase, DNA-activated, catalytic polypeptide (Prkdc) were quantified by RT-PCR or Western blot. Phosphorylated histone H2AX (γH2AX) level was determined by Western blotting. Obesity decreased (P < 0.05) basal protein abundance of PRKDC and BRCA1 proteins but increased (P < 0.05) γH2AX and PARP1 proteins. Ovarian ATM, XRCC6, PRKDC, RAD51 and PARP1 proteins were increased (P < 0.05) by DMBA exposure in lean mice. A blunted DMBA-induced increase (P < 0.05) in XRCC6, PRKDC, RAD51 and BRCA1 was observed in ovaries from obese mice, relative to lean counterparts. Taken together, DMBA exposure induced γH2AX as well as the ovarian DDR, supporting that DMBA causes ovarian DNA damage. Additionally, ovarian DDR was partially attenuated in obese females raising concern that obesity may be an additive factor during chemical-induced ovotoxicity. - Highlights: • DMBA induces markers of ovarian DNA damage. • Obesity induces low level ovarian DNA damage. • DMBA-induced DNA repair response is altered by obesity.

  12. Loss of the interferon-γ-inducible regulatory immunity-related GTPase (IRG), Irgm1, causes activation of effector IRG proteins on lysosomes, damaging lysosomal function and predicting the dramatic susceptibility of Irgm1-deficient mice to infection

    NARCIS (Netherlands)

    Maric-Biresev, Jelena; Hunn, Julia P; Krut, Oleg; Helms, J Bernd; Martens, Sascha; Howard, Jonathan C

    2016-01-01

    BACKGROUND: The interferon-γ (IFN-γ)-inducible immunity-related GTPase (IRG), Irgm1, plays an essential role in restraining activation of the IRG pathogen resistance system. However, the loss of Irgm1 in mice also causes a dramatic but unexplained susceptibility phenotype upon infection with a

  13. World Health Organization Guidelines for Containment of Poliovirus Following Type-Specific Polio Eradication - Worldwide, 2015.

    Science.gov (United States)

    Previsani, Nicoletta; Tangermann, Rudolph H; Tallis, Graham; Jafari, Hamid S

    2015-08-28

    In 1988, the World Health Assembly of the World Health Organization (WHO) resolved to eradicate polio worldwide. Among the three wild poliovirus (WPV) types (type 1, type 2, and type 3), WPV type 2 (WPV2) has been eliminated in the wild since 1999, and WPV type 3 (WPV3) has not been reported since 2012. In 2015, only Afghanistan and Pakistan have reported WPV transmission. On May 25, 2015, all WHO Member States endorsed World Health Assembly resolution 68.3 on full implementation of the Polio Eradication and Endgame Strategic Plan 2013-2018 (the Endgame Plan), and with it, the third Global Action Plan to minimize poliovirus facility-associated risk (GAPIII). All WHO Member States have committed to implementing appropriate containment of WPV2 in essential laboratory and vaccine production facilities* by the end of 2015 and of type 2 oral poliovirus vaccine (OPV2) within 3 months of global withdrawal of OPV2, which is planned for April 2016. This report summarizes critical steps for essential laboratory and vaccine production facilities that intend to retain materials confirmed to contain or potentially containing type-specific WPV, vaccine-derived poliovirus (VDPV), or OPV/Sabin viruses, and steps for nonessential facilities† that process specimens that contain or might contain polioviruses. National authorities will need to certify that the essential facilities they host meet the containment requirements described in GAPIII. After certification of WPV eradication, the use of all OPV will cease; final containment of all polioviruses after polio eradication and OPV cessation will minimize the risk for reintroduction of poliovirus into a polio-free world.

  14. Fecal transplantation does not transfer either susceptibility or resistance to food borne listeriosis in C57BL/6 and BALB/c/By mice [v1; ref status: indexed, http://f1000r.es/1jt

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    Tanya Myers-Morales

    2013-08-01

    Full Text Available The composition of the intestinal microbiota has wide reaching effects on the health of an individual, including the development of protective innate immune responses.  In this report, a fecal transplantation approach was used to determine whether resistance to food borne listeriosis was dependent on the murine gut microbiota.  Transplantation of BALB/c/By feces did not increase the susceptibility of C57BL/6 mice to Listeria monocytogenes infection.   Likewise, transplantation of C57BL/6 fecal matter did not enhance the resistance of BALB/c/By mice.  Thus, intestinal microbiota composition is not a key factor that confers either susceptibility or resistance to food borne listeriosis in mice.

  15. Positional cloning of "Lisch-Like", a candidate modifier of susceptibility to type 2 diabetes in mice.

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    Marija Dokmanovic-Chouinard

    2008-07-01

    Full Text Available In 404 Lep(ob/ob F2 progeny of a C57BL/6J (B6 x DBA/2J (DBA intercross, we mapped a DBA-related quantitative trait locus (QTL to distal Chr1 at 169.6 Mb, centered about D1Mit110, for diabetes-related phenotypes that included blood glucose, HbA1c, and pancreatic islet histology. The interval was refined to 1.8 Mb in a series of B6.DBA congenic/subcongenic lines also segregating for Lep(ob. The phenotypes of B6.DBA congenic mice include reduced beta-cell replication rates accompanied by reduced beta-cell mass, reduced insulin/glucose ratio in blood, reduced glucose tolerance, and persistent mild hypoinsulinemic hyperglycemia. Nucleotide sequence and expression analysis of 14 genes in this interval identified a predicted gene that we have designated "Lisch-like" (Ll as the most likely candidate. The gene spans 62.7 kb on Chr1qH2.3, encoding a 10-exon, 646-amino acid polypeptide, homologous to Lsr on Chr7qB1 and to Ildr1 on Chr16qB3. The largest isoform of Ll is predicted to be a transmembrane molecule with an immunoglobulin-like extracellular domain and a serine/threonine-rich intracellular domain that contains a 14-3-3 binding domain. Morpholino knockdown of the zebrafish paralog of Ll resulted in a generalized delay in endodermal development in the gut region and dispersion of insulin-positive cells. Mice segregating for an ENU-induced null allele of Ll have phenotypes comparable to the B.D congenic lines. The human ortholog, C1orf32, is in the middle of a 30-Mb region of Chr1q23-25 that has been repeatedly associated with type 2 diabetes.

  16. Development of an enzyme immunoassay for poliovirus antigens

    Directory of Open Access Journals (Sweden)

    Newton Hashimoto

    2007-01-01

    Full Text Available An indirect solid-phase enzyme immunoassay (EIA was developed for the detection of poliovirus antigen. Virus antigen was obtained in LLC-MK2 cell cultures and used to prepare antibodies in rabbit and guinea pig. Antibodies were evaluated by double immunodiffusion and neutralization test. Optimal concentrations of guinea pig and rabbit immunoglobulins were determined by checkerboard titration. Microtitre plates were coated with 15.0 µg/ml guinea pig anti-polio immunoglobulin and rabbit anti-polio immunoglobulin at the concentration of 7.94 µg/ml was used as detecting antibody. The standard curve with eight different antigen concentrations in eight replicates resulted in a coefficient of variation (CV between 2.1% to 7.8%. The dose-response relationship was determined by simple linear regression with a coefficient of correlation (R² equal to 96.4%. The assay detected a minimum of 2.3 µg/ml poliovirus antigen.O trabalho apresenta o desenvolvimento de um ensaio imunoenzimático indireto para a detecção de antígeno de poliovírus. O antígeno viral foi obtido em cultura de células LLC-MK2 e usado para imunização de coelho e cobaia. Os soros hiperimunes foram avaliados por imunodifusão dupla e teste de neutralização. Após padronização, o soro de captura, produzido em cobaia, foi usado na concentração protéica de 15.0 µg/ml para sensibilizar microplacas de poliestireno e o soro de coelho (detector foi usado na concentração de 7.94 µg/ml. A curva padrão resultante da utilização de oito diferentes concentrações do antígeno padrão definiu um coeficiente de variação de 2.1% a 7.8%. A relação dose-resposta foi determinada por regressão linear simples com o estabelecimento do coeficiente de correlação (R² igual a 96.4%. O ensaio possibilitou a detecção mínima de 2.3 µg/ml de antígeno de poliovírus.

  17. Preventing Vaccine-Derived Poliovirus Emergence during the Polio Endgame.

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    Margarita Pons-Salort

    2016-07-01

    Full Text Available Reversion and spread of vaccine-derived poliovirus (VDPV to cause outbreaks of poliomyelitis is a rare outcome resulting from immunisation with the live-attenuated oral poliovirus vaccines (OPVs. Global withdrawal of all three OPV serotypes is therefore a key objective of the polio endgame strategic plan, starting with serotype 2 (OPV2 in April 2016. Supplementary immunisation activities (SIAs with trivalent OPV (tOPV in advance of this date could mitigate the risks of OPV2 withdrawal by increasing serotype-2 immunity, but may also create new serotype-2 VDPV (VDPV2. Here, we examine the risk factors for VDPV2 emergence and implications for the strategy of tOPV SIAs prior to OPV2 withdrawal. We first developed mathematical models of VDPV2 emergence and spread. We found that in settings with low routine immunisation coverage, the implementation of a single SIA increases the risk of VDPV2 emergence. If routine coverage is 20%, at least 3 SIAs are needed to bring that risk close to zero, and if SIA coverage is low or there are persistently "missed" groups, the risk remains high despite the implementation of multiple SIAs. We then analysed data from Nigeria on the 29 VDPV2 emergences that occurred during 2004-2014. Districts reporting the first case of poliomyelitis associated with a VDPV2 emergence were compared to districts with no VDPV2 emergence in the same 6-month period using conditional logistic regression. In agreement with the model results, the odds of VDPV2 emergence decreased with higher routine immunisation coverage (odds ratio 0.67 for a 10% absolute increase in coverage [95% confidence interval 0.55-0.82]. We also found that the probability of a VDPV2 emergence resulting in poliomyelitis in >1 child was significantly higher in districts with low serotype-2 population immunity. Our results support a strategy of focused tOPV SIAs before OPV2 withdrawal in areas at risk of VDPV2 emergence and in sufficient number to raise population

  18. Preventing Vaccine-Derived Poliovirus Emergence during the Polio Endgame.

    Science.gov (United States)

    Pons-Salort, Margarita; Burns, Cara C; Lyons, Hil; Blake, Isobel M; Jafari, Hamid; Oberste, M Steven; Kew, Olen M; Grassly, Nicholas C

    2016-07-01

    Reversion and spread of vaccine-derived poliovirus (VDPV) to cause outbreaks of poliomyelitis is a rare outcome resulting from immunisation with the live-attenuated oral poliovirus vaccines (OPVs). Global withdrawal of all three OPV serotypes is therefore a key objective of the polio endgame strategic plan, starting with serotype 2 (OPV2) in April 2016. Supplementary immunisation activities (SIAs) with trivalent OPV (tOPV) in advance of this date could mitigate the risks of OPV2 withdrawal by increasing serotype-2 immunity, but may also create new serotype-2 VDPV (VDPV2). Here, we examine the risk factors for VDPV2 emergence and implications for the strategy of tOPV SIAs prior to OPV2 withdrawal. We first developed mathematical models of VDPV2 emergence and spread. We found that in settings with low routine immunisation coverage, the implementation of a single SIA increases the risk of VDPV2 emergence. If routine coverage is 20%, at least 3 SIAs are needed to bring that risk close to zero, and if SIA coverage is low or there are persistently "missed" groups, the risk remains high despite the implementation of multiple SIAs. We then analysed data from Nigeria on the 29 VDPV2 emergences that occurred during 2004-2014. Districts reporting the first case of poliomyelitis associated with a VDPV2 emergence were compared to districts with no VDPV2 emergence in the same 6-month period using conditional logistic regression. In agreement with the model results, the odds of VDPV2 emergence decreased with higher routine immunisation coverage (odds ratio 0.67 for a 10% absolute increase in coverage [95% confidence interval 0.55-0.82]). We also found that the probability of a VDPV2 emergence resulting in poliomyelitis in >1 child was significantly higher in districts with low serotype-2 population immunity. Our results support a strategy of focused tOPV SIAs before OPV2 withdrawal in areas at risk of VDPV2 emergence and in sufficient number to raise population immunity above the

  19. Strongyloides venezuelensis infection susceptibility of seven inbred strains of mice Susceptibilidade de sete linhagens isogênicas de camundongos à infecções por Strongyloides venezuelensis

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    A.F.T. Amarante

    2002-06-01

    Full Text Available A trial was carried out to investigate the susceptibility of seven strains of mice to Strongyloides venezuelensis primary and secondary experimental infections, in order to provide the basis for genetic studies about resistance. Twelve six-week-old male inbred mice of the A/J, BALB/c, CBA/J, C3H/Hepos, C57BL/6, DBA/2 and NIH strains were infected s.c. with 2000 infective larvae. The mean worm counts (± SD in the small intestine six days after infection were, in increasing order: 28 (± 19 in NIH; 647 (± 228 in BALB/c; 709 (± 425 in DBA/2; 731 (± 151 in C3H/Hepos, 801 (± 174 in CBA/J; 1024 (± 267 in C57BL/6 and 1313 (± 483 in A/J. C57BL/6 mice showed the highest fecal egg counts and NIH, the lowest. No eggs in fecal exams or nematodes in small intestines were recovered from animals reinfected 14 days after primary infection. NIH strain was highly resistant to primary infection by S. venezuelensis. The most susceptible of the other six strains appeared to be the C57BL/6 strain which presented a high nematode counting in intestine and the highest egg output.Foi investigada a susceptibilidade de sete linhagens isogênicas de camundongos à infecção experimental, primária e secundária, por Strongyloides venezuelensis a fim de servir de base para estudos genéticos sobre a resistência. Foram utilizados 12 camundongos machos, com seis semanas de idade, das seguintes linhagens isogênicas: A/J, BALB/c, CBA/J, C3H/Hepos, C57BL/6, DBA/2 e NIH. Os animais foram inoculados, via sub-cutânea, com 2000 larvas infectantes. As contagens médias (± desvio padrão de parasitas no intestino delgado dos camundongos seis dias após a infecção, em ordem crescente, foram: 28 (± 19 na linhagem NIH; 647 (± 228 na BALB/c; 709 (± 425 na DBA/2; 731 (± 151 na C3H/Hepos, 801 (± 174 na CBA/J; 1024 (± 267 na C57BL/6 e 1313 (± 483 na A/J. Os camundongos C57BL/6 apresentaram as mais elevadas contagens de ovos de S. venezuelensis por grama de fezes (OPG e os

  20. Gestational ingestion of oxidized frying oil by C57BL/6J mice differentially affects the susceptibility of the male and female offspring to diet-induced obesity in adulthood.

    Science.gov (United States)

    Chuang, Hui-Ching; Huang, Chin-Fang; Chang, Yi-Chun; Lin, Yu-Shun; Chao, Pei-Min

    2013-03-01

    The aim of this study was to investigate whether maternal ingestion of oxidized frying oil (OFO) during pregnancy influences the susceptibility to diet-induced obesity (DIO) of the adult offspring. Pregnant C57BL/6J mice were fed either a control diet [10% fresh soybean oil (SO)] or an OFO-containing diet (10% OFO) throughout the entire gestational period. After parturition, all pups were nursed by SO-fed dams for 3 wk, weaned onto a nonpurified standard diet for 4 wk, and shifted to a high-fat diet (29% butter + 1% SO) for 5 wk. Consequently, 4 groups of offspring were obtained, consisting of the male (m) or female (f) offspring of dams fed the OFO diet (OFO-m and OFO-f) or the SO diet (SO-m and SO-f). At pregnancy d 18, higher amounts (P diets showed that adult OFO-f mice were prone to DIO, whereas adult OFO-m mice were resistant. The adult OFO-m mice also had higher expression of PPARα target genes in the liver and white adipose tissue (WAT) and of thermogenic genes in the WAT than adult SO-m mice, whereas adult OFO-f and SO-f mice did not differ. We conclude that uterine PPARα activation caused by maternal OFO ingestion affects hepatic PPARα activity and adipose thermogenic capacity and contributes to the differential susceptibility to DIO in the male and female offspring in adulthood.

  1. Different effect of proteasome inhibition on vesicular stomatitis virus and poliovirus replication.

    Directory of Open Access Journals (Sweden)

    Nickolay Neznanov

    2008-04-01

    Full Text Available Proteasome activity is an important part of viral replication. In this study, we examined the effect of proteasome inhibitors on the replication of vesicular stomatitis virus (VSV and poliovirus. We found that the proteasome inhibitors significantly suppressed VSV protein synthesis, virus accumulation, and protected infected cells from toxic effect of VSV replication. In contrast, poliovirus replication was delayed, but not diminished in the presence of the proteasome inhibitors MG132 and Bortezomib. We also found that inhibition of proteasomes stimulated stress-related processes, such as accumulation of chaperone hsp70, phosphorylation of eIF2alpha, and overall inhibition of translation. VSV replication was sensitive to this stress with significant decline in replication process. Poliovirus growth was less sensitive with only delay in replication. Inhibition of proteasome activity suppressed cellular and VSV protein synthesis, but did not reduce poliovirus protein synthesis. Protein kinase GCN2 supported the ability of proteasome inhibitors to attenuate general translation and to suppress VSV replication. We propose that different mechanisms of translational initiation by VSV and poliovirus determine their sensitivity to stress induced by the inhibition of proteasomes. To our knowledge, this is the first study that connects the effect of stress induced by proteasome inhibition with the efficiency of viral infection.

  2. Estimated Effect of Inactivated Poliovirus Vaccine Campaigns, Nigeria and Pakistan, January 2014-April 2016.

    Science.gov (United States)

    Shirreff, George; Wadood, Mufti Zubair; Vaz, Rui Gama; Sutter, Roland W; Grassly, Nicholas C

    2017-02-01

    In 2014, inactivated poliovirus vaccine (IPV) campaigns were implemented in Nigeria and Pakistan after clinical trials showed that IPV boosts intestinal immunity in children previously given oral poliovirus vaccine (OPV). We estimated the effect of these campaigns by using surveillance data collected during January 2014-April 2016. In Nigeria, campaigns with IPV and trivalent OPV (tOPV) substantially reduced the incidence of poliomyelitis caused by circulating serotype-2 vaccine-derived poliovirus (incidence rate ratio [IRR] 0.17 for 90 days after vs. 90 days before campaigns, 95% CI 0.04-0.78) and the prevalence of virus in environmental samples (prevalence ratio [PR] 0.16, 95% CI 0.02-1.33). Campaigns with tOPV alone resulted in similar reductions (IRR 0.59, 95% CI 0.18-1.97; PR 0.45, 95% CI 0.21-0.95). In Pakistan, the effect of IPV+tOPV campaigns on wild-type poliovirus was not significant. Results suggest that administration of IPV alongside OPV can decrease poliovirus transmission if high vaccine coverage is achieved.

  3. Detection of vaccine-derived polioviruses in Mexico using environmental surveillance.

    Science.gov (United States)

    Esteves-Jaramillo, Alejandra; Estívariz, Concepción F; Peñaranda, Silvia; Richardson, Vesta L; Reyna, Jesús; Coronel, Diana L; Carrión, Veronica; Landaverde, Jose M; Wassilak, Steven G F; Pérez-Sánchez, Elda E; López-Martínez, Irma; Burns, Cara C; Pallansch, Mark A

    2014-11-01

    Early detection and control of vaccine-derived poliovirus (VDPV) emergences are essential to secure the gains of polio eradication. Serial sewage samples were collected in 4 towns of Mexico before, throughout, and after the May 2010 oral poliovirus vaccine (OPV) mass immunization campaign. Isolation and molecular analysis of polioviruses from sewage specimens monitored the duration of vaccine-related strains in the environment and emergence of vaccine-derived polioviruses in a population partially immunized with inactivated poliovirus vaccine (IPV). Sabin strains were identified up to 5-8 weeks after the campaign in all towns; in Aguascalientes, 1 Sabin 3 was isolated 16 weeks after the campaign, following 7 weeks with no Sabin strains detected. In Tuxtla Gutiérrez, type 2 VDPV was isolated from 4 samples collected before and during the campaign, and type 1 VDPV from 1 sample collected 19 weeks afterward. During 2009-2010, coverage in 4 OPV campaigns conducted averaged only 57% and surveillance for acute flaccid paralysis (AFP) was suboptimal (AFP rate<1 per 100,000 population<15 years of age) in Tuxtla Gutierrez. VDPVs may emerge and spread in settings with inadequate coverage with IPV/OPV vaccination. Environmental surveillance can facilitate early detection in these settings. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  4. Radiation sensitivity of poliovirus, a model for norovirus, inoculated in oyster ( Crassostrea gigas) and culture broth under different conditions

    Science.gov (United States)

    Jung, Pil-Mun; Park, Jae Seok; Park, Jin-Gyu; Park, Jae-Nam; Han, In-Jun; Song, Beom-Seok; Choi, Jong-il; Kim, Jae-Hun; Byun, Myung-Woo; Baek, Min; Chung, Young-Jin; Lee, Ju-Woon

    2009-07-01

    Poliovirus is a recognized surrogate for norovirus, pathogen in water and food, due to the structural and genetic similarity. Although radiation sensitivity of poliovirus in water or media had been reported, there has been no research in food model such as shellfish. In this study, oyster ( Crassostrea gigas) was incubated in artificial seawater contaminated with poliovirus, and thus radiation sensitivity of poliovirus was determined in inoculated oyster. The effects of ionizing radiation on the sensitivity of poliovirus were also evaluated under different conditions such as pH (4-7) and salt concentration (1-15%) in culture broth, and temperature during irradiation. The D10 value of poliovirus in PBS buffer, virus culture broth and oyster was determined to 0.46, 2.84 and 2.94 kGy, respectively. The initial plaque forming unit (PFU) of poliovirus in culture broth was slightly decreased as the decrease of pH and the increase of salt concentration, but radiation sensitivity was not affected by pH and salt contents. However, radiation resistance of poliovirus was increased at frozen state. These results provide the basic information for the inactivation of pathogenic virus in foods by using irradiation.

  5. Radiation sensitivity of poliovirus, a model for norovirus, inoculated in oyster (Crassostrea gigas) and culture broth under different conditions

    Energy Technology Data Exchange (ETDEWEB)

    Jung, Pil-Mun [Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of); Park, Jae Seok [Korea Food and Drug Administration, Seoul 122-704 (Korea, Republic of); Park, Jin-Gyu; Park, Jae-Nam; Han, In-Jun; Song, Beom-Seok; Choi, Jong-il; Kim, Jae-Hun; Byun, Myung-Woo [Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of); Baek, Min [Atomic Energy Policy Division, Ministry of Education, Science and Technology, Gwacheon 427-715 (Korea, Republic of); Chung, Young-Jin [Department of Food and Nutrition, Chungnam National University, Daejeon 305-764 (Korea, Republic of); Lee, Ju-Woon [Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of)], E-mail: sjwlee@kaeri.re.kr

    2009-07-15

    Poliovirus is a recognized surrogate for norovirus, pathogen in water and food, due to the structural and genetic similarity. Although radiation sensitivity of poliovirus in water or media had been reported, there has been no research in food model such as shellfish. In this study, oyster (Crassostrea gigas) was incubated in artificial seawater contaminated with poliovirus, and thus radiation sensitivity of poliovirus was determined in inoculated oyster. The effects of ionizing radiation on the sensitivity of poliovirus were also evaluated under different conditions such as pH (4-7) and salt concentration (1-15%) in culture broth, and temperature during irradiation. The D{sub 10} value of poliovirus in PBS buffer, virus culture broth and oyster was determined to 0.46, 2.84 and 2.94 kGy, respectively. The initial plaque forming unit (PFU) of poliovirus in culture broth was slightly decreased as the decrease of pH and the increase of salt concentration, but radiation sensitivity was not affected by pH and salt contents. However, radiation resistance of poliovirus was increased at frozen state. These results provide the basic information for the inactivation of pathogenic virus in foods by using irradiation.

  6. Three-dimensional structure of poliovirus serotype 1 neutralizing determinants.

    Science.gov (United States)

    Page, G S; Mosser, A G; Hogle, J M; Filman, D J; Rueckert, R R; Chow, M

    1988-01-01

    Antigenic mutants of poliovirus (Sabin strain, serotype 1) were isolated by the resistance of the virus to anti-Sabin neutralizing monoclonal antibodies. The amino acid replacements within the capsid protein sequence causing the altered antigenicity were identified for each of 63 isolates. The mutations cluster into distinct nonoverlapping peptide segments that group into three general immunological phenotypes on the basis of cross-neutralization analyses with 15 neutralizing anti-Sabin monoclonal antibodies. Location of the mutated amino acid residues within the three-dimensional structure of the virion indicates that the majority of these amino acid residues are highly exposed and located within prominent structural features of the viral surface. Those mutated amino acid residues that are less accessible to antibody interaction are often involved in hydrogen bonds or salt bridges that would stabilize the local tertiary structure of the antigenic site. The interactions of the peptide segments that form these neutralizing sites suggest specific models for the generation of neutralization-resistant variants and for the interaction between the viral surface and antibody. Images PMID:2451757

  7. Localization of norovirus and poliovirus in Pacific oysters.

    Science.gov (United States)

    McLeod, C; Hay, B; Grant, C; Greening, G; Day, D

    2009-04-01

    To examine the uptake and tissue distribution of norovirus (NoV) and poliovirus (PV) experimentally bioaccumulated in feeding Pacific oysters (Crassostrea gigas). Pacific oysters were allowed to bioaccumulated either PV or NoV under tidally synchronized feeding conditions in laboratory tanks. Oysters were then either fixed and paraffin wax embedded prior to localizing virus within tissues by immunohistochemistry (IHC), or they were dissected into digestive tract (stomach, intestine and digestive diverticula), gill and labial palp tissues, and the viral load determined by quantitative RT-PCR. Both PV and NoV immunoreactivities were predominantly found in the lumen and within cells of the digestive tract tissues; however, PV was also found within cells of nondigestive tract tissues, and in the gills and labial palp. Quantitative RT-PCR of tissue extracts corroborate the immunohistochemical data in that the major site for virus localization is the gut, but significant amounts of viral RNA were identified in the gills and labial palp. The human enteric viruses, PV and NoV, are readily bioaccumulated by feeding Pacific oysters and that some of the virus is internalized within cells of both digestive and nondigestive tissues. Oysters that have been virally contaminated even after depuration (cleaning) in uncontaminated seawater could pose a human health risk if consumed.

  8. Nitric oxide and superoxide mediate diesel particle effects in cytokine-treated mice and murine lung epithelial cells--implications for susceptibility to traffic-related air pollution.

    Science.gov (United States)

    Manzo, Nicholas D; LaGier, Adriana J; Slade, Ralph; Ledbetter, Allen D; Richards, Judy H; Dye, Janice A

    2012-11-15

    Epidemiologic studies associate childhood exposure to traffic-related air pollution with increased respiratory infections and asthmatic and allergic symptoms. The strongest associations between traffic exposure and negative health impacts are observed in individuals with respiratory inflammation. We hypothesized that interactions between nitric oxide (NO), increased during lung inflammatory responses, and reactive oxygen species (ROS), increased as a consequence of traffic exposure ─ played a key role in the increased susceptibility of these at-risk populations to traffic emissions. Diesel exhaust particles (DEP) were used as surrogates for traffic particles. Murine lung epithelial (LA-4) cells and BALB/c mice were treated with a cytokine mixture (cytomix: TNFα, IL-1β, and IFNγ) to induce a generic inflammatory state. Cells were exposed to saline or DEP (25 μg/cm(2)) and examined for differential effects on redox balance and cytotoxicity. Likewise, mice undergoing nose-only inhalation exposure to air or DEP (2 mg/m(3) × 4 h/d × 2 d) were assessed for differential effects on lung inflammation, injury, antioxidant levels, and phagocyte ROS production. Cytomix treatment significantly increased LA-4 cell NO production though iNOS activation. Cytomix +  DEP-exposed cells incurred the greatest intracellular ROS production, with commensurate cytotoxicity, as these cells were unable to maintain redox balance. By contrast, saline + DEP-exposed cells were able to mount effective antioxidant responses. DEP effects were mediated by: (1) increased ROS including superoxide anion (O(2)(·-)), related to increased xanthine dehydrogenase expression and reduced cytosolic superoxide dismutase activity; and (2) increased peroxynitrite generation related to interaction of O(2)(·-) with cytokine-induced NO. Effects were partially reduced by superoxide dismutase (SOD) supplementation or by blocking iNOS induction. In mice, cytomix +  DEP-exposure resulted in

  9. Nitric oxide and superoxide mediate diesel particle effects in cytokine-treated mice and murine lung epithelial cells — implications for susceptibility to traffic-related air pollution

    Science.gov (United States)

    2012-01-01

    Background Epidemiologic studies associate childhood exposure to traffic-related air pollution with increased respiratory infections and asthmatic and allergic symptoms. The strongest associations between traffic exposure and negative health impacts are observed in individuals with respiratory inflammation. We hypothesized that interactions between nitric oxide (NO), increased during lung inflammatory responses, and reactive oxygen species (ROS), increased as a consequence of traffic exposure ─ played a key role in the increased susceptibility of these at-risk populations to traffic emissions. Methods Diesel exhaust particles (DEP) were used as surrogates for traffic particles. Murine lung epithelial (LA-4) cells and BALB/c mice were treated with a cytokine mixture (cytomix: TNFα, IL-1β, and IFNγ) to induce a generic inflammatory state. Cells were exposed to saline or DEP (25 μg/cm2) and examined for differential effects on redox balance and cytotoxicity. Likewise, mice undergoing nose-only inhalation exposure to air or DEP (2 mg/m3 × 4 h/d × 2 d) were assessed for differential effects on lung inflammation, injury, antioxidant levels, and phagocyte ROS production. Results Cytomix treatment significantly increased LA-4 cell NO production though iNOS activation. Cytomix +  DEP-exposed cells incurred the greatest intracellular ROS production, with commensurate cytotoxicity, as these cells were unable to maintain redox balance. By contrast, saline + DEP-exposed cells were able to mount effective antioxidant responses. DEP effects were mediated by: (1) increased ROS including superoxide anion (O2˙-), related to increased xanthine dehydrogenase expression and reduced cytosolic superoxide dismutase activity; and (2) increased peroxynitrite generation related to interaction of O2˙- with cytokine-induced NO. Effects were partially reduced by superoxide dismutase (SOD) supplementation or by blocking iNOS induction. In mice, cytomix +  DEP

  10. Nitric oxide and superoxide mediate diesel particle effects in cytokine-treated mice and murine lung epithelial cells — implications for susceptibility to traffic-related air pollution

    Directory of Open Access Journals (Sweden)

    Manzo Nicholas D

    2012-11-01

    Full Text Available Abstract Background Epidemiologic studies associate childhood exposure to traffic-related air pollution with increased respiratory infections and asthmatic and allergic symptoms. The strongest associations between traffic exposure and negative health impacts are observed in individuals with respiratory inflammation. We hypothesized that interactions between nitric oxide (NO, increased during lung inflammatory responses, and reactive oxygen species (ROS, increased as a consequence of traffic exposure ─ played a key role in the increased susceptibility of these at-risk populations to traffic emissions. Methods Diesel exhaust particles (DEP were used as surrogates for traffic particles. Murine lung epithelial (LA-4 cells and BALB/c mice were treated with a cytokine mixture (cytomix: TNFα, IL-1β, and IFNγ to induce a generic inflammatory state. Cells were exposed to saline or DEP (25 μg/cm2 and examined for differential effects on redox balance and cytotoxicity. Likewise, mice undergoing nose-only inhalation exposure to air or DEP (2 mg/m3 × 4 h/d × 2 d were assessed for differential effects on lung inflammation, injury, antioxidant levels, and phagocyte ROS production. Results Cytomix treatment significantly increased LA-4 cell NO production though iNOS activation. Cytomix + DEP-exposed cells incurred the greatest intracellular ROS production, with commensurate cytotoxicity, as these cells were unable to maintain redox balance. By contrast, saline + DEP-exposed cells were able to mount effective antioxidant responses. DEP effects were mediated by: (1 increased ROS including superoxide anion (O2˙-, related to increased xanthine dehydrogenase expression and reduced cytosolic superoxide dismutase activity; and (2 increased peroxynitrite generation related to interaction of O2˙- with cytokine-induced NO. Effects were partially reduced by superoxide dismutase (SOD supplementation or by blocking iNOS induction. In mice, cytomix

  11. Modulation of gene expression in a human cell line caused by poliovirus, vaccinia virus and interferon

    Directory of Open Access Journals (Sweden)

    Hoddevik Gunnar

    2007-03-01

    Full Text Available Abstract Background The project was initiated to describe the response of a human embryonic fibroblast cell line to the replication of two different viruses, and, more specifically, to look for candidate genes involved in viral defense. For this purpose, the cells were synchronously infected with poliovirus in the absence or presence of interferon-alpha, or with vaccinia virus, a virus that is not inhibited by interferon. By comparing the changes in transcriptosome due to these different challenges, it should be possible to suggest genes that might be involved in defense. Results The viral titers were sufficient to yield productive infection in a majority of the cells. The cells were harvested in triplicate at various time-points, and the transcriptosome compared with mock infected cells using oligo-based, global 35 k microarrays. While there was very limited similarities in the response to the different viruses, a large proportion of the genes up-regulated by interferon-alpha were also up-regulated by poliovirus. Interferon-alpha inhibited poliovirus replication, but there were no signs of any interferons being induced by poliovirus. The observations suggest that the cells do launch an antiviral response to poliovirus in the absence of interferon. Analyses of the data led to a list of candidate antiviral genes. Functional information was limited, or absent, for most of the candidate genes. Conclusion The data are relevant for our understanding of how the cells respond to poliovirus and vaccinia virus infection. More annotations, and more microarray studies with related viruses, are required in order to narrow the list of putative defence-related genes.

  12. Hybrid proteins between Pseudomonas exotoxin A and poliovirus protease 2Apro.

    Science.gov (United States)

    Novoa, I; Feduchi, E; Carrasco, L

    1994-11-21

    Two hybrid proteins between Pseudomonas aeruginosa exotoxin A (PE) and poliovirus protease 2Apro have been generated. One hybrid protein contains the poliovirus 2Apro sequence replacing the region of PE corresponding to amino acids 413-607. The other hybrid contains in addition the transforming growth factor sequence. The two hybrid proteins were efficiently synthesized in E. coli cells using the inducible pET vectors. Both hybrid toxins cleaved p220 (eIF-4 gamma) when the recombinant plasmids were transfected in COS cells infected with recombinant vaccinia virus bearing the T7 RNA polymerase gene.

  13. Poliovirus infection and expression of the poliovirus protein 2B provoke the disassembly of the Golgi complex, the organelle target for the antipoliovirus drug Ro-090179.

    Science.gov (United States)

    Sandoval, I V; Carrasco, L

    1997-06-01

    Infection of Vero cells with poliovirus results in complete disassembly of the Golgi complex. Milestones of the process of disassembly are the release to the cytosol of the beta-COP bound to Golgi membranes, the disruption of the cis-Golgi network into fragments scattered throughout the cytoplasm, and the disassembly of the stacked cisternae by a process mediated by long tubular structures. Transient expression of the viral protein 2B in COS-7 cells also causes the disassembly of the Golgi complex by a process preceded by the accumulation of the protein in the Golgi area. Vero cells infected for 3 h show no recognizable Golgi complexes at the ultrastructural level and display an enormously swollen endoplasmic reticulum (ER) with extensive areas of its surface heavily coated. Ro-090179 (Ro), a flavonoid isolated from the herb Agastache rugosa, provokes the specific swelling and disruption of the Golgi complex and strongly inhibits poliovirus infection. Ro provokes the swelling and the disruption of the stacked cisternae and trans-Golgi elements without affecting the cis-most Golgi cisternae much. Moreover, Ro inhibits the fusion of the Golgi complex with the ER in cells treated with brefeldin A and provokes the accumulation of the intermediate compartment membrane protein p58 into ERD2-positive Golgi elements but has no effect on the anterograde transport involved in protein secretion. Our results indicate that the secretory pathway and specifically the Golgi complex are preferential targets of poliovirus.

  14. Innovative IPV from attenuated Sabin poliovirus or newly designed alternative seed strains.

    Science.gov (United States)

    Hamidi, Ahd; Bakker, Wilfried A M

    2012-11-01

    This article gives an overview of the patent literature related to innovative inactivated polio vaccine (i-IPV) based on using Sabin poliovirus strains and newly developed alternative recombinant poliovirus strains. This innovative approach for IPV manufacturing is considered to attribute to the requirement for affordable IPV in the post-polio-eradication era, which is on the horizon. Although IPV is a well-established vaccine, the number of patent applications in this field was seen to have significantly increased in the past decade. Currently, regular IPV appears to be too expensive for universal use. Future affordability may be achieved by using alternative cell lines, alternative virus seed strains, improved and optimized processes, dose sparing, or the use of adjuvants. A relatively short-term option to achieve cost-price reduction is to work on regular IPV, using wild-type poliovirus strains, or on Sabin-IPV, based on using attenuated poliovirus strains. This price reduction can be achieved by introducing efficiency in processing. There are also multiple opportunities to work on dose sparing, for example, by using adjuvants or fractional doses. Renewed interest in this field was clearly reflected in the number and diversity of patent applications. In a later stage, several innovative approaches may become even more attractive, for example the use of recombinant virus strains or even a totally synthetic vaccine. Currently, such work is mainly carried out by research institutes and universities and therefore clinical data are not available.

  15. Different virucidal activities of hyperbranched quaternary ammonium coatings on poliovirus and influenza virus

    NARCIS (Netherlands)

    Tuladhar, E.; Koning, de M.C.; Fundeanu, I.; Beumer, R.R.; Duizer, E.

    2012-01-01

    Virucidal activity of immobilized quaternary ammonium compounds (IQACs) coated onto glass and plastic surfaces was tested against enveloped influenza A (H1N1) virus and nonenveloped poliovirus Sabin1. The IQACs tested were virucidal against the influenza virus within 2 min, but no virucidal effect

  16. Prevention of rhinovirus and poliovirus uncoating by WIN 51711, a new antiviral drug.

    Science.gov (United States)

    Fox, M P; Otto, M J; McKinlay, M A

    1986-07-01

    WIN 51711, a potent new antipicornavirus drug, has been shown to inhibit an early event in the replication cycle of human poliovirus type 2 and human rhinovirus type 2. WIN 51711 was not virucidal and had no measurable effect on the adsorption of [3H]uridine-labeled virions to cells. When virion penetration of the plasma membrane was determined through loss of sensitivity to neutralizing antisera, WIN 51711 had no effect on poliovirus penetration, but inhibited rhinovirus penetration by 40%. In the presence of WIN 51711, exposure of neutral red-encapsidated virus-infected cells to light at 3 h postinfection resulted in a 3-log reduction in the number of infectious centers, indicating that WIN 51711 maintained the viral RNA in the encapsidated state after penetrating the cell membrane. The inhibition of uncoating by WIN 51711 in the neutral red assay was found to be concentration dependent, with a concentration of 0.03 micrograms/ml resulting in a 90% inhibition of uncoating. Sucrose gradient sedimentation of lysates from whole cells infected with [3H]uridine-labeled poliovirus showed that poliovirions remained intact in the presence of WIN 51711, but were uncoated in the absence of drug. WIN 51711 also prevented thermal inactivation of poliovirus infectivity, indicating a direct stabilizing effect of this compound on virion capsid conformation.

  17. Solar disinfection of poliovirus and Acanthamoeba polyphaga cysts in water - a laboratory study using simulated sunlight.

    Science.gov (United States)

    Heaselgrave, W; Patel, N; Kilvington, S; Kehoe, S C; McGuigan, K G

    2006-08-01

    To determine the efficacy of solar disinfection (SODIS) in disinfecting water contaminated with poliovirus and Acanthamoeba polyphaga cysts. Organisms were subjected to a simulated global solar irradiance of 850 Wm(-2) in water temperatures between 25 and 55 degrees C. SODIS at 25 degrees C totally inactivated poliovirus after 6-h exposure (reduction of 4.4 log units). No SODIS-induced reduction in A. polyphaga cyst viability was observed for sample temperatures below 45 degrees C. Total cyst inactivation was only observed after 6-h SODIS exposure at 50 degrees C (3.6 log unit reduction) and after 4 h at 55 degrees C (3.3 log unit reduction). SODIS is an effective means of disinfecting water contaminated with poliovirus and A. polyphaga cysts, provided water temperatures of 50-55 degrees C are attained in the latter case. This research presents the first SODIS inactivation curve for poliovirus and provides further evidence that batch SODIS provides effective protection against waterborne protozoan cysts.

  18. [Poliovirus immunology: vaccines, problems for the prevention/eradication and future interventions].

    Science.gov (United States)

    Fernández-Cruz Pérez, Eduardo; Rodríguez-Sainz, Carmen

    2013-01-01

    Polio is a contagious disease that is caused by the poliovirus, an enterovirus in the family Picornaviridae. The virus enters through the oral mucosa and multiplies in epithelial cells of both the oropharynx as the gastrointestinal tract, releasing virus in oropharyngeal secretions and through the stool. The mode of transmission is fecal-oral and/or oral-oral. The virus preferentially infects children under 5 years. Most infections are asymptomatic and self-limiting gastrointestinal tract. Eventually it spreads to the central nervous system and affects the anterior horn motor neurons of the spinal cord causing paralysis and even death. We will describe host-virus interaction and the natural history of infection which depends on many factors, including the type of viral inoculum (serotypes VP1, 2 and 3) and host factors, such as nutritional status, concurrent infections and the ability to induce protective immune responses, such as, humoral anti-viral antibody responses with neutralizing antibodies, mucosal immunity and systemic adaptative immune responses. We will discuss the relevant aspects of the immuno-pathogenesis of the infection by poliovirus and the problems related to the host-virus interactions in the subjects vaccinated, with the latest advances in the strategies to develop optimal protection with the different poliovirus vaccines that could allow the development of a more effective immunization with induction of the effect or mechanisms that would prevent development of the disease, transmission of the virus, out-breaks and eventually the poliovirus eradication.

  19. Alternative splicing, a new target to block cellular gene expression by poliovirus 2A protease

    Energy Technology Data Exchange (ETDEWEB)

    Alvarez, Enrique, E-mail: ealvarez@cbm.uam.es [Centro de Biologia Molecular Severo Ochoa (CSIC-UAM), Nicolas Cabrera, 1 Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid (Spain); Castello, Alfredo; Carrasco, Luis; Izquierdo, Jose M. [Centro de Biologia Molecular Severo Ochoa (CSIC-UAM), Nicolas Cabrera, 1 Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid (Spain)

    2011-10-14

    Highlights: {yields} Novel role for poliovirus 2A protease as splicing modulator. {yields} Poliovirus 2A protease inhibits the alternative splicing of pre-mRNAs. {yields} Poliovirus 2A protease blocks the second catalytic step of splicing. -- Abstract: Viruses have developed multiple strategies to interfere with the gene expression of host cells at different stages to ensure their own survival. Here we report a new role for poliovirus 2A{sup pro} modulating the alternative splicing of pre-mRNAs. Expression of 2A{sup pro} potently inhibits splicing of reporter genes in HeLa cells. Low amounts of 2A{sup pro} abrogate Fas exon 6 skipping, whereas higher levels of protease fully abolish Fas and FGFR2 splicing. In vitro splicing of MINX mRNA using nuclear extracts is also strongly inhibited by 2A{sup pro}, leading to accumulation of the first exon and the lariat product containing the unspliced second exon. These findings reveal that the mechanism of action of 2A{sup pro} on splicing is to selectively block the second catalytic step.

  20. Intratypic differentiation of polioviruses isolated from suspected cases of poliomyelitis in Brazil during the period of 1990 to 1993

    Directory of Open Access Journals (Sweden)

    A. M. B. de Filippis

    1994-12-01

    Full Text Available This study analyzed 3129 fecal samples derived from 1626 patients with sudden onset acute flaccid paralysis clinically compatible with poliomyelitis. The samples were collected in the period ranging from January 1990 to September 1993 in all regions of Brazil. Among the 1626 cases studied, 196 had isolation of poliovirus. Nevertheless, it was observed that some factors influenced the isolation rate and the intratypic characterization of these polioviruses. No cases of acute flaccid paralysis has been found to be etiologically related with wild polioviruses.

  1. Genetics of chemical carcinogenesis--II. Papilloma induction and malignant conversion in susceptible (Car-s) and resistant (Car-R) lines of mice produced by bidirectional selective breeding and in their (Car-S X Car-R) F1 hybrids

    National Research Council Canada - National Science Library

    Pioli, C; Saran, A; Mouton, D; Troiani, C; Doria, G; Covelli, V; Neveu, T; Biozzi, G

    1994-01-01

    Susceptible (Car-S) and resistant (Car-R) lines of mice separated by 10 consecutive generations of bidirectional selective breeding present a very large difference in responsiveness to two-stage skin carcinogenesis...

  2. Five of Five VHHs Neutralizing Poliovirus Bind the Receptor-Binding Site

    Science.gov (United States)

    Strauss, Mike; Schotte, Lise; Thys, Bert; Filman, David J.

    2016-01-01

    ABSTRACT Nanobodies, or VHHs, that recognize poliovirus type 1 have previously been selected and characterized as candidates for antiviral agents or reagents for standardization of vaccine quality control. In this study, we present high-resolution cryo-electron microscopy reconstructions of poliovirus with five neutralizing VHHs. All VHHs bind the capsid in the canyon at sites that extensively overlap the poliovirus receptor-binding site. In contrast, the interaction involves a unique (and surprisingly extensive) surface for each of the five VHHs. Five regions of the capsid were found to participate in binding with all five VHHs. Four of these five regions are known to alter during the expansion of the capsid associated with viral entry. Interestingly, binding of one of the VHHs, PVSS21E, resulted in significant changes of the capsid structure and thus seems to trap the virus in an early stage of expansion. IMPORTANCE We describe the cryo-electron microscopy structures of complexes of five neutralizing VHHs with the Mahoney strain of type 1 poliovirus at resolutions ranging from 3.8 to 6.3Å. All five VHHs bind deep in the virus canyon at similar sites that overlap extensively with the binding site for the receptor (CD155). The binding surfaces on the VHHs are surprisingly extensive, but despite the use of similar binding surfaces on the virus, the binding surface on the VHHs is unique for each VHH. In four of the five complexes, the virus remains essentially unchanged, but for the fifth there are significant changes reminiscent of but smaller in magnitude than the changes associated with cell entry, suggesting that this VHH traps the virus in a previously undescribed early intermediate state. The neutralizing mechanisms of the VHHs and their potential use as quality control agents for the end game of poliovirus eradication are discussed. PMID:26764003

  3. Effects of poliovirus 2A(pro) on vaccinia virus gene expression.

    Science.gov (United States)

    Feduchi, E; Aldabe, R; Novoa, I; Carrasco, L

    1995-12-15

    The effects of transient expression of poliovirus 2A(pro) on p220 cleavage in COS cells have been analyzed. When 2A(pro) was cloned in plasmid pTM1 and transiently expressed in COS cells, efficient cleavage of p220 occurred after infection of these cells with a recombinant vaccinia virus bearing phage T7 RNA polymerase. High numbers of COS cells were transfected with pTM1-2A, as judged by p220 cleavage, thereby allowing an analysis of the effects of poliovirus 2A(pro) on vaccinia virus gene expression. A 40-50% cleavage of p220 by transfected poliovirus 2A(pro) was observed ten hours post infection and cleavage was almost complete (80-90%) 20-25 hours post infection with vaccinia virus. Profound inhibition of vaccinia virus protein synthesis was detectable ten hours post infection and was maximal 20-25 hours post infection. This inhibition resulted from neither a blockade of transcription of vaccinia virus nor a lack of translatability of the mRNAs present in cells that synthesize poliovirus 2A(pro). Addition of ara-C inhibited the replication of vaccinia virus and allowed the continued synthesis of cellular proteins. Under these conditions, 2A(pro) is expressed and blocks cellular translation. Finally, p220 cleavage by 2A(pro) did not inhibit the translation of a mRNA encoding poliovirus protein 2C, as directed by the 5' leader sequences of encephalomiocarditis virus. Therefore, these findings show a correlation between p220 cleavage and inhibition of translation from newly made mRNAs. Our results are discussed in the light of present knowledge of p220 function, and new approaches are considered that might provide further insights into the function(s) of initiation factor eIF-4F.

  4. Bcgitis and vaccine-derived poliovirus infection in a patient with a novel deletion in RAG1 binding site.

    Science.gov (United States)

    Canessa, C; Romano, F; Lippi, F; Bianchi, L; Kashef, S; Rezaei, N; Moriondo, M; Nieddu, F; Martini, M; Azzari, C

    2013-01-01

    A girl who developed severe BCGitis and vaccine-derived poliovirus infection was discovered to have a novel deletion of RAG1. A neonatal screening program for SCID would identify affected infants at birth, before live vaccines are administered.

  5. Prolonged Excretion of Poliovirus among Individuals with Primary Immunodeficiency Disorder: An Analysis of the World Health Organization Registry

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    Grace Macklin

    2017-09-01

    Full Text Available Individuals with primary immunodeficiency disorder may excrete poliovirus for extended periods and will constitute the only remaining reservoir of virus after eradication and withdrawal of oral poliovirus vaccine. Here, we analyzed the epidemiology of prolonged and chronic immunodeficiency-related vaccine-derived poliovirus cases in a registry maintained by the World Health Organization, to identify risk factors and determine the length of excretion. Between 1962 and 2016, there were 101 cases, with 94/101 (93% prolonged excretors and 7/101 (7% chronic excretors. We documented an increase in incidence in recent decades, with a shift toward middle-income countries, and a predominance of poliovirus type 2 in 73/101 (72% cases. The median length of excretion was 1.3 years (95% confidence interval: 1.0, 1.4 and 90% of individuals stopped excreting after 3.7 years. Common variable immunodeficiency syndrome and residence in high-income countries were risk factors for long-term excretion. The changing epidemiology of cases, manifested by the greater incidence in recent decades and a shift to from high- to middle-income countries, highlights the expanding risk of poliovirus transmission after oral poliovirus vaccine cessation. To better quantify and reduce this risk, more sensitive surveillance and effective antiviral therapies are needed.

  6. Effect of buffer on the immune response to trivalent oral poliovirus vaccine in Bangladesh: a community based randomized controlled trial.

    Science.gov (United States)

    Chandir, Subhash; Ahamed, Kabir U; Baqui, Abdullah H; Sutter, Roland W; Okayasu, Hiromasa; Pallansch, Mark A; Oberste, Mark S; Moulton, Lawrence H; Halsey, Neal A

    2014-11-01

    Polio eradication efforts have been hampered by low responses to trivalent oral poliovirus vaccine (tOPV) in some developing countries. Since stomach acidity may neutralize vaccine viruses, we assessed whether administration of a buffer solution could improve the immunogenicity of tOPV. Healthy infants 4-6 weeks old in Sylhet, Bangladesh, were randomized to receive tOPV with or without a sodium bicarbonate and sodium citrate buffer at age 6, 10, and 14 weeks. Levels of serum neutralizing antibodies for poliovirus types 1, 2, and 3 were measured before and after vaccination, at 6 and 18 weeks of age, respectively. Serologic response rates following 3 doses of tOPV for buffer recipients and control infants were 95% and 88% (P=.065), respectively, for type 1 poliovirus; 95% and 97% (P=.543), respectively, for type 2 poliovirus; and 90% and 89% (P=.79), respectively, for type 3 poliovirus. Administration of a buffer solution prior to vaccination was not associated with statistically significant increases in the immune response to tOPV; however, a marginal 7% increase (P=.065) in serologic response to poliovirus type 1 was observed. NCT01579825. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  7. Nectin-like interactions between poliovirus and its receptor trigger conformational changes associated with cell entry.

    Science.gov (United States)

    Strauss, Mike; Filman, David J; Belnap, David M; Cheng, Naiqian; Noel, Roane T; Hogle, James M

    2015-04-01

    Poliovirus infection is initiated by attachment to a receptor on the cell surface called Pvr or CD155. At physiological temperatures, the receptor catalyzes an irreversible expansion of the virus to form an expanded form of the capsid called the 135S particle. This expansion results in the externalization of the myristoylated capsid protein VP4 and the N-terminal extension of the capsid protein VP1, both of which become inserted into the cell membrane. Structures of the expanded forms of poliovirus and of several related viruses have recently been reported. However, until now, it has been unclear how receptor binding triggers viral expansion at physiological temperature. Here, we report poliovirus in complex with an enzymatically partially deglycosylated form of the 3-domain ectodomain of Pvr at a 4-Å resolution, as determined by cryo-electron microscopy. The interaction of the receptor with the virus in this structure is reminiscent of the interactions of Pvr with its natural ligands. At a low temperature, the receptor induces very few changes in the structure of the virus, with the largest changes occurring within the footprint of the receptor, and in a loop of the internal protein VP4. Changes in the vicinity of the receptor include the displacement of a natural lipid ligand (called "pocket factor"), demonstrating that the loss of this ligand, alone, is not sufficient to induce particle expansion. Finally, analogies with naturally occurring ligand binding in the nectin family suggest which specific structural rearrangements in the virus-receptor complex could help to trigger the irreversible expansion of the capsid. The cell-surface receptor (Pvr) catalyzes a large structural change in the virus that exposes membrane-binding protein chains. We fitted known atomic models of the virus and Pvr into three-dimensional experimental maps of the receptor-virus complex. The molecular interactions we see between poliovirus and its receptor are reminiscent of the nectin

  8. Survey of poliovirus antibodies in Borno and Yobe States, North-Eastern Nigeria.

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    Mustapha Modu Gofama

    Full Text Available Nigeria remains one of only three polio-endemic countries in the world. In 2016, after an absence of 2 years, wild poliovirus serotype 1 was again detected in North-Eastern Nigeria. To better guide programmatic action, we assessed the immunity status of infants and children in Borno and Yobe states, and evaluated the impact of recently introduced inactivated poliovirus vaccine (IPV on antibody seroprevalence.We conducted a facility-based study of seroprevalence to poliovirus serotypes 1, 2 and 3 among health-seeking patients in two sites each of Borno and Yobe States. Enrolment was conducted amongst children 6-9 and 36-47 months of age attending the paediatrics outpatient department of the selected hospitals in the two states between 11 January and 5 February 2016. Detailed demographic and immunization history of the child was taken and an assessment of the child's health and nutritional state was conducted via physical examination. Blood was collected to test for levels of neutralizing antibody titres against the three poliovirus serotypes. The seroprevalence in the two age groups, potential determinants of seropositivity and the impact of one dose of IPV on humoral immunity were assessed. A total of 583 subjects were enrolled and provided sufficient quantities of serum for testing. Among 6-9-month-old infants, the seroprevalence was 81% (74-87%, 86% (79-91%, and 72% (65-79% in Borno State, and 75% (67-81%, 74% (66-81% and 69% (61-76% in Yobe States, for serotypes-1, 2 and 3, respectively. Among children aged 36-47 months, the seroprevalence was >90% in both states for all three serotypes, with the exception of type 3 seroprevalence in Borno [87% (80-91%]. Median reciprocal anti-polio neutralizing antibody titers were consistently >900 for serotypes 1 and 2 across age groups and states; with lower estimates for serotype 3, particularly in Borno. IPV received in routine immunization was found to be a significant determinant of seropositivity and

  9. Nectin-Like Interactions between Poliovirus and Its Receptor Trigger Conformational Changes Associated with Cell Entry

    Science.gov (United States)

    Strauss, Mike; Filman, David J.; Belnap, David M.; Cheng, Naiqian; Noel, Roane T.

    2015-01-01

    ABSTRACT Poliovirus infection is initiated by attachment to a receptor on the cell surface called Pvr or CD155. At physiological temperatures, the receptor catalyzes an irreversible expansion of the virus to form an expanded form of the capsid called the 135S particle. This expansion results in the externalization of the myristoylated capsid protein VP4 and the N-terminal extension of the capsid protein VP1, both of which become inserted into the cell membrane. Structures of the expanded forms of poliovirus and of several related viruses have recently been reported. However, until now, it has been unclear how receptor binding triggers viral expansion at physiological temperature. Here, we report poliovirus in complex with an enzymatically partially deglycosylated form of the 3-domain ectodomain of Pvr at a 4-Å resolution, as determined by cryo-electron microscopy. The interaction of the receptor with the virus in this structure is reminiscent of the interactions of Pvr with its natural ligands. At a low temperature, the receptor induces very few changes in the structure of the virus, with the largest changes occurring within the footprint of the receptor, and in a loop of the internal protein VP4. Changes in the vicinity of the receptor include the displacement of a natural lipid ligand (called “pocket factor”), demonstrating that the loss of this ligand, alone, is not sufficient to induce particle expansion. Finally, analogies with naturally occurring ligand binding in the nectin family suggest which specific structural rearrangements in the virus-receptor complex could help to trigger the irreversible expansion of the capsid. IMPORTANCE The cell-surface receptor (Pvr) catalyzes a large structural change in the virus that exposes membrane-binding protein chains. We fitted known atomic models of the virus and Pvr into three-dimensional experimental maps of the receptor-virus complex. The molecular interactions we see between poliovirus and its receptor are

  10. Comparison of the cytokine immune response to pathogenic Yersinia enterocolitica bioserotype 1B/O:8 and 2/O:9 in susceptible BALB/C and resistant C57BL/6 mice.

    Science.gov (United States)

    Wang, Xin; Gu, Wenpeng; Qiu, Haiyan; Xia, Shengli; Zheng, Han; Xiao, Yuchun; Liang, Junrong; Jing, Huaiqi

    2013-10-01

    We investigated the lethality of pathogenic Yersinia enterocolitica bioserotypes 1B/O:8 and 2/O:9 in susceptible BALB/C and resistant C57BL/6 mice; the cytokine alterations and histopathological changes were observed comparing the two strains in BALB/C mice. The data showed the 50% lethal dose (LD50) for the pathogenic Y. enterocolitica bioserotype 1B/O:8 was 10³ cfu in both BALB/C and C57BL/6 mice; while the LD50 for the 2/O:9 was 10⁸ cfu in BALB/C mice and 10⁹ cfu in C57BL/6 mice, a large difference. After infection with the two strains in BALB/C mice, GM-CSF (granulocyte-macrophage colony stimulating factor), IFN-γ (interferon-γ), IL-1β (interleukin-1β), IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, and TNF-α (tumor necrosis factor-α) appeared as a cytokine storm in a short period, reached peak values, and then quickly decreased. This appeared important for the immune response and cytokine immunopathogenesis in pathogenic Y. enterocolitica infections. In the initial infection stage, GM-CSF, IL-6, and TNF-α of 2/O:9 were higher than 1B/O:8; and subsequently the status was reversed. However, levels of IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-10, IL-12 following infection with 1B/O:8 were always higher than with 2/O:9. The histopathological changes in the liver and spleen in BALB/C mice infected with the two strains were similar at different times and doses. These observations show the different immunological effects and changes for pathogenic Y. enterocolitica 1B/O:8 and 2/O:9 infections using the mouse model. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. The probability of undetected wild poliovirus circulation: Can we do better?

    Science.gov (United States)

    Houy, Nicolas

    2015-10-07

    Acute flaccid paralysis surveillance actively detects new paralytic infections caused by wild poliovirus (WPV). However, most WPV infections occur with no symptom. This complicates determining when WPV is eradicated in the context of stopping oral poliovirus vaccine (OPV). Previous studies have used the time since the last paralytic infection as a variable of interest to construct this probability. In this study, we show that more freely available information can be used. In particular, we focus on enriching the computation of the probability of WPV silent circulation with the date of occurrence of the last paralytic infection. We show that this information can for at least one set of conditions have crucial importance for an accurate estimation of the risk of false positive when declaring WPV eradicated. We also look at the importance of this information for optimal dynamic vaccination strategies. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Cryo-electron microscopy reconstruction of a poliovirus-receptor-membrane complex

    Science.gov (United States)

    Bubeck, Doryen; Filman, David J; Hogle, James M

    2006-01-01

    To study non-enveloped virus cell entry, a versatile in vitro model system was developed in which liposomes containing nickel- chelating lipids were decorated with His-tagged poliovirus receptors and bound to virus. This system provides an exciting opportunity for structural characterization of the early steps in cell entry in the context of a membrane. Here we report the three-dimensional structure of a poliovirus-receptor-membrane complex solved by cryo-electron microscopy (cryo-EM) at a resolution of 32Å. Methods were developed to establish the symmetry of the complex objectively. This reconstruction demonstrates that receptor binding brings a viral five-fold axis close to the membrane. Density is clearly defined for the icosahedral virus, for receptors (including known glycosylation sites) and for the membrane bilayer. Apparent perturbations of the bilayer close to the viral five-fold axis may function in subsequent steps of cell entry. PMID:15965485

  13. L'infection persistante de cellules nerveuses humaines par le poliovirus

    OpenAIRE

    Colbère-Garapin, Florence; Pelletier, Isabelle; Pavio, N.; Duncan, G

    1997-01-01

    L'infection persistante de cellules nerveuses humaines par le poliovirus Virologie. Volume 1, Numéro 3, 237-47, Mai - Juin 1997, Revues Résumé Summary Auteur(s) : F. Colbère-Garapin, I. Pelletier, N. Pavio, G. Duncan, Groupe de génétique virale, Unité de neurovirologie et régénération du système nerveux, Institut Pasteur, 25, rue du Dr-Roux, 75724 Paris Cedex 15. Résumé : La poliomyélite paralytique est une maladie en voie d'éradication, mais le poliovirus (PV), son agent étiologique, continu...

  14. A monoclonal antibody that neutralizes poliovirus by cross-linking virions.

    OpenAIRE

    Thomas, A A; Brioen, P; Boeyé, A

    1985-01-01

    The neutralization of type 1 poliovirus by monoclonal antibody 35-1f4 was studied. The virions were rapidly linked by antibody into oligomers and larger aggregates, followed by slow redistribution of antibody between the immune complexes. The antibody content and infectivity of immune complexes were determined. Remaining single virions were fully infectious and free of antibody. The oligomers and larger aggregates did not significantly contribute to the residual infectivity, which therefore c...

  15. Survival of human immunodeficiency virus (HIV), HIV-infected lymphocytes, and poliovirus in water.

    OpenAIRE

    Moore, B E

    1993-01-01

    The potential for human immunodeficiency virus (HIV) to enter domestic sewers via contaminated body fluids such as blood has spurred interest in the survival of this virus in water and wastewater. This study focused on establishing the inactivation of HIV and productively infected lymphocytes in dechlorinated tap water. In addition, HIV survival was compared with that of poliovirus. Results indicated that either free HIV or cell-associated HIV was rapidly inactivated, with a 90% loss of infec...

  16. Molecular epidemiology of silent introduction and sustained transmission of wild poliovirus type 1, Israel, 2013.

    Science.gov (United States)

    Shulman, L M; Gavrilin, E; Jorba, J; Martin, J; Burns, C C; Manor, Y; Moran-Gilad, J; Sofer, D; Hindiyeh, M Y; Gamzu, R; Mendelson, E; Grotto, I

    2014-02-20

    Poliovirus vaccine coverage in Israel is over 90%. The last nine birth cohorts have been vaccinated exclusively with inactivated polio vaccine (IPV). However, between February and July 2013 type 1 wild poliovirus (WPV1) was detected persistently in 10 and intermittently in 8 of 47 environmental surveillance sites in southern and central Israel and in 30 stool samples collected during July from healthy individuals in southern Israel. We report results of sequence and phylogenetic analyses of genes encoding capsid proteins to determine the source and transmission mode of the virus. WPV1 capsid protein 1 nucleotide sequences were most closely related to South Asia (SOAS) cluster R3A polioviruses circulating in Pakistan in 2012 and isolated from Egyptian sewage in December 2012. There was no noticeable geographical clustering within WPV1-positive sites. Uniform codon usage among isolates from Pakistan, Egypt and Israel showed no signs of optimisation or deoptimisation. Bayesian phylogenetic time clock analysis of the entire capsid coding region (2,643 nt) with a 1.1% evolutionary rate indicated that Israeli and Egyptian WPV1-SOAS lineages diverged in September 2012, while Israeli isolates split into two sub-branches after January 2013. This suggests one or more introduction events into Israel with subsequent silent circulation despite high population immunity.

  17. Structural factors that control conformational transitions and serotype specificity in type 3 poliovirus.

    Science.gov (United States)

    Filman, D J; Syed, R; Chow, M; Macadam, A J; Minor, P D; Hogle, J M

    1989-01-01

    The three-dimensional structure of the Sabin strain of type 3 poliovirus has been determined at 2.4 A resolution. Significant structural differences with the Mahoney strain of type 1 poliovirus are confined to loops and terminal extensions of the capsid proteins, occur in all of the major antigenic sites of the virion and typically involve insertions, deletions or the replacement of prolines. Several newly identified components of the structure participate in assembly-dependent interactions which are relevant to the biologically important processes of viral assembly and uncoating. These include two sites of lipid substitution, two putative nucleotides and a beta sheet formed by the N-termini of capsid proteins VP4 and VP1. The structure provides an explanation for the temperature sensitive phenotype of the P3/Sabin strain. Amino acids that regulate temperature sensitivity in type 3 poliovirus are located in the interfaces between promoters, in the binding site for a lipid substituent and in an assembly-dependent extended beta sheet that stabilizes the association of pentamers. Several lines of evidence indicate that these structural components also control conformational transitions at various stages of the viral life cycle. Images PMID:2548847

  18. Three-dimensional structure of a mouse-adapted type 2/type 1 poliovirus chimera.

    Science.gov (United States)

    Yeates, T O; Jacobson, D H; Martin, A; Wychowski, C; Girard, M; Filman, D J; Hogle, J M

    1991-01-01

    The crystal structure of V510, a chimeric type 2/type 1 poliovirus, has been determined at 2.6 A resolution. Unlike the parental Mahoney strain of type 1 poliovirus, V510 is able to replicate in the mouse central nervous system, due entirely to the replacement of six amino acids in the exposed BC loop of capsid protein VP1. Significant structural differences between the two strains cluster in a major antigenic site of the virus, located at the apex of the radial projection which surrounds the viral five-fold axis. Residues implicated in the mouse-virulence of poliovirus by genetic studies are located in this area, and include the residues which are responsible for stabilizing the conformation of the BC loop in V510. Despite evidence that this area is not involved in receptor binding in cultured primate cells, the genetic and structural observations suggest that this area plays a critical role in receptor interactions in the mouse central nervous system. These results provide a structural framework for further investigation of the molecular determinants of host and tissue tropism in viruses. Images PMID:1651227

  19. Simian virus 40, poliovirus vaccines, and human cancer: research progress versus media and public interests

    Science.gov (United States)

    Butel, J. S.

    2000-01-01

    From 1955 through early 1963, millions of people were inadvertently exposed to simian virus 40 (SV40) as a contaminant of poliovirus vaccines; the virus had been present in the monkey kidney cultures used to prepare the vaccines and had escaped detection. SV40 was discovered in 1960 and subsequently eliminated from poliovirus vaccines. This article reviews current knowledge about SV40 and considers public responses to reports in the media. SV40 is a potent tumour virus with broad tissue tropism that induces tumours in rodents and transforms cultured cells from many species. It is also an important laboratory model for basic studies of molecular processes in eukaryotic cells and mechanisms of neoplastic transformation. SV40 neutralizing antibodies have been detected in individuals not exposed to contaminated poliovirus vaccines. There have been many reports of detection of SV40 DNA in human tumours, especially mesotheliomas, brain tumours and osteosarcomas; and DNA sequence analyses have ruled out the possibility that the viral DNA in tumours was due to laboratory contamination or that the virus had been misidentified. However, additional studies are necessary to prove that SV40 is the cause of certain human cancers. A recently published review article evaluated the status of the field and received much media attention. The public response emphasized that there is great interest in the possibility of health risks today from vaccinations received in the past.

  20. The efficacy of simulated solar disinfection (SODIS) against coxsackievirus, poliovirus and hepatitis A virus.

    Science.gov (United States)

    Heaselgrave, Wayne; Kilvington, Simon

    2012-12-01

    The antimicrobial activity of simulated solar disinfection (SODIS) against enteric waterborne viruses including coxsackievirus-B5, poliovirus-2 and hepatitis A virus was investigated in this study. Assays were conducted in transparent 12-well polystyrene microtitre plates containing the appropriate viral test suspension. Plates were exposed to simulated sunlight at an optical irradiance of 550 Wm(-2) (watts per square metre) delivered from a SUNTEST™ CPS+ solar simulator for 6 hours. Aliquots of the viral test suspensions were taken at set time points and the level of inactivation of the viruses was determined by either culture on a HeLa cell monolayer for coxsackievirus-B5 and poliovirus-2 or by utilising a chromogenic antibody-based approach for hepatitis A virus. With coxsackievirus-B5, poliovirus-2 and hepatitis A virus, exposure to SODIS at an optical irradiance of 550 Wm(-2) for 1-2 hours resulted in complete inactivation of each virus. The findings from this study suggest that under appropriate conditions SODIS may be an effective technique for the inactivation of enteric viruses in drinking water. However, further verification studies need to be performed using natural sunlight in the region where the SODIS technology is to be employed to validate our results.

  1. Expression of poliovirus 2Apro in mammalian cells: effects on translation.

    Science.gov (United States)

    Aldabe, R; Feduchi, E; Novoa, I; Carrasco, L

    1995-12-11

    Poliovirus protease 2Apro has been efficiently expressed in HeLa and COS cells upon transfection with vector pTM1-2A and infection with the recombinant vaccinia virus bearing the T7 RNA polymerase. The expressed poliovirus protease localizes to the cytoplasm of the transfected cells, both in the endoplasmic reticulum and in vesicles scattered in the cytoplasm. Cleavage of p220, a component of initiation factor eIF-4F, selectively occurs from 5 h post-infection in transfected cells infected with the recombinant virus. This cleavage correlates in time with the profound inhibition observed in the synthesis of vaccinia virus proteins. A similar blockade of vesicular stomatitis virus translation takes place upon 2Apro expression. Finally, the synthesis of poliovirus protein 2C from a recombinant vaccinia virus that expresses this protein under the EMC untranslated leader region is not affected by the synthesis of 2Apro. These findings lend support to the idea that translation of capped mRNAs requires the integrity of p220, while this requirement is not observed when translation of a mRNA bearing a picornavirus leader region is assayed.

  2. A Stable HeLa Cell Line That Inducibly Expresses Poliovirus 2Apro: Effects on Cellular and Viral Gene Expression

    Science.gov (United States)

    Barco, Angel; Feduchi, Elena; Carrasco, Luis

    2000-01-01

    A HeLa cell clone (2A7d) that inducibly expresses the gene for poliovirus protease 2A (2Apro) under the control of tetracycline has been obtained. Synthesis of 2Apro induces severe morphological changes in 2A7d cells. One day after tetracycline removal, cells round up and a few hours later die. Poliovirus 2Apro cleaves both forms of initiation factor eIF4G, causing extensive inhibition of capped-mRNA translation a few hours after protease induction. Methoxysuccinyl-Ala-Ala-Pro-Val-chloromethylketone, a selective inhibitor of 2Apro, prevents both eIF4G cleavage and inhibition of translation but not cellular death. Expression of 2Apro still allows both the replication of poliovirus and the translation of mRNAs containing a picornavirus leader sequence, while vaccinia virus replication is drastically inhibited. Translation of transfected capped mRNA is blocked in 2A7d-On cells, while luciferase synthesis from a mRNA bearing a picornavirus internal ribosome entry site (IRES) sequence is enhanced by the presence of 2Apro. Moreover, synthesis of 2Apro in 2A7d cells complements the translational defect of a poliovirus 2Apro-defective variant. These results show that poliovirus 2Apro expression mimics some phenotypical characteristics of poliovirus-infected cells, such as cell rounding, inhibition of protein synthesis and enhancement of IRES-driven translation. This cell line constitutes a useful tool to further analyze 2Apro functions, to complement poliovirus 2Apro mutants, and to test antiviral compounds. PMID:10666269

  3. Susceptibility to Entamoeba histolytica intestinal infection is related to reduction in natural killer T-lymphocytes in C57BL/6 mice.

    Science.gov (United States)

    Oliveira, Fabrício M S; Horta, Bernardo C; Prata, Luana O; Santiago, Andrezza F; Alves, Andréa C; Faria, Ana M C; Gomes, Maria A; Caliari, Marcelo V

    2012-04-27

    Entamoeba histolytica is a protozoan that causes amoebiasis. Recent studies demonstrated that natural killer T lymphocytes (NKT) are critical for preventing the development of amoebic liver abscess. In spite of that, there are only a handful of studies in the area. Herein, we explored the role of NKT cells in E. histolytica infection using C57BL/6 wild-type and CD1(-/-) mice. Animals were inoculated with E. histolytica and sacrificed 48 hours later to collect caecum samples that were used for quantitative analyses of lesions, trophozoites, NK1.1(+) T lymphocytes and expression of the mucus protein MUC-2 by immunohistochemistry technique. Quantitative analyses confirmed that the frequency of NK1.1(+) T cells was significantly lower in samples from C57BL/6 CD1(-/-) mice as compared to their wild type (WT) counterparts. The extension of necrotic mucosa was larger and the number of trophozoites higher in Entamoeba (Eh)-infected CD1(-/-) mice when compared with Eh-infected WT mice. In mice from both groups, non-infected (CTRL) and Eh-infected CD1(-/-), there was a reduction in the thickness of the caecal mucosa and in the MUC-2-stained area in comparison with CTRL- and Eh-WT mice. Our results showed that NKT lymphocytes contribute to resistance against Entamoeba histolytica infection and to the control of inflammation in the colitis induced by infection. The presence of a normal epithelial layer containing appropriate levels of mucus had also a protective role against infection.

  4. Susceptibility to Entamoeba histolytica intestinal infection is related to reduction in natural killer T-lymphocytes in C57BL/6 mice

    Directory of Open Access Journals (Sweden)

    Fabrício M.S. Oliveira

    2012-04-01

    Full Text Available Entamoeba histolytica is a protozoan that causes amoebiasis. Recent studies demonstrated that natural killer T lymphocytes (NKT are critical for preventing the development of amoebic liver abscess. In spite of that, there are only a handful of studies in the area. Herein, we explored the role of NKT cells in E. histolytica infection using C57BL/6 wild-type and CD1-/- mice. Animals were inoculated with E. histolytica and sacrificed 48 hours later to collect caecum samples that were used for quantitative analyses of lesions, trophozoites, NK1.1+ T lymphocytes and expression of the mucus protein MUC-2 by immunohistochemistry technique. Quantitative analyses confirmed that the frequency of NK1.1+ T cells was significantly lower in samples from C57BL/6 CD1-/- mice as compared to their wild type (WT counterparts. The extension of necrotic mucosa was larger and the number of trophozoites higher in Entamoeba (Eh-infected CD1-/- mice when compared with Eh-infected WT mice. In mice from both groups, noninfected (CTRL and Eh-infected CD1-/-, there was a reduction in the thickness of the caecal mucosa and in the MUC-2-stained area in comparison with CTRL- and Eh-WT mice. Our results showed that NKT lymphocytes contribute to resistance against Entamoeba histolytica infection and to the control of inflammation in the colitis induced by infection. The presence of a normal epithelial layer containing appropriate levels of mucus had also a protective role against infection.

  5. Mouse-hamster chimeric prion protein (PrP) devoid of N-terminal residues 23-88 restores susceptibility to 22L prions, but not to RML prions in PrP-knockout mice.

    Science.gov (United States)

    Uchiyama, Keiji; Miyata, Hironori; Yano, Masashi; Yamaguchi, Yoshitaka; Imamura, Morikazu; Muramatsu, Naomi; Das, Nandita Rani; Chida, Junji; Hara, Hideyuki; Sakaguchi, Suehiro

    2014-01-01

    Prion infection induces conformational conversion of the normal prion protein PrPC, into the pathogenic isoform PrPSc, in prion diseases. It has been shown that PrP-knockout (Prnp0/0) mice transgenically reconstituted with a mouse-hamster chimeric PrP lacking N-terminal residues 23-88, or Tg(MHM2Δ23-88)/Prnp 0/0 mice, neither developed the disease nor accumulated MHM2ScΔ23-88 in their brains after inoculation with RML prions. In contrast, RML-inoculated Tg(MHM2Δ23-88)/Prnp 0/+ mice developed the disease with abundant accumulation of MHM2ScΔ23-88 in their brains. These results indicate that MHM2Δ23-88 itself might either lose or greatly reduce the converting capacity to MHM2ScΔ23-88, and that the co-expressing wild-type PrPC can stimulate the conversion of MHM2Δ23-88 to MHM2ScΔ23-88 in trans. In the present study, we confirmed that Tg(MHM2Δ23-88)/Prnp 0/0 mice remained resistant to RML prions for up to 730 days after inoculation. However, we found that Tg(MHM2Δ23-88)/Prnp 0/0 mice were susceptible to 22L prions, developing the disease with prolonged incubation times and accumulating MHM2ScΔ23-88 in their brains. We also found accelerated conversion of MHM2Δ23-88 into MHM2ScΔ23-88 in the brains of RML- and 22L-inoculated Tg(MHM2Δ23-88)/Prnp 0/+ mice. However, wild-type PrPSc accumulated less in the brains of these inoculated Tg(MHM2Δ23-88)/Prnp 0/+ mice, compared with RML- and 22L-inoculated Prnp 0/+ mice. These results show that MHM2Δ23-88 itself can convert into MHM2ScΔ23-88 without the help of the trans-acting PrPC, and that, irrespective of prion strains inoculated, the co-expressing wild-type PrPC stimulates the conversion of MHM2Δ23-88 into MHM2ScΔ23-88, but to the contrary, the co-expressing MHM2Δ23-88 disturbs the conversion of wild-type PrPC into PrPSc.

  6. Neil2-null Mice Accumulate Oxidized DNA Bases in the Transcriptionally Active Sequences of the Genome and Are Susceptible to Innate Inflammation* ♦

    Science.gov (United States)

    Chakraborty, Anirban; Wakamiya, Maki; Venkova-Canova, Tatiana; Pandita, Raj K.; Aguilera-Aguirre, Leopoldo; Sarker, Altaf H.; Singh, Dharmendra Kumar; Hosoki, Koa; Wood, Thomas G.; Sharma, Gulshan; Cardenas, Victor; Sarkar, Partha S.; Sur, Sanjiv; Pandita, Tej K.; Boldogh, Istvan; Hazra, Tapas K.

    2015-01-01

    Why mammalian cells possess multiple DNA glycosylases (DGs) with overlapping substrate ranges for repairing oxidatively damaged bases via the base excision repair (BER) pathway is a long-standing question. To determine the biological role of these DGs, null animal models have been generated. Here, we report the generation and characterization of mice lacking Neil2 (Nei-like 2). As in mice deficient in each of the other four oxidized base-specific DGs (OGG1, NTH1, NEIL1, and NEIL3), Neil2-null mice show no overt phenotype. However, middle-aged to old Neil2-null mice show the accumulation of oxidative genomic damage, mostly in the transcribed regions. Immuno-pulldown analysis from wild-type (WT) mouse tissue showed the association of NEIL2 with RNA polymerase II, along with Cockayne syndrome group B protein, TFIIH, and other BER proteins. Chromatin immunoprecipitation analysis from mouse tissue showed co-occupancy of NEIL2 and RNA polymerase II only on the transcribed genes, consistent with our earlier in vitro findings on NEIL2's role in transcription-coupled BER. This study provides the first in vivo evidence of genomic region-specific repair in mammals. Furthermore, telomere loss and genomic instability were observed at a higher frequency in embryonic fibroblasts from Neil2-null mice than from the WT. Moreover, Neil2-null mice are much more responsive to inflammatory agents than WT mice. Taken together, our results underscore the importance of NEIL2 in protecting mammals from the development of various pathologies that are linked to genomic instability and/or inflammation. NEIL2 is thus likely to play an important role in long term genomic maintenance, particularly in long-lived mammals such as humans. PMID:26245904

  7. Genetic Susceptibility to Chronic Hepatitis Is Inherited Codominantly in Helicobacter hepaticus-Infected AB6F1 and B6AF1 Hybrid Male Mice, and Progression to Hepatocellular Carcinoma Is Linked to Hepatic Expression of Lipogenic Genes and Immune Function-Associated Networks▿ †

    Science.gov (United States)

    García, Alexis; Ihrig, Melanie M.; Fry, Rebecca C.; Feng, Yan; Xu, Sandy; Boutin, Samuel R.; Rogers, Arlin B.; Muthupalani, Suresh; Samson, Leona D.; Fox, James G.

    2008-01-01

    Helicobacter hepaticus causes hepatitis in susceptible strains of mice. Previous studies indicated that A/JCr mice are susceptible and C57BL/6NCr mice are resistant to H. hepaticus-induced hepatitis. We used F1 hybrid mice derived from A/J and C57BL/6 matings to investigate their phenotype and determine their hepatic gene expression profile in response to H. hepaticus infection. F1 hybrid mice, as well as parental A/J and C57BL/6 mice, were divided equally into control and H. hepaticus-infected groups and euthanized at 18 months postinoculation. Hepatic lesions were evaluated histologically and the differential hepatic gene expression in F1 mice was determined by microarray-based global gene expression profiling analysis. H. hepaticus-infected parental strains including A/J and C57BL/6 mice, as well as F1 mice, developed significant hepatitis. Overall, hepatocellular carcinomas or dysplastic liver lesions were observed in 69% of H. hepaticus-infected F1 male mice and H. hepaticus was isolated from hepatic tissues of all F1 mice with liver tumors. Liver tumors, characterized by hepatic steatosis, developed in livers with high hepatitis scores. To identify gene expression specific to H. hepaticus-induced hepatitis and progression to hepatocellular carcinoma in F1 mice, a method using comparative group transcriptome analysis was utilized. The canonical pathway most significantly enriched was immunological disease. Fatty acid synthase and steaoryl-coenzyme A desaturase, the two rate-limiting enzymes in lipogenesis, were upregulated in neoplastic relative to dysplastic livers. This study suggests a synergistic interaction between hepatic steatosis and infectious hepatitis leading to hepatocellular carcinoma. The use of AB6F1 and B6AF1 mice, as well as genetically engineered mice, on a C57BL/6 background will allow studies investigating the role of chronic microbial hepatitis and steatohepatitis in the pathogenesis of liver cancer. PMID:18285497

  8. Susceptibility to Coccidioides species in C57BL/6 mice is associated with expression of a truncated splice variant of Dectin-1 (Clec7a)

    NARCIS (Netherlands)

    del Pilar Jiménez-A, M.; Viriyakosol, S.; Walls, L.; Datta, S. K.; Kirkland, T.; Heinsbroek, S. E. M.; Brown, G.; Fierer, J.

    2008-01-01

    Coccidioides posadasii spherules stimulate macrophages to make cytokines via TLR-2 and Dectin-1. We used formalin-killed spherules and 1,3-beta-glucan purified from spherules to stimulate elicited peritoneal macrophages and myeloid dendritic cells (mDCs) from susceptible (C57BL/6) and resistant

  9. Sporadic isolation of sabin-like polioviruses and high-level detection of non-polio enteroviruses during sewage surveillance in seven Italian cities, after several years of inactivated poliovirus vaccination.

    Science.gov (United States)

    Battistone, A; Buttinelli, G; Fiore, S; Amato, C; Bonomo, P; Patti, A M; Vulcano, A; Barbi, M; Binda, S; Pellegrinelli, L; Tanzi, M L; Affanni, P; Castiglia, P; Germinario, C; Mercurio, P; Cicala, A; Triassi, M; Pennino, F; Fiore, L

    2014-08-01

    Sewage surveillance in seven Italian cities between 2005 and 2008, after the introduction of inactivated poliovirus vaccination (IPV) in 2002, showed rare polioviruses, none that were wild-type or circulating vaccine-derived poliovirus (cVDPV), and many other enteroviruses among 1,392 samples analyzed. Two of five polioviruses (PV) detected were Sabin-like PV2 and three PV3, based on enzyme-linked immunosorbent assay (ELISA) and PCR results. Neurovirulence-related mutations were found in the 5'noncoding region (5'NCR) of all strains and, for a PV2, also in VP1 region 143 (Ile>Thr). Intertypic recombination in the 3D region was detected in a second PV2 (Sabin 2/Sabin 1) and a PV3 (Sabin 3/Sabin 2). The low mutation rate in VP1 for all PVs suggests limited interhuman virus passages, consistent with efficient polio immunization in Italy. Nonetheless, these findings highlight the risk of wild or Sabin poliovirus reintroduction from abroad. Non-polio enteroviruses (NPEVs) were detected, 448 of which were coxsackievirus B (CVB) and 294 of which were echoviruses (Echo). Fifty-six NPEVs failing serological typing were characterized by sequencing the VP1 region (nucleotides [nt] 2628 to 2976). A total of 448 CVB and 294 Echo strains were identified; among those strains, CVB2, CVB5, and Echo 11 predominated. Environmental CVB5 and CVB2 strains from this study showed high sequence identity with GenBank global strains. The high similarity between environmental NPEVs and clinical strains from the same areas of Italy and the same periods indicates that environmental strains reflect the viruses circulating in the population and highlights the potential risk of inefficient wastewater treatments. This study confirmed that sewage surveillance can be more sensitive than acute flaccid paralysis (AFP) surveillance in monitoring silent poliovirus circulation in the population as well as the suitability of molecular approaches to enterovirus typing.

  10. Adult-onset deletion of the Prader-Willi syndrome susceptibility gene Snord116 in mice results in reduced feeding and increased fat mass.

    Science.gov (United States)

    Purtell, Louise; Qi, Yue; Campbell, Lesley; Sainsbury, Amanda; Herzog, Herbert

    2017-04-01

    The imprinted small nucleolar RNA (snoRNA) Snord116 is implicated in the aetiology of Prader-Willi syndrome (PWS), a disease associated with hyperphagia and obesity. Germline deletion of Snord116 in mice has been found to lead to increased food intake but not to the development of obesity. To determine the role of Snord116 independent of potential compensatory developmental factors, we investigated the effects of conditional adult-onset deletion of Snord116 in mice. Deletion of Snord116 was induced at 8 weeks of age by oral administration of tamoxifen to male Snordlox/lox; ROSAcre/+ mice, with vehicle-treated mice used as controls. Body weight (BW) was monitored weekly and body composition was measured by dual-energy X-ray absorptiometry and tissue dissection. Non-fasted and fasting-induced food intake was determined, and glucose and insulin tolerance tests were performed. Twenty-four-hour energy expenditure and physical activity were assessed by indirect calorimetry. Adult-onset deletion of Snord116 led to reduced food intake and increased adiposity, albeit with no concomitant change in BW or lean mass compared to controls. Adult onset Snord116 deletion was also associated with worsened glucose tolerance and insulin sensitivity. This study identified a key role for Snord116 in feeding behaviour and growth. Further, it is likely that the effects of this gene are modulated by developmental stage, as mice with adult-onset deletion showed an opposite phenotype, with respect to food intake and body composition, to previously published data on mice with germline deletion.

  11. Efficient cleavage of p220 by poliovirus 2Apro expression in mammalian cells: effects on vaccinia virus.

    Science.gov (United States)

    Aldabe, R; Feduchi, E; Novoa, I; Carrasco, L

    1995-10-24

    Poliovirus protease 2A cleaves p220, a component of initiation factor eIF-4F. Polyclonal antibodies that recognize p220 and the cleaved products from different species have been raised. Transfection of several cell lines with poliovirus 2Apro cloned in different plasmids leads to efficient cleavage of p220 upon infection with VT7, a recombinant vaccinia virus that expresses the T7 RNA polymerase. Under these conditions vaccinia virus protein synthesis is severely inhibited, while expression of poliovirus protein 2C from a similar plasmid has no effect. These results show by the first time the effects of p220 cleavage on vaccinia virus translation in the infected cells.

  12. The role of supplementary environmental surveillance to complement acute flaccid paralysis surveillance for wild poliovirus in Pakistan - 2011-2013.

    Science.gov (United States)

    Cowger, Tori L; Burns, Cara C; Sharif, Salmaan; Gary, Howard E; Iber, Jane; Henderson, Elizabeth; Malik, Farzana; Zahoor Zaidi, Syed Sohail; Shaukat, Shahzad; Rehman, Lubna; Pallansch, Mark A; Orenstein, Walter A

    2017-01-01

    More than 99% of poliovirus infections are non-paralytic and therefore, not detected by acute flaccid paralysis (AFP) surveillance. Environmental surveillance (ES) can detect circulating polioviruses from sewage without relying on clinical presentation. With extensive ES and continued circulation of polioviruses, Pakistan presents a unique opportunity to quantify the impact of ES as a supplement to AFP surveillance on overall completeness and timeliness of poliovirus detection. Genetic, geographic and temporal data were obtained for all wild poliovirus (WPV) isolates detected in Pakistan from January 2011 through December 2013. We used viral genetics to assess gaps in AFP surveillance and ES as measured by detection of 'orphan viruses' (≥1.5% different in VP1 capsid nucleotide sequence). We compared preceding detection of closely related circulating isolates (≥99% identity) detected by AFP surveillance or ES to determine which surveillance system first detected circulation before the presentation of each polio case. A total of 1,127 WPV isolates were detected by AFP surveillance and ES in Pakistan from 2011-2013. AFP surveillance and ES combined exhibited fewer gaps (i.e., % orphan viruses) in detection than AFP surveillance alone (3.3% vs. 7.7%, respectively). ES detected circulation before AFP surveillance in nearly 60% of polio cases (200 of 346). For polio cases reported from provinces conducting ES, ES detected circulation nearly four months sooner on average (117.6 days) than did AFP surveillance. Our findings suggest ES in Pakistan is providing earlier, more sensitive detection of wild polioviruses than AFP surveillance alone. Overall, targeted ES through strategic selection of sites has important implications in the eradication endgame strategy.

  13. The absence of cutaneous lymph nodes results in a Th2 response and increased susceptibility to Leishmania major infection in mice.

    Science.gov (United States)

    Ehrchen, Jan M; Roth, Johannes; Roebrock, Kirsten; Varga, Georg; Domschke, Wolfram; Newberry, Rodney; Sorg, Clemens; Müller-Tidow, Carsten; Sunderkötter, Cord; Kucharzik, Torsten; Spahn, Thomas W

    2008-09-01

    Lymph nodes (LNs) are important sentinel organs where antigen-presenting cells interact with T cells to induce adaptive immune responses. In cutaneous infection of mice with Leishmania major, resistance depends on the induction of a T-helper-cell-1 (Th1)-mediated cellular immune response in draining, peripheral LNs. We investigated whether draining, peripheral LNs are absolutely required for resistance against L. major infection. We investigated the course of experimental leishmaniasis in wild-type (wt) mice lacking peripheral LNs (pLNs), which we generated by in utero blockade of membrane-bound lymphotoxin, and in mice lacking pLNs or all LNs due to genetic deletion of lymphotoxin ligands or receptors. wt mice of the resistant C57BL/6 strain without local skin-draining LNs were still able to generate specific T-cell responses, but this yielded Th2 cells. This switch to a Th2 response resulted in severe systemic infection. We also confirmed these results with mice lacking pLNs due to genetic depletion of lymphotoxin-beta. The complete absence of LNs due to a genetic depletion of the lymphotoxin-beta receptor also resulted in a marked deterioration of disease and a Th2 response. Thus, in the absence of pLNs, an L. major-specific Th2 response is induced in the remaining secondary lymphoid organs, such as the spleen and non-skin-draining LNs. This indicates a critical requirement for pLNs to induce protective Th1 immunity and suggests that whether Th1 or Th2 priming to the same antigen occurs depends on the site of the primary antigen recognition.

  14. Induction of protection against leishmaniasis in susceptible BALB/c mice using simple DOTAP cationic nanoliposomes containing soluble Leishmania antigen (SLA).

    Science.gov (United States)

    Firouzmand, Hengameh; Badiee, Ali; Khamesipour, Ali; Heravi Shargh, Vahid; Alavizadeh, Seyedeh Hoda; Abbasi, Azam; Jaafari, Mahmoud Reza

    2013-12-01

    A suitable adjuvant and delivery system are needed to develop an effective vaccine against leishmaniasis. To induce a Th1 type of response and protection in BALB/c mice against Leishmania major infection, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) nanoliposomes bearing an intrinsic adjuvanticity, were used as an antigen delivery system and immunoadjuvant for soluble Leishmania antigens (SLA). DOTAP liposomes containing different concentrations of SLA were prepared by using lipid film method followed by sonication. The prepared vesicles showed a diameter of about 100nm, a positive zeta potential and approximately 70% encapsulation efficiency of SLA. BALB/c mice were immunized subcutaneously (SC), three times in a 3-week interval with different concentrations of liposomal SLA (12.5, 25, and 50μg of SLA/50μl/mice), free SLA and as well as free liposome. The group of mice received 50μg of SLA in DOTAP-nanoliposomes showed a significantly (p<0.001) smaller footpad swelling and the lowest spleen and footpad parasite burden after the challenge. This group also showed the highest IFN-γ production compared to the other groups, lower IL-4 level and higher IgG2a antibody titer. Taken together, the results indicated that simple DOTAP nanoliposome containing 1μg/μl SLA are appropriate delivery systems to induce a Th1 type of immune response and protection against L. major infection in BALB/c mice. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. The interferon-induced gene Ifi27l2a is active in lung macrophages and lymphocytes after influenza A infection but deletion of Ifi27l2a in mice does not increase susceptibility to infection.

    Science.gov (United States)

    Tantawy, Mohamed A; Hatesuer, Bastian; Wilk, Esther; Dengler, Leonie; Kasnitz, Nadine; Weiß, Siegfried; Schughart, Klaus

    2014-01-01

    Interferons represent one of the first and essential host defense mechanisms after infection, and the activation of the IFN-pathway results in the transcriptional activation of hundreds of interferon-stimulated genes. The alpha-inducible protein 27 like 2A (Ifi27l2a) gene (human synonym: ISG12) is strongly up-regulated in the lung after influenza A infection in mice and has been shown in gene expression studies to be highly correlated to other activated genes. Therefore, we investigated the role of Ifi27l2a for the host defense to influenza A infections in more detail. RT-PCR analyses in non-infected mice demonstrated that Ifi27l2a was expressed in several tissues, including the lung. Detailed analyses of reporter gene expression in lungs from Ifi27l2a-LacZ mice revealed that Ifi27l2a was expressed in macrophages and lymphocytes but not in alveolar cells or bronchiolar epithelium cells. The number of macrophages and lymphocyte strongly increased in the lung after infection, but no significant increase in expression levels of the LacZ reporter gene was found within individual immune cells. Also, no reporter gene expression was found in bronchiolar epithelial cells, alveolar cells or infiltrating neutrophils after infection. Thus, up-regulation of Ifi27l2a in infected lungs is mainly due to the infiltration of macrophages and lymphocytes. Most surprisingly, deletion of Ifi27l2a in mouse knock-out lines did not result in increased susceptibility to infections with H1N1 or H7N7 influenza A virus compared to wild type C57BL/6N mice, suggesting a less important role of the gene for the host response to influenza infections than for bacterial infections.

  16. Antibodies against the chemically synthesized genome-linked protein of poliovirus react with native virus-specific proteins.

    Science.gov (United States)

    Baron, M H; Baltimore, D

    1982-02-01

    The genome-linked protein (VPg) of poliovirus has been chemically synthesized, coupled to bovine serum albumin carrier and injected into rabbits. An antibody response was elicited not only by the full-length synthetic VPg peptide, but also by a synthetic 14-amino acid carboxy-terminal peptide. All antisera reacted with virus-specific proteins from HeLa cells infected with poliovirus. Three of these proteins have previously been implicated by others as precursors of VPg. No free cytoplasmic VPg could be detected, and the antibodies did not react with radiolabeled proteins from uninfected cells.

  17. Limits of variation, specific infectivity, and genome packaging of massively recoded poliovirus genomes

    Science.gov (United States)

    Song, Yutong; Liu, Ying; Mugavero, JoAnn; Shen, Sam H.; Ward, Charles B.; Asare, Emmanuel; Jiang, Ping; Paul, Aniko V.; Mueller, Steffen; Wimmer, Eckard

    2017-01-01

    Computer design and chemical synthesis generated viable variants of poliovirus type 1 (PV1), whose ORF (6,189 nucleotides) carried up to 1,297 “Max” mutations (excess of overrepresented synonymous codon pairs) or up to 2,104 “SD” mutations (randomly scrambled synonymous codons). “Min” variants (excess of underrepresented synonymous codon pairs) are nonviable except for P2Min, a variant temperature-sensitive at 33 and 39.5 °C. Compared with WT PV1, P2Min displayed a vastly reduced specific infectivity (si) (WT, 1 PFU/118 particles vs. P2Min, 1 PFU/35,000 particles), a phenotype that will be discussed broadly. Si of haploid PV presents cellular infectivity of a single genotype. We performed a comprehensive analysis of sequence and structures of the PV genome to determine if evolutionary conserved cis-acting packaging signal(s) were preserved after recoding. We showed that conserved synonymous sites and/or local secondary structures that might play a role in determining packaging specificity do not survive codon pair recoding. This makes it unlikely that numerous “cryptic, sequence-degenerate, dispersed RNA packaging signals mapping along the entire viral genome” [Patel N, et al. (2017) Nat Microbiol 2:17098] play the critical role in poliovirus packaging specificity. Considering all available evidence, we propose a two-step assembly strategy for +ssRNA viruses: step I, acquisition of packaging specificity, either (a) by specific recognition between capsid protein(s) and replication proteins (poliovirus), or (b) by the high affinity interaction of a single RNA packaging signal (PS) with capsid protein(s) (most +ssRNA viruses so far studied); step II, cocondensation of genome/capsid precursors in which an array of hairpin structures plays a role in virion formation. PMID:28973853

  18. Mutational analysis of poliovirus 2Apro. Distinct inhibitory functions of 2apro on translation and transcription.

    Science.gov (United States)

    Ventoso, I; Barco, A; Carrasco, L

    1998-10-23

    Transient expression of poliovirus 2Apro in mammalian cells by means of the recombinant vaccinia virus vT7 expression system leads to drastic inhibition of both cellular and vaccinia virus gene expression (Aldabe, R., Feduchi, E., Novoa, I., and Carrasco, L. (1995) FEBS Lett. 377, 1-5; Aldabe, R., Feduchi, E., Novoa, I., and Carrasco, L. (1995) Biochem. Biophys. Res. Commun. 215, 928-936). To obtain further insights into the molecular basis of this inhibition, a number of 2Apro variants were generated and expressed in COS-1 cells. The effect of these variants on cellular translation, on vaccinia virus-specific translation, and on transcription of the reporter gene luciferase was analyzed. The ability of the different 2Apro variants to block cellular translation depends on their capacities to cleave eIF-4G. The blockade exerted by 2Apro on transcription of the luciferase gene reinforces the notion that this protease is a potent inhibitor of RNA polymerase II-mediated transcription. Some of the 2Apro variants tested failed to block luciferase transcription, despite the fact that eIF-4G cleavage and inhibition of translation were observed. Two reconstituted polioviruses mutated in 2Apro were defective in inhibiting luciferase transcription, yet were still able to cleave eIF-4G and block translation. These findings indicate that 2Apro interferes with cellular gene expression at both the transcriptional and translational levels. Moreover, these two effects probably reflect the inactivation of different host proteins by poliovirus 2Apro.

  19. Separation of native and truncated forms of poliovirus protease 3C produced in Escherichia coli.

    OpenAIRE

    Polgár, L; ERDÉLYI, F.; Hajnal, E; Löw, M.; Gráf, L; Korant, B D

    1993-01-01

    Poliovirus protease 3C is a cysteine enzyme that is essential for the processing of the viral precursor polyprotein containing structural proteins and enzymes, including the protease itself. We have constructed the plasmid pSD/PV3C which produced protease 3C as inclusion bodies when expressed in Escherichia coli. In addition to the full-length protease, a truncated form was also generated, starting from an internal initiation site (Met-27). The enzyme was renatured by dilution of a 6 M guanid...

  20. Update on Vaccine-Derived Polioviruses - Worldwide, January 2016-June 2017.

    Science.gov (United States)

    Jorba, Jaume; Diop, Ousmane M; Iber, Jane; Henderson, Elizabeth; Sutter, Roland W; Wassilak, Steven G F; Burns, Cara C

    2017-11-03

    In 1988, the World Health Assembly launched the Global Polio Eradication Initiative (GPEI) (1). Among the three wild poliovirus (WPV) serotypes, only type 1 (WPV1) has been detected since 2012. Since 2014, detection of WPV1 has been limited to three countries, with 37 cases in 2016 and 11 cases in 2017 as of September 27. The >99.99% decline worldwide in polio cases since the launch of the GPEI is attributable to the extensive use of the live, attenuated oral poliovirus vaccine (OPV) in mass vaccination campaigns and comprehensive national routine immunization programs. Despite its well-established safety record, OPV use can be associated with rare emergence of genetically divergent vaccine-derived polioviruses (VDPVs) whose genetic drift from the parental OPV strains indicates prolonged replication or circulation (2). VDPVs can also emerge among persons with primary immunodeficiencies (PIDs). Immunodeficiency-associated VDPVs (iVDPVs) can replicate for years in some persons with PIDs. In addition, circulating vaccine-derived polioviruses (cVDPVs) can emerge very rarely among immunologically normal vaccine recipients and their contacts in areas with inadequate OPV coverage and can cause outbreaks of paralytic polio. This report updates previous summaries regarding VDPVs (3). During January 2016-June 2017, new cVDPV outbreaks were identified, including two in the Democratic Republic of the Congo (DRC) (eight cases), and another in Syria (35 cases), whereas the circulation of cVDPV type 2 (cVDPV2) in Nigeria resulted in cVDPV2 detection linked to a previous emergence. The last confirmed case from the 2015-2016 cVDPV type 1 (cVDPV1) outbreak in Laos occurred in January 2016. Fourteen newly identified persons in 10 countries were found to excrete iVDPVs, and three previously reported patients in the United Kingdom and Iran (3) were still excreting type 2 iVDPV (iVDPV2) during the reporting period. Ambiguous VDPVs (aVDPVs), isolates that cannot be classified

  1. Early immune response in susceptible and resistant mice strains with chronic Pseudomonas aeruginosa lung infection determines the type of T-helper cell response

    DEFF Research Database (Denmark)

    Moser, C; Hougen, H P; Song, Z

    1999-01-01

    Most cystic fibrosis (CF) patients become chronically infected with Pseudomonas aeruginosa in the lungs. The infection is characterized by a pronounced antibody response and a persistant inflammation dominated by polymorphonuclear neutrophils. Moreover a high antibody response correlates...... with a poor prognosis. We speculated that a change from this Th2-like response to a Th1-like response might decrease the lung inflammation and thus improve the prognosis in CF patients. To investigate this, we infected C3H/HeN and BALB/c mice intratracheally with P. aeruginosa. In addition, we studied...... with chronic P. aeruginosa lung infection have a better disease outcome compared to the Th2-reacting BALB/c mice, indicating that a Th1 response might be beneficial in CF patients with chronic P. aeruginosa lung infection....

  2. PER.C6(®) cells as a serum-free suspension cell platform for the production of high titer poliovirus: a potential low cost of goods option for world supply of inactivated poliovirus vaccine

    NARCIS (Netherlands)

    Sanders, Barbara P.; Edo-Matas, Diana; Custers, Jerome H. H. V.; Koldijk, Martin H.; Klaren, Vincent; Turk, Marije; Luitjens, Alfred; Bakker, Wilfried A. M.; Uytdehaag, Fons; Goudsmit, Jaap; Lewis, John A.; Schuitemaker, Hanneke

    2013-01-01

    There are two highly efficacious poliovirus vaccines: Sabin's live-attenuated oral polio vaccine (OPV) and Salk's inactivated polio vaccine (IPV). OPV can be made at low costs per dose and is easily administrated. However, the major drawback is the frequent reversion of the OPV vaccine strains to

  3. [Immunoreactivity of chimeric proteins carrying poliovirus epitopes on the VP6 of rotavirus as a vector].

    Science.gov (United States)

    Pan, X-X; Zhao, B-X; Teng, Y-M; Xia, W-Y; Wang, J; Li, X-F; Liao, G-Y; Yang, С; Chen, Y-D

    2016-01-01

    Rotavirus and poliovirus continue to present significant risks and burden of disease to children in developing countries. Developing a combined vaccine may effectively prevent both illnesses and may be advantageous in terms of maximizing compliance and vaccine coverage at the same visit. Recently, we sought to generate a vaccine vector by incorporating multiple epitopes into the rotavirus group antigenic protein, VP6. In the present study, a foreign epitope presenting a system using VP6 as a vector was created with six sites on the outer surface of the vector that could be used for insertion of foreign epitopes, and three VP6-based PV1 epitope chimeric proteins were constructed. The chimeric proteins were confirmed by immunoblot, immunofluorescence assay, and injected into guinea pigs to analyze the epitope-specific humoral response. Results showed that these chimeric proteins reacted with anti-VP6F and -PV1 antibodies, and elicited antibodies against both proteins in guinea pigs. Antibodies against the chimeric proteins carrying PV1 epitopes neutralized rotavirus Wa and PV1 infection in vitro. Our study contributes to a better understanding of the use of VP6-based vectors as multiple-epitope delivery vehicles and the epitopes displayed in this form could be considered for development of epitope-based vaccines against rotavirus and poliovirus.

  4. Immune responses to oral poliovirus vaccine in HIV-exposed uninfected Zimbabwean infants

    Science.gov (United States)

    Church, James A.; Rukobo, Sandra; Govha, Margaret; Carmolli, Marya P.; Diehl, Sean A.; Chasekwa, Bernard; Ntozini, Robert; Mutasa, Kuda; Humphrey, Jean H.; Kirkpatrick, Beth D.; Prendergast, Andrew J.

    2017-01-01

    ABSTRACT It remains uncertain whether HIV-exposed uninfected (HEU) infants have impaired responses to oral vaccines. We performed a cross-sectional study of 6-month-old infants recruited at birth to the ZVITAMBO trial in Zimbabwe between 1997–2001, before introduction of prevention of mother-to-child transmission interventions. We measured poliovirus-specific IgA to type 1–3 polio strains by semi-quantitative capture ELISA in cryopreserved serum samples collected from 85 HEU and 101 HIV-unexposed infants at 6 months of age, one month after their last immunisation with trivalent OPV. Almost all infants were breastfed, with the majority in both groups mixed breastfed (70.6% HEU versus 71.3% HIV-unexposed). Median (IQR) vaccine titers for HEU and HIV-unexposed infants were 1592 (618–4896) vs. 1774 (711–5431) for Sabin 1 (P = 0.46); 1895 (810–4398) vs. 2308 (1081–4283) for Sabin 2 (P = 0.52); and 1798 (774–4192) vs. 2260 (996–5723) for Sabin 3 (P = 0.18). There were no significant differences in vaccine titers between HEU and HIV-unexposed infants, suggesting that vertical HIV exposure does not impact oral poliovirus vaccine immunogenicity. PMID:28857649

  5. All-atom molecular dynamics calculation study of entire poliovirus empty capsids in solution

    Energy Technology Data Exchange (ETDEWEB)

    Andoh, Y.; Yoshii, N.; Yamada, A.; Kojima, H.; Mizutani, K.; Okazaki, S., E-mail: okazaki@apchem.nagoya-u.ac.jp [Department of Applied Chemistry, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603 (Japan); Fujimoto, K. [Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Nojihigashi, Kusatsu, Shiga 525-8577 (Japan); Nakagawa, A. [Institute for Protein Research, Osaka University, Yamadaoka, Suita, Osaka 565-0871 (Japan); Nomoto, A. [Institute of Microbial Chemistry, Kamiosaki, Shinagawa-ku, Tokyo 141-0021 (Japan)

    2014-10-28

    Small viruses that belong, for example, to the Picornaviridae, such as poliovirus and foot-and-mouth disease virus, consist simply of capsid proteins and a single-stranded RNA (ssRNA) genome. The capsids are quite stable in solution to protect the genome from the environment. Here, based on long-time and large-scale 6.5 × 10{sup 6} all-atom molecular dynamics calculations for the Mahoney strain of poliovirus, we show microscopic properties of the viral capsids at a molecular level. First, we found equilibrium rapid exchange of water molecules across the capsid. The exchange rate is so high that all water molecules inside the capsid (about 200 000) can leave the capsid and be replaced by water molecules from the outside in about 25 μs. This explains the capsid's tolerance to high pressures and deactivation by exsiccation. In contrast, the capsid did not exchange ions, at least within the present simulation time of 200 ns. This implies that the capsid can function, in principle, as a semipermeable membrane. We also found that, similar to the xylem of trees, the pressure of the solution inside the capsid without the genome was negative. This is caused by coulombic interaction of the solution inside the capsid with the capsid excess charges. The negative pressure may be compensated by positive osmotic pressure by the solution-soluble ssRNA and the counter ions introduced into it.

  6. Effect of booster doses of poliovirus vaccine in previously vaccinated children, Clinical Trial Results 2013.

    Science.gov (United States)

    Habib, Muhammad Atif; Soofi, Sajid; Mach, Ondrej; Samejo, Tariq; Alam, Didar; Bhatti, Zaid; Weldon, William C; Oberste, Steven M; Sutter, Roland; Bhutta, Zulfiqar A

    2016-07-19

    Considering the current polio situation Pakistan needs vaccine combinations to reach maximum population level immunity. The trial assessed whether inactivated poliovirus vaccine (IPV) can be used to rapidly boost immunity among children in Pakistan. A five-arm randomized clinical trial was conducted among children (6-24months, 5-6years and 10-11years). Children were randomized in four intervention arms as per the vaccines they received (bOPV, IPV, bOPV+vitamin A, and bOPV+IPV) and a control arm which did not receive any vaccine. Baseline seroprevalence of poliovirus antibodies and serological immune response 28days after intervention were assessed. The baseline seroprevalence was high for all serotypes and the three age groups [PV1: 97%, 100%, 96%, PV2: 86%, 100%, 99%, PV3: 83%, 95%, 87% for the three age groups respectively]. There was significantly higher rate of immune response observed in the study arms which included IPV (95-99%) compared with bOPV only arms (11-43%), [p0.5]. IPV has shown the ability to efficiently close existing immunity gaps in a vulnerable population of children in rural Pakistan. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Introduction of Inactivated Poliovirus Vaccine in National Immunization Program and Polio Endgame Strategy.

    Science.gov (United States)

    Vashishtha, Vipin M; Choudhary, Jaydeep; Yadav, Sangeeta; Unni, Jeeson C; Jog, Pramod; Kamath, Sachidanand S; Sachdeva, Anupam; Srirampur, Sanjay; Prajapati, Baldev; Parekh, Bakul J

    2016-08-08

    The World Health Organization declared India among other 10 countries in South East Region - as 'polio-free' in 2014. Since then, the Government of India (GoI) has scaled up its initiatives against polio endgame which targets virus eradication and sequential withdrawal of type 2 virus from oral polio vaccine (OPV). However, prior to choosing the switch from trivalent OPV (t-OPV) to bivalent OPV (b-OPV), it was suggested to include inactivated poliovirus vaccine (IPV) in the national immunization schedule to protect vaccine naïve population against type 2 poliovirus. The GoI declared introduction of single dose of intramuscular IPV at 14 weeks since October 2015. In addition, anticipating the scarcity of IPV at present in India, GoI also recommended two intradermal doses of IPV in few states since April 2016. This review discusses the programmatic implications of these strategies along with recommendations by the Advisory Committee on Vaccines and Immunization Practices of Indian Academy of Pediatrics (IAP-ACVIP) on polio endgame strategy.

  8. Lessons Learned From the Introduction of Inactivated Poliovirus Vaccine in Bangladesh.

    Science.gov (United States)

    Estivariz, Concepcion F; Snider, Cynthia J; Anand, Abhijeet; Hampton, Lee M; Bari, Tajul I; Billah, Mallick M; Chai, Shua J; Wassilak, Steven G; Heffelfinger, James D; Zaman, K

    2017-07-01

    We assessed programmatic adaptations and infants' uptake of inactivated poliovirus vaccine (IPV) after its introduction into the routine immunization schedule in Bangladesh. Using convenience and probability sampling, we selected 23 health facilities, 36 vaccinators, and 336 caregivers, within 5 districts and 3 city corporations. We collected data during August-October 2015 by conducting interviews, reviewing vaccination records, and observing activities. Knowledge about IPV was high among vaccinators (94%). No problems with IPV storage, transport, or waste disposal were detected, but shortages were reported in 20 health facilities (87%). Wastage per 5-dose vaccine vial was above the recommended 30% in 20 health facilities (87%); all were related to providing <5 doses per open vial. Among eligible infants, 87% and 86% received the third dose of pentavalent and oral poliovirus vaccine, respectively, but only 65% received IPV at the same visit. Among 73 infants not vaccinated with IPV, 58% of caregivers reported that vaccine was unavailable. Bangladesh successfully introduced IPV, but shortages related to insufficient global supply and high vaccine wastage in small outreach immunization sessions might reduce its impact on population immunity. Minimizing wastage and use of a 2-dose fractional-IPV schedule could extend IPV immunization to more children.

  9. Disruption of bbe02 by Insertion of a Luciferase Gene Increases Transformation Efficiency of Borrelia burgdorferi and Allows Live Imaging in Lyme Disease Susceptible C3H Mice.

    Directory of Open Access Journals (Sweden)

    Kamfai Chan

    Full Text Available Lyme disease is the most prevalent tick-borne disease in North America and Europe. The causative agent, Borrelia burgdorferi persists in the white-footed mouse. Infection with B. burgdorferi can cause acute to persistent multisystemic Lyme disease in humans. Some disease manifestations are also exhibited in the mouse model of Lyme disease. Genetic manipulation of B. burgdorferi remains difficult. First, B. burgdorferi contains a large number of endogenous plasmids with unique sequences encoding unknown functions. The presence of these plasmids needs to be confirmed after each genetic manipulation. Second, the restriction modification defense systems, including that encoded by bbe02 gene lead to low transformation efficiency in B. burgdorferi. Therefore, studying the molecular basis of Lyme pathogenesis is a challenge. Furthermore, investigation of the role of a specific B. burgdorferi protein throughout infection requires a large number of mice, making it labor intensive and expensive. To overcome the problems associated with low transformation efficiency and to reduce the number of mice needed for experiments, we disrupted the bbe02 gene of a highly infectious and pathogenic B. burgdorferi strain, N40 D10/E9 through insertion of a firefly luciferase gene. The bbe02 mutant shows higher transformation efficiency and maintains luciferase activity throughout infection as detected by live imaging of mice. Infectivity and pathogenesis of this mutant were comparable to the wild-type N40 strain. This mutant will serve as an ideal parental strain to examine the roles of various B. burgdorferi proteins in Lyme pathogenesis in the mouse model in the future.

  10. BAG3 (Bcl-2-Associated Athanogene-3) Coding Variant in Mice Determines Susceptibility to Ischemic Limb Muscle Myopathy by Directing Autophagy.

    Science.gov (United States)

    McClung, Joseph M; McCord, Timothy J; Ryan, Terence E; Schmidt, Cameron A; Green, Tom D; Southerland, Kevin W; Reinardy, Jessica L; Mueller, Sarah B; Venkatraman, Talaignair N; Lascola, Christopher D; Keum, Sehoon; Marchuk, Douglas A; Spangenburg, Espen E; Dokun, Ayotunde; Annex, Brian H; Kontos, Christopher D

    2017-07-18

    Critical limb ischemia is a manifestation of peripheral artery disease that carries significant mortality and morbidity risk in humans, although its genetic determinants remain largely unknown. We previously discovered 2 overlapping quantitative trait loci in mice, Lsq-1 and Civq-1, that affected limb muscle survival and stroke volume after femoral artery or middle cerebral artery ligation, respectively. Here, we report that a Bag3 variant (Ile81Met) segregates with tissue protection from hind-limb ischemia. We treated mice with either adeno-associated viruses encoding a control (green fluorescent protein) or 2 BAG3 (Bcl-2-associated athanogene-3) variants, namely Met81 or Ile81, and subjected the mice to hind-limb ischemia. We found that the BAG3 Ile81Met variant in the C57BL/6 (BL6) mouse background segregates with protection from tissue necrosis in a shorter congenic fragment of Lsq-1 (C.B6-Lsq1-3). BALB/c mice treated with adeno-associated virus encoding the BL6 BAG3 variant (Ile81; n=25) displayed reduced limb-tissue necrosis and increased limb tissue perfusion compared with Met81- (n=25) or green fluorescent protein- (n=29) expressing animals. BAG3Ile81, but not BAG3Met81, improved ischemic muscle myopathy and muscle precursor cell differentiation and improved muscle regeneration in a separate, toxin-induced model of injury. Systemic injection of adeno-associated virus-BAG3Ile81 (n=9), but not BAG3Met81 (n=10) or green fluorescent protein (n=5), improved ischemic limb blood flow and limb muscle histology and restored muscle function (force production). Compared with BAG3Met81, BAG3Ile81 displayed improved binding to the small heat shock protein (HspB8) in ischemic skeletal muscle cells and enhanced ischemic muscle autophagic flux. Taken together, our data demonstrate that genetic variation in BAG3 plays an important role in the prevention of ischemic tissue necrosis. These results highlight a pathway that preserves tissue survival and muscle function in the

  11. Studies towards the potential of poliovirus as a vector for the expression of HPV 16 virus-like-particles.

    NARCIS (Netherlands)

    Kuppeveld, F.J.M. van; Jong, A.S. de; Dijkman, H.B.P.M.; Andino, R.; Melchers, W.J.G.

    2002-01-01

    Development of human cervical carcinomas is associated with infection by certain human papillomavirus (HPV) types. Thus, protection against HPV infection through vaccination may prevent development of cervical cancer. The purpose of this study was to investigate the possibility of using a poliovirus

  12. Ausencia de circulación de poliovirus en departamentos colombianos con coberturas vacunales inferiores a 80%

    Directory of Open Access Journals (Sweden)

    María Mercedes González

    2012-08-01

    Full Text Available El presente estudio se propuso explorar la posible circulación silente de poliovirus salvajes y derivados de la vacuna (VDPV, por sus siglas en inglés, en departamentos de Colombia con cobertura de vacunación para polio (OPV, por sus siglas en inglés menor de 80%. Se colectaron 52 muestras de aguas residuales que se concentraron mediante precipitación con polietilenglicol y cloruro de sodio. La detección viral se realizó mediante aislamiento y la identificación por neutralización del efecto citopático, así como mediante reacción en cadena de la polimerasa convencional y en tiempo real, posterior a la transcripción reversa (TR-RCP y rTR-RCP. Los poliovirus aislados se caracterizaron por secuenciación del gen VP1. En dos de las 52 muestras hubo presencia de poliovirus Sabin 2 con más de 99% de similitud de secuencia con la cepa OPV Sabin 2. Se detectó circulación de enterovirus no polio en 17,3% de las muestras. Los serotipos identificados correspondieron a coxsackievirus B1, echovirus 30 y echovirus 11. No se detectaron evidencias de circulación de VDPV ni poliovirus salvaje en los departamentos de Colombia con coberturas de OPV inferiores a 80%.

  13. Estudio virológico de casos mortales de poliomelitis paralítica II. Aislamiento de Poliovirus de Líquido Cefalorraquídeo (post Mortem)

    OpenAIRE

    Célis G., Eduardo; Facultad de Medicina, Universidad Nacional Mayor de San Marcos, Lima, Perú; Nicho N., Nelly; Facultad de Medicina, Universidad Nacional Mayor de San Marcos, Lima, Perú

    2014-01-01

    6 samples of cerebrospinal fluid was subjected to virological study post-mortem, from 6 cases of Paralytic Poliomiellitis occurred in the Children's Hospital (Lima), having obtained the following results: In case 1, poliovirus type II was isolated; in case 3, poliovirus type III asisló; in case 4, Poliovirus Type I, and the cases 2, 5 and 6 were negative was isolated. Se sometió al estudio virológico 6 muestras de líquido cefalorraquídeo post-mortem, proveniente de 6 casos de Poliomielliti...

  14. Susceptibility and morbidity between male and female Swiss mice infected with Angiostrongylus costaricensis: Susceptibilidade e morbidade entre camundongos Swiss machos e fêmeas infectados com Angiostrongylus costaricensis

    Directory of Open Access Journals (Sweden)

    Márcia B. Mentz

    2010-10-01

    Full Text Available The gender of vertebrate hosts may affect the outcome of parasitic infections. An experimental murine infection with Angiostrongylus costaricensis was followed with determinations of body weight, fecal larval elimination, number and length of adult worms, number of macroscopic intestinal lesions, and mortality. Groups of male and female Swiss mice were infected with 10 3rd-stage A. costaricensis larvae per animal. The results indicate there are no significant differences related to gender of the host, except for higher length of worms developed in male mice.O sexo dos hospedeiros vertebrados pode influenciar no resultado de infecções parasitárias. A infecção experimental de camundongos com Angiostrongylus costaricensis foi acompanhada com observação do peso corporal, eliminação de larvas nas fezes, número e comprimento dos vermes adultos, número de lesões macroscópicas nos intestinos e mortalidade. Grupos de camundongos Swiss machos e fêmeas foram infectados cada um com 10 larvas de terceiro estágio de A. costaricensis. Os resultados indicam que não há diferenças significativas relacionados ao sexo dos hospedeiros, exceto pelo maior comprimento dos vermes nos hospedeiros machos.

  15. Differential susceptibility of C57BL/6NCr and B6.Cg-Ptprca mice to commensal bacteria after whole body irradiation in translational bone marrow transplant studies

    Directory of Open Access Journals (Sweden)

    Toubai Tomomi

    2008-02-01

    Full Text Available Abstract Background The mouse is an important and widely utilized animal model for bone marrow transplant (BMT translational studies. Here, we document the course of an unexpected increase in mortality of congenic mice that underwent BMT. Methods Thirty five BMTs were analyzed for survival differences utilizing the Log Rank test. Affected animals were evaluated by physical examination, necropsy, histopathology, serology for antibodies to infectious disease, and bacterial cultures. Results Severe bacteremia was identified as the main cause of death. Gastrointestinal (GI damage was observed in histopathology. The bacteremia was most likely caused by the translocation of bacteria from the GI tract and immunosuppression caused by the myeloablative irradiation. Variability in groups of animals affected was caused by increased levels of gamma and X-ray radiation and the differing sensitivity of the two nearly genetically identical mouse strains used in the studies. Conclusion Our retrospective analysis of thirty five murine BMTs performed in three different laboratories, identified C57BL/6NCr (Ly5.1 as being more radiation sensitive than B6.Cg-Ptprca/NCr (Ly5.2. This is the first report documenting a measurable difference in radiation sensitivity and its effects between an inbred strain of mice and its congenic counterpart eventually succumbing to sepsis after BMT.

  16. Mercury species in lymphoid and non-lymphoid tissues after exposure to methyl mercury: correlation with autoimmune parameters during and after treatment in susceptible mice

    DEFF Research Database (Denmark)

    Havarinasab, Said; Björn, Erik; Nielsen, Jesper Bo

    2007-01-01

    IA). This study aimed at exploring the effect of MeHg with regard to HgIA, and especially the immunological events after stopping treatment, correlated with the presence of MeHg and Hg(2+) in the organs. Treatment of A.SW mice for 30 days with 4.2 mg MeHg/L drinking water (corresponding to approximately 420...... microg Hg/kg body weight/day) caused all the HgIA features observed after primary treatment with inorganic Hg, except systemic immune complex deposits. The total Hg concentration was 5-fold higher in the kidneys as compared with lymph nodes, but the fraction of Hg(2+) was similar (17-20%). After stopping...

  17. CaMKII Activation Promotes Cardiac Electrical Remodeling and Increases the Susceptibility to Arrhythmia Induction in High-fat Diet-Fed Mice With Hyperlipidemia Conditions.

    Science.gov (United States)

    Zhong, Peng; Quan, Dajun; Huang, Yan; Huang, He

    2017-10-01

    Obesity/hyperlipidemia is closely related to both atrial and ventricular arrhythmias. CaMKII, a multifunctional serine/threonine kinase, has been involved in cardiac arrhythmias of different etiologies. However, its role in obesity/hyperlipidemia-related cardiac arrhythmia is unexplored. The aim of this was to determine the involvement of CaMKII in the process. Adult male APOE mice were fed a high-fat diet (HFD), administrated with KN93 (10 mg·kg·2d), a specific inhibitor of CaMKII. Serum lipid and glucose profile, cardiac function, and surface electrocardiogram were determined. Electrophysiological study and epicardial activation mapping were performed in Langendorff-perfused heart. Expression of cardiac ion channels, gap junction proteins, Ca handling proteins, and CaMKII were evaluated, coupled with histological analysis. A hyperlipidemia condition was induced by HFD in the APOE mice, which was associated with increased expression and activity of CaMKII in the hearts. In Langendorff-perfused hearts, HFD-induced heart showed increased arrhythmia inducibility, prolonged action potential duration, and decreased action potential duration alternans thresholds, coupled with slow ventricular conduction, connexin-43 upregulation, and interstitial fibrosis. Downregulation of ion channels including Cav1.2 and Kv4.2/Kv4.3 and disturbed Ca handling proteins were also observed in HFD-induced heart. Interestingly, all these alterations were significantly inhibited by KN93 treatment. Our results demonstrated an adverse effect of metabolic components on cardiac electrophysiology and implicated an important role of CaMKII underlying this process.

  18. Natural Type 3/Type 2 Intertypic Vaccine-Related Poliovirus Recombinants with the First Crossover Sites within the VP1 Capsid Coding Region

    DEFF Research Database (Denmark)

    Zhang, Yong; Zhu, Shuangli; Yan, Dongmei

    2010-01-01

    Ten uncommon natural type 3/type 2 intertypic poliovirus recombinants were isolated from stool specimens from nine acute flaccid paralysis case patients and one healthy vaccinee in China from 2001 to 2008....

  19. Integration of vitamin A supplementation with the expanded program on immunization does not affect seroconversion to oral poliovirus vaccine in infants.

    NARCIS (Netherlands)

    R.D. Semba; M. Muhilal; N.E. Mohgaddam (Nasrin); Z. Munasir; A. Akib; D. Permaesih; M.S. Muherdiyantiningsih; A.D.M.E. Osterhaus (Albert)

    1999-01-01

    textabstractChildhood immunization programs may provide infrastructure for delivering vitamin A supplements to infants in developing countries. The effect of giving vitamin A, an immune enhancer, on antibody responses to trivalent oral poliovirus vaccine (TOPV) is unknown. A

  20. Pulmonary but Not Subcutaneous Delivery of BCG Vaccine Confers Protection to Tuberculosis-Susceptible Mice by an Interleukin 17-Dependent Mechanism.

    Science.gov (United States)

    Aguilo, Nacho; Alvarez-Arguedas, Samuel; Uranga, Santiago; Marinova, Dessislava; Monzón, Marta; Badiola, Juan; Martin, Carlos

    2016-03-01

    Some of the most promising novel tuberculosis vaccine strategies currently under development are based on respiratory vaccination, mimicking the natural route of infection. In this work, we have compared pulmonary and subcutaneous delivery of BCG vaccine in the tuberculosis-susceptible DBA/2 mouse strain, a model in which parenterally administered BCG vaccine does not protect against tuberculosis. Our data show that intranasally but not subcutaneously administered BCG confers robust protection against pulmonary tuberculosis challenge. In addition, our results indicate that pulmonary vaccination triggers a Mycobacterium tuberculosis-specific mucosal immune response orchestrated by interleukin 17A (IL-17A). Thus, IL-17A neutralization in vivo reduces protection and abrogates M. tuberculosis-specific immunoglobulin A (IgA) secretion to respiratory airways and lung expression of polymeric immunoglobulin receptor induced following intranasal vaccination. Together, our results demonstrate that pulmonary delivery of BCG can overcome the lack of protection observed when BCG is given parenterally, suggesting that respiratory tuberculosis vaccines could have an advantage in tuberculosis-endemic countries, where intradermally administered BCG has inefficient effectiveness against pulmonary tuberculosis. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  1. Molecular characterization and phylogenetic relationship of wild type 1 poliovirus strains circulating across Pakistan and Afghanistan bordering areas during 2010-2012.

    Directory of Open Access Journals (Sweden)

    Shahzad Shaukat

    Full Text Available Pakistan and Afghanistan share a long uncontrolled border with extensive population movement on both sides. Wild poliovirus transmission has never been interrupted in this block due to war against terrorism, poor public health infrastructure, misconceptions about polio vaccines and inadequate immunization activities. All these issues complicate the eradication operations and reinforce the complexity of wiping out poliomyelitis from this region. This study illustrates the origins and routes of cross-border wild poliovirus type 1 (WPV1 transmission during 2010-2012 between Pakistan and Afghanistan. Sequence analyses were conducted based on complete VP1 capsid protein sequences for WPV1 study strains to determine the origin of poliovirus genetic lineages and their evolutionary relationships. Phylogenetic tree was constructed from VP1 gene sequences applying Maximum Likelihood method using Kimura 2- parameter model in MEGA program v 5.0. A total of 72 (14.3% out of 502 wild-type 1 polioviruses were found circulating in border areas of both countries during 2010-2012. Molecular phylogenetic analysis classified these strains in to two sub-genotypes with four clusters and 18 lineages. Genetic data confirmed that the most of WPV1 lineages (12; 66.6% were transmitted from Pakistan to Afghanistan. However, the genetic diversity was significantly reduced during 2012 as most of the lineages were completely eliminated. In conclusion, Pakistan-Afghanistan block has emerged as a single poliovirus reservoir sharing the multiple poliovirus lineages due to uncontrolled movement of people across the borders between two countries. If it is neglected, it can jeopardize the extensive global efforts done so-far to eradicate the poliovirus infection. Our data will be helpful to devise the preventive strategies for effective control of wild poliovirus transmission in this region.

  2. Antigenic modification of attenuated Sabin type 1 poliovirus by in vitro passages at supraoptimal temperatures.

    Science.gov (United States)

    Crainic, R; Blondel, B; Candréa, A; Dufraisse, G; Horaud, F

    1985-01-01

    Mutants were selected from Sabin type 1 attenuated poliovirus (LSc2ab strain), capable of growing at a high temperature (39.5 degrees C). They proved to be neurovirulent for monkeys. No correlation was found between neurovirulence and antigenic structure in Sabin type 1 virus as demonstrated by the analysis of the neutralization epitope formulae of thermo-resistant, neurovirulent mutants derived from LSs2ab strain. The lack of correlation between the antigenic pattern of the virus and the virulence was also confirmed by a mutant resistant to neutralization with monoclonal antibodies derived from the wild Mahoney parent of the Sabin type 1 virus. This mutant continued to be neurovirulent in spite of the complete conversion of its neutralization epitope formula to the Sabin virus pattern.

  3. Structure of the Fab-Labeled “Breathing” State of Native Poliovirus

    Science.gov (United States)

    Lin, Jun; Lee, Lily Y.; Roivainen, Merja; Filman, David J.; Hogle, James M.

    2012-01-01

    At 37°C, the structure of poliovirus is dynamic, and internal polypeptides VP4 and N terminus of VP1 (residues 1 to 53) externalize reversibly. An Fab fragment of a monospecific antibody, which binds to residues 39 to 55 of VP1, was utilized to locate the N termini of VP1 in native (160S) particles in this “breathing” state. Fab and virus were mixed and imaged via cryogenic electron microscopy. The resulting reconstruction showed the capsid expands similarly to the irreversibly altered cell entry intermediate (135S) particle, but the N terminus of VP1 is located near the 2-fold axes, instead of the “propeller tip” as in 135S particles. PMID:22398295

  4. Survival of polioviruses and echoviruses in Acanthamoeba castellanii cultivated in vitro.

    Science.gov (United States)

    Danes, L; Cerva, L

    1981-01-01

    Cultures of Acanthamoeba castellanii, kept at room temperature in sterile Bacto-Casitone (Difco) medium, were artificially infected with vaccination poliovirus strains type 1 and type 3 and with echovirus type 4 and echovirus type 30. No remarkable virus cumulation was observed on the surface or inside amoeba cells during the observation period of 21 days. Amoeba-adsorbed viruses were impossible to remove by repeated washings. Virus neutralization with specific antisera showed that enteroviruses were most probably present only on amoeba surfaces. In contrast to amoeba-free virus suspension, echoviruses bound to amoebae and their cell pulp persisted even after 52 to 75 days. However, the tested amoeba species played only the role of a solids-like carrier in this survival of echoviruses.

  5. Molecular epidemiology of wild poliovirus type 1 circulation in West and Central Africa, from 1997 to 1999, using genotyping with a restriction fragment length polymorphism assay.

    Science.gov (United States)

    Gouandjika-Vasilache, Ionela; Burns, Cara C; Gumede, Nicksy; Guillot, Sophie; Ménard, Didier; Dosseh, Annick; Akoua-Koffi, Chantal; Pallansch, Mark A; Kew, Olen M; Delpeyroux, Francis

    2008-01-01

    Virological surveillance is an important element in the Polio Eradication Initiative to provide information rapidly about circulating wild polioviruses. Molecular tools have been developed to identify the serotype of the poliovirus strains and whether they are of vaccine or wild origin (intratypic differentiation) and to perform the molecular epidemiology of wild strains. The main objective of this study was to show that restriction fragment length polymorphism (RFLP) is a tool that can be used for molecular epidemiology of wild polioviruses. This is retrospective study of poliovirus type 1 strains received at the Institut Pasteur of Bangui (IPB), a WHO Regional Reference Laboratory for Africa, since 1994. We describe our experience with isolates from Western and Central Africa and show a positive correlation between the genotypes as determined by sequencing the gene for the VP1 capsid protein and the RFLP patterns. Although genomic sequencing is the gold standard method for detailed molecular epidemiology analysis of poliovirus isolates, these results show that RFLP is a potentially valuable tool for molecular epidemiological analysis of poliovirus type 1 strains: it could be used by many laboratories as a rapid method for ITD and genotype screening where sequencing capacity is not readily available.

  6. RNA Transfer from Poliovirus 135S Particles across Membranes Is Mediated by Long Umbilical Connectors

    Science.gov (United States)

    Strauss, Mike; Levy, Hazel C.; Bostina, Mihnea; Filman, David J.

    2013-01-01

    During infection, the binding of poliovirus to its cell surface receptor at 37°C triggers an expansion of the virus in which internal polypeptides that bind to membranes are externalized. Subsequently, in a poorly understood process, the viral RNA genome is transferred directly across an endosomal membrane, and into the host cell cytoplasm, to initiate infection. Here, cryoelectron tomography demonstrates the results of 37°C warming of a poliovirus-receptor-liposome model complex that was produced using Ni-nitrilotriacetic acid lipids and His-tagged receptor ectodomains. In total, 651 subtomographic volumes were aligned, classified, and averaged to obtain detailed pictures, showing both the conversion of virus into its expanded form and the passage of RNA into intact liposomes. Unexpectedly, the virus and membrane surfaces were located ∼50 Å apart, with the 5-fold axis tilted away from the perpendicular, and the solvent spaces between them were spanned by either one or two long “umbilical” density features that lie at an angle to the virus and membrane. The thinner connector, which sometimes appears alone, is 28 to 30 Å in diameter and has a footprint on the virus surface located close to either a 5-fold or a 3-fold axis. The broader connector has a footprint near the quasi-3-fold hole that opens upon virus expansion and is hypothesized to include RNA, shielded from enzymatic degradation by polypeptides that include the N-terminal extension of VP1 and capsid protein VP4. The implications of these observations for the mechanism of RNase-protected RNA transfer in picornaviruses are discussed. PMID:23365424

  7. Poliovirus RNA Is Released from the Capsid near a Twofold Symmetry Axis ▿

    Science.gov (United States)

    Bostina, Mihnea; Levy, Hazel; Filman, David J.; Hogle, James M.

    2011-01-01

    After recognizing and binding to its host cell, poliovirus (like other nonenveloped viruses) faces the challenge of translocating its genome across a cellular membrane and into the cytoplasm. To avoid entanglement with the capsid, the RNA must exit via a single site on the virion surface. However, the mechanism by which a single site is selected (from among 60 equivalents) is unknown; and until now, even its location on the virion surface has been controversial. To help to elucidate the mechanism of infection, we have used single-particle cryo-electron microscopy and tomography to reconstruct conformationally altered intermediates that are formed by the poliovirion at various stages of the poliovirus infection process. Recently, we reported icosahedrally symmetric structures for two forms of the end-state 80S empty capsid particle. Surprisingly, RNA was frequently visible near the capsid; and in a subset of the virions, RNA was seen on both the inside and outside of the capsid, caught in the act of exiting. To visualize RNA exiting, we have now determined asymmetric reconstructions from that subset, using both single-particle cryo-electron microscopy and cryo-electron tomographic methods, producing independent reconstructions at ∼50-Å resolution. Contrary to predictions in the literature, the footprint of RNA on the capsid surface is located close to a viral 2-fold axis, covering a slot-shaped area of reduced density that is present in both of the symmetrized 80S reconstructions and which extends by about 20 Å away from the 2-fold axis toward each neighboring 5-fold axis. PMID:20980499

  8. An Externalized Polypeptide Partitions between Two Distinct Sites on Genome-Released Poliovirus Particles ▿

    Science.gov (United States)

    Lin, Jun; Cheng, Naiqian; Chow, Marie; Filman, David J.; Steven, Alasdair C.; Hogle, James M.; Belnap, David M.

    2011-01-01

    During cell entry, native poliovirus (160S) converts to a cell-entry intermediate (135S) particle, resulting in the externalization of capsid proteins VP4 and the amino terminus of VP1 (residues 1 to 53). Externalization of these entities is followed by release of the RNA genome (uncoating), leaving an empty (80S) particle. The antigen-binding fragment (Fab) of a monospecific peptide 1 (P1) antibody, which was raised against a peptide corresponding to amino-terminal residues 24 to 40 of VP1, was utilized to track the location of the amino terminus of VP1 in the 135S and 80S states of poliovirus particles via cryogenic electron microscopy (cryo-EM) and three-dimensional image reconstruction. On 135S, P1 Fabs bind to a prominent feature on the external surface known as the “propeller tip.” In contrast, our initial 80S-P1 reconstruction showed P1 Fabs also binding to a second site, at least 50 Å distant, at the icosahedral 2-fold axes. Further analysis showed that the overall population of 80S-P1 particles consisted of three kinds of capsids: those with P1 Fabs bound only at the propeller tips, P1 Fabs bound only at the 2-fold axes, or P1 Fabs simultaneously bound at both positions. Our results indicate that, in 80S particles, a significant fraction of VP1 can deviate from icosahedral symmetry. Hence, this portion of VP1 does not change conformation synchronously when switching from the 135S state. These conclusions are compatible with previous observations of multiple conformations of the 80S state and suggest that movement of the amino terminus of VP1 has a role in uncoating. Similar deviations from icosahedral symmetry may be biologically significant during other viral transitions. PMID:21775460

  9. Inactivation of Ascaris suum and poliovirus in biosolids under thermophilic anaerobic digestion conditions.

    Science.gov (United States)

    Aitken, Michael D; Sobsey, Mark D; Blauth, Kimberly E; Shehee, Mina; Crunk, Phillip L; Walters, Glenn W

    2005-08-01

    There is considerable interest in the United States in production of Class A (low pathogen content) biosolids from the treatment of municipal wastewater sludge. Current requirements imposed by the U.S. Environmental Protection Agency make it difficult for thermophilic anaerobic digestion, in its simplest process configurations, to achieve Class A status. In particular, the time-temperature requirements necessitate long batch treatment times at temperatures associated with thermophilic anaerobic digestion. The time-temperature requirements are meant to ensure extensive inactivation of helminth eggs and enteric viruses, considered to be the most heat-resistant of the relevant pathogen classes. However, data on inactivation kinetics of these pathogens at precisely controlled and well-characterized temperatures are scarce. We measured inactivation of vaccine-strain poliovirus and eggs from the helminth Ascaris suum at temperatures from 49 to 55 degrees C in a lab-scale batch reactor containing biosolids from a continuous-flow thermophilic anaerobic digester. Both microbes were inactivated rapidly, with Ascaris more resistant to inactivation than poliovirus, and the relationships between inactivation rate and temperature were steep. The Arrhenius correlation between inactivation rate and temperature over the range 49-53 degrees C is consistent with protein denaturation as the inactivation mechanism for both microbes. The least stringent of the EPA time-temperature equations for thermal processes requires batch treatment times more than 2 orders of magnitude greater than would be required for three-log reduction of Ascaris at the rates we measured, suggesting an overly conservative regulatory approach. Such a grossly conservative approach can hinder full-scale implementation of thermophilic anaerobic digestion.

  10. Structures of coxsackievirus, rhinovirus, and poliovirus polymerase elongation complexes solved by engineering RNA mediated crystal contacts.

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    Peng Gong

    Full Text Available RNA-dependent RNA polymerases play a vital role in the growth of RNA viruses where they are responsible for genome replication, but do so with rather low fidelity that allows for the rapid adaptation to different host cell environments. These polymerases are also a target for antiviral drug development. However, both drug discovery efforts and our understanding of fidelity determinants have been hampered by a lack of detailed structural information about functional polymerase-RNA complexes and the structural changes that take place during the elongation cycle. Many of the molecular details associated with nucleotide selection and catalysis were revealed in our recent structure of the poliovirus polymerase-RNA complex solved by first purifying and then crystallizing stalled elongation complexes. In the work presented here we extend that basic methodology to determine nine new structures of poliovirus, coxsackievirus, and rhinovirus elongation complexes at 2.2-2.9 Å resolution. The structures highlight conserved features of picornaviral polymerases and the interactions they make with the template and product RNA strands, including a tight grip on eight basepairs of the nascent duplex, a fully pre-positioned templating nucleotide, and a conserved binding pocket for the +2 position template strand base. At the active site we see a pre-bound magnesium ion and there is conservation of a non-standard backbone conformation of the template strand in an interaction that may aid in triggering RNA translocation via contact with the conserved polymerase motif B. Moreover, by engineering plasticity into RNA-RNA contacts, we obtain crystal forms that are capable of multiple rounds of in-crystal catalysis and RNA translocation. Together, the data demonstrate that engineering flexible RNA contacts to promote crystal lattice formation is a versatile platform that can be used to solve the structures of viral RdRP elongation complexes and their catalytic cycle

  11. Level and specificity of antibodies evoked by crude and purified antigens of poliovirus I and echovirus 7.

    Science.gov (United States)

    Frommhagen, L H

    1965-11-01

    Preparations of poliovirus I and echovirus 7, purified by density gradient centrifugation, liquid-phase partition, and anion exchange (diethylaminoethyl) chromatography, have been shown to evoke high antibody levels of substantial specificity in the complement-fixation assay. Certain practical aspects of the three purification methods are discussed. These results argue for the use of purified viral antigens, particularly in view of the simplicity of the purification methods now available.

  12. Cross-border collaboration between China and Myanmar for emergency response to imported vaccine derived poliovirus case

    OpenAIRE

    Wang, Hai-Bo; Zhang, Li-Fen; Yu, Wen-Zhou; Wen, Ning; Yan, Dong-Mei; Tang, Jing-Jing; Zhang, Yong; Fan, Chun-Xiang; Reilly, Kathleen H.; Xu, Wen-Bo; Li, Li; Ding, Zheng-Rong; Luo, Hui-Ming

    2015-01-01

    Background This report describes emergency response following an imported vaccine derived poliovirus (VDPV) case from Myanmar to Yunnan Province, China and the cross-border collaboration between China and Myanmar. Immediately after confirmation of the VDPV case, China disseminated related information to Myanmar with the assistance of the World Health Organization. Methods A series of epidemiological investigations were conducted, both in China and Myanmar, including retrospective searches of ...

  13. Cryo-electron Microscopy Structures of Expanded Poliovirus with VHHs Sample the Conformational Repertoire of the Expanded State.

    Science.gov (United States)

    Strauss, Mike; Schotte, Lise; Karunatilaka, Krishanthi S; Filman, David J; Hogle, James M

    2017-02-01

    By using cryo-electron microscopy, expanded 80S-like poliovirus virions (poliovirions) were visualized in complexes with four 80S-specific camelid VHHs (Nanobodies). In all four complexes, the VHHs bind to a site on the top surface of the capsid protein VP3, which is hidden in the native virus. Interestingly, although the four VHHs bind to the same site, the structures of the expanded virus differ in detail in each complex, suggesting that each of the Nanobodies has sampled a range of low-energy structures available to the expanded virion. By stabilizing unique structures of expanded virions, VHH binding permitted a more detailed view of the virus structure than was previously possible, leading to a better understanding of the expansion process that is a critical step in infection. It is now clear which polypeptide chains become disordered and which become rearranged. The higher resolution of these structures also revealed well-ordered conformations for the EF loop of VP2, the GH loop of VP3, and the N-terminal extensions of VP1 and VP2, which, in retrospect, were present in lower-resolution structures but not recognized. These structural observations help to explain preexisting mutational data and provide insights into several other stages of the poliovirus life cycle, including the mechanism of receptor-triggered virus expansion. When poliovirus infects a cell, it undergoes a change in its structure in order to pass RNA through its protein coat, but this altered state is short-lived and thus poorly understood. The structures of poliovirus bound to single-domain antibodies presented here capture the altered virus in what appear to be intermediate states. A careful analysis of these structures lets us better understand the molecular mechanism of infection and how these changes in the virus lead to productive-infection events. Copyright © 2017 American Society for Microbiology.

  14. Cryo-electron Microscopy Structures of Expanded Poliovirus with VHHs Sample the Conformational Repertoire of the Expanded State

    Science.gov (United States)

    Strauss, Mike; Schotte, Lise; Karunatilaka, Krishanthi S.; Filman, David J.

    2016-01-01

    ABSTRACT By using cryo-electron microscopy, expanded 80S-like poliovirus virions (poliovirions) were visualized in complexes with four 80S-specific camelid VHHs (Nanobodies). In all four complexes, the VHHs bind to a site on the top surface of the capsid protein VP3, which is hidden in the native virus. Interestingly, although the four VHHs bind to the same site, the structures of the expanded virus differ in detail in each complex, suggesting that each of the Nanobodies has sampled a range of low-energy structures available to the expanded virion. By stabilizing unique structures of expanded virions, VHH binding permitted a more detailed view of the virus structure than was previously possible, leading to a better understanding of the expansion process that is a critical step in infection. It is now clear which polypeptide chains become disordered and which become rearranged. The higher resolution of these structures also revealed well-ordered conformations for the EF loop of VP2, the GH loop of VP3, and the N-terminal extensions of VP1 and VP2, which, in retrospect, were present in lower-resolution structures but not recognized. These structural observations help to explain preexisting mutational data and provide insights into several other stages of the poliovirus life cycle, including the mechanism of receptor-triggered virus expansion. IMPORTANCE When poliovirus infects a cell, it undergoes a change in its structure in order to pass RNA through its protein coat, but this altered state is short-lived and thus poorly understood. The structures of poliovirus bound to single-domain antibodies presented here capture the altered virus in what appear to be intermediate states. A careful analysis of these structures lets us better understand the molecular mechanism of infection and how these changes in the virus lead to productive-infection events. PMID:27852863

  15. Combined use of inactivated and oral poliovirus vaccines in refugee camps and surrounding communities - Kenya, December 2013.

    Science.gov (United States)

    Sheikh, Mohamed A; Makokha, Frederick; Hussein, Abdullahi M; Mohamed, Gedi; Mach, Ondrej; Humayun, Kabir; Okiror, Samuel; Abrar, Leila; Nasibov, Orkhan; Burton, John; Unshur, Ahmed; Wannemuehler, Kathleen; Estivariz, Concepcion F

    2014-03-21

    Since the launch of the Global Polio Eradication Initiative (GPEI) in 1988, circulation of indigenous wild poliovirus (WPV) has continued without interruption in only three countries: Afghanistan, Nigeria, and Pakistan. During April-December 2013, a polio outbreak caused by WPV type 1 (WPV1) of Nigerian origin resulted in 217 cases in or near the Horn of Africa, including 194 cases in Somalia, 14 cases in Kenya, and nine cases in Ethiopia (all cases were reported as of March 10, 2014). During December 14-18, 2013, Kenya conducted the first-ever campaign providing inactivated poliovirus vaccine (IPV) together with oral poliovirus vaccine (OPV) as part of its outbreak response. The campaign targeted 126,000 children aged ≤59 months who resided in Somali refugee camps and surrounding communities near the Kenya-Somalia border, where most WPV1 cases had been reported, with the aim of increasing population immunity levels to ensure interruption of any residual WPV transmission and prevent spread from potential new importations. A campaign evaluation and vaccination coverage survey demonstrated that combined administration of IPV and OPV in a mass campaign is feasible and can achieve coverage >90%, although combined IPV and OPV campaigns come at a higher cost than OPV-only campaigns and require particular attention to vaccinator training and supervision. Future operational studies could assess the impact on population immunity and the cost-effectiveness of combined IPV and OPV campaigns to accelerate interruption of poliovirus transmission during polio outbreaks and in certain areas in which WPV circulation is endemic.

  16. Effect of substituting IPV for tOPV on immunity to poliovirus in Bangladeshi infants: An open-label randomized controlled trial.

    Science.gov (United States)

    Mychaleckyj, Josyf C; Haque, Rashidul; Carmolli, Marya; Zhang, Dadong; Colgate, E Ross; Nayak, Uma; Taniuchi, Mami; Dickson, Dorothy; Weldon, William C; Oberste, M Steven; Zaman, K; Houpt, Eric R; Alam, Masud; Kirkpatrick, Beth D; Petri, William A

    2016-01-12

    The Polio Endgame strategy includes phased withdrawal of oral poliovirus vaccines (OPV) coordinated with introduction of inactivated poliovirus vaccine (IPV) to ensure population immunity. The impact of IPV introduction into a primary OPV series of immunizations in a developing country is uncertain. Between May 2011 and November 2012, we enrolled 700 Bangladeshi infant-mother dyads from Dhaka slums into an open-label randomized controlled trial to test whether substituting an injected IPV dose for the standard Expanded Program on Immunization (EPI) fourth tOPV dose at infant age 39 weeks would reduce fecal shedding and enhance systemic immunity. The primary endpoint was mucosal immunity to poliovirus at age one year, measured by fecal excretion of any Sabin virus at five time points up to 25 days post-52 week tOPV challenge, analyzed by the intention to treat principle. We randomized 350 families to the tOPV and IPV vaccination arms. Neither study arm resulted in superior intestinal protection at 52 weeks measured by the prevalence of infants shedding any of three poliovirus serotypes, but the IPV dose induced significantly higher seroprevalence and seroconversion rates. This result was identical for poliovirus detection by cell culture or RT-qPCR. The non-significant estimated culture-based shedding risk difference was -3% favoring IPV, and the two vaccination schedules were inferred to be equivalent within a 95% confidence margin of -10% to +4%. Results for shedding analyses stratified by poliovirus type were similar. Neither of the vaccination regimens is superior to the other in enhancing intestinal immunity as measured by poliovirus shedding at 52 weeks of age and the IPV regimen provides similar intestinal immunity to the four tOPV series, although the IPV regimen strongly enhances humoral immunity. The IPV-modified regimen may be considered for vaccination programs without loss of intestinal protection. Copyright © 2015 The Authors. Published by Elsevier

  17. A stable HeLa cell line that inducibly expresses poliovirus 2A(pro): effects on cellular and viral gene expression.

    Science.gov (United States)

    Barco, A; Feduchi, E; Carrasco, L

    2000-03-01

    A HeLa cell clone (2A7d) that inducibly expresses the gene for poliovirus protease 2A (2A(pro)) under the control of tetracycline has been obtained. Synthesis of 2A(pro) induces severe morphological changes in 2A7d cells. One day after tetracycline removal, cells round up and a few hours later die. Poliovirus 2A(pro) cleaves both forms of initiation factor eIF4G, causing extensive inhibition of capped-mRNA translation a few hours after protease induction. Methoxysuccinyl-Ala-Ala-Pro-Val-chloromethylketone, a selective inhibitor of 2A(pro), prevents both eIF4G cleavage and inhibition of translation but not cellular death. Expression of 2A(pro) still allows both the replication of poliovirus and the translation of mRNAs containing a picornavirus leader sequence, while vaccinia virus replication is drastically inhibited. Translation of transfected capped mRNA is blocked in 2A7d-On cells, while luciferase synthesis from a mRNA bearing a picornavirus internal ribosome entry site (IRES) sequence is enhanced by the presence of 2A(pro). Moreover, synthesis of 2A(pro) in 2A7d cells complements the translational defect of a poliovirus 2A(pro)-defective variant. These results show that poliovirus 2A(pro) expression mimics some phenotypical characteristics of poliovirus-infected cells, such as cell rounding, inhibition of protein synthesis and enhancement of IRES-driven translation. This cell line constitutes a useful tool to further analyze 2A(pro) functions, to complement poliovirus 2A(pro) mutants, and to test antiviral compounds.

  18. Relação entre a patogenicidade do Schistosoma mansoni em camundongos e a susceptibilidade do molusco vetor: III. Mortalidade, pesos corporal e das vísceras Relationship between the pathogenicity of Schistosoma mansoni in mice and the susceptibility of the vector mollusc: III. Mortality, body weight and viscera weights

    Directory of Open Access Journals (Sweden)

    Eliana Maria Zanotti-Magalhães

    1995-08-01

    Full Text Available Estudou-se a relação entre o desenvolvimento da hepatomegalia, da esplenomegalia, peso corporal e taxa de mortalidade em camundongos experimentalmente infectados por Schistosoma mansoni com o grau de susceptibilidade de Biomphalaria glahrata e B. tenagophila nas quais se desenvolveram as cercárias infectantes respectivamente, das linhagens BH e SJ. Foram utilizados como hospedeiro definitivo camundongos Swiss, SPF e como hospedeiros intermediários populações de moluscos selecionados geneticamente para o caráter susceptibilidade. Foram observados menores pesos corporais e das visceras em camundongos infectados com cercárias provenientes de moluscos que apresentaram elevado grau de susceptibilidade. A maior susceptibilidade dos moluscos à infecção pelo S. mansoni correspondeu a uma menor sobrevivência dos camundongos infectados. Os resultados fazem crer que a maior adaptação do parasita ao hospedeiro intermediário, traduzidos pelas taxas mais elevadas de susceptibilidade, pode levar a um comportamento diferente deste parasita no hospedeiro definitivo.The relationship between the development of hepatomegaly, splenomegaly, body weight and mortality rate and the degree of susceptibility of Biomphalaria glabrata and B. tenagophila at which infective cercariae developed was studied. The study utilized Swiss mice, SPF, as definitive hosts and populations of snails genetically selected for character susceptibility as intermediate hosts. Low body weight and smaller viscera were observed in infected mice with cercariae originating from snails that showed a high degree of susceptibility. The higher susceptibility of molluscs infected with S. mansoni corresponded to a lower survival of the infected mice. These results lead to the conclusion that the higher degree of adaptation of the parasite to its intermediate hosts, evidenced by the high indexes of susceptibility, leads to different behaviour on the part of this parasite in its definitive

  19. Neurovirulent vaccine-derived polioviruses in sewage from highly immune populations.

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    Lester M Shulman

    Full Text Available BACKGROUND: Vaccine-derived polioviruses (VDPVs have caused poliomyelitis outbreaks in communities with sub-optimal vaccination. Israeli environmental surveillance of sewage from populations with high (>95% documented vaccine coverage of confirmed efficacy identified two separate evolutionary clusters of VDPVs: Group 1 (1998-2005, one system, population 1.6x10(6 and Group 2 (2006, 2 systems, populations 0.7x10(6 and 5x10(4. PRINCIPAL FINDINGS: Molecular analyses support evolution of nine Group 1 VDPVs along five different lineages, starting from a common ancestral type 2 vaccine-derived Sabin-2/Sabin-1 recombinant strain, and independent evolution of three Group 2 VDPVs along one lineage starting from a different recombinant strain. The primary evidence for two independent origins was based on comparison of unique recombination fingerprints, the number and distribution of identical substitutions, and evolutionary rates. Geometric mean titers of neutralizing antibodies against Group 1 VDPVs were significantly lower than against vaccine strains in all age-group cohorts tested. All individuals had neutralizing titers >1:8 against these VDPVs except 7% of the 20-50 year cohort. Group 1 VDPVs were highly neurovirulent in a transgenic mouse model. Intermediate levels of protective immunity against Group 2 VDPVs correlated with fewer (5.0+1.0 amino acid substitutions in neutralizing antigenic sites than in Group 1 VDPV's (12.1+/-1.5. SIGNIFICANCE: VDPVs that revert from live oral attenuated vaccines and reacquire characteristics of wild-type polioviruses not only threaten populations with poor immune coverage, but are also a potential source for re-introduction of poliomyelitis into highly immune populations through older individuals with waning immunity. The presence of two independently evolved groups of VDPVs in Israel and the growing number of reports of environmental VDPV elsewhere make it imperative to determine the global frequency of

  20. Alternative inactivated poliovirus vaccines adjuvanted with Quillaja brasiliensis or Quil-a saponins are equally effective in inducing specific immune responses.

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    Fernanda de Costa

    Full Text Available Inactivated polio vaccines (IPV have an important role at the final stages of poliomyelitis eradication programs, reducing the risks associated with the use of attenuated polio vaccine (OPV. An affordable option to enhance vaccine immunogenicity and reduce costs of IPV may be the use of an effective and renewable adjuvant. In the present study, the adjuvant activity of aqueous extract (AE and saponin fraction QB-90 from Quillaja brasiliensis using poliovirus antigen as model were analyzed and compared to a preparation adjuvanted with Quil-A, a well-known saponin-based commercial adjuvant. Experimental vaccines were prepared with viral antigen plus saline (control, Quil-A (50 µg, AE (400 µg or QB-90 (50 µg. Sera from inoculated mice were collected at days 0, 28, 42 and 56 post-inoculation of the first dose of vaccine. Serum levels of specific IgG, IgG1 and IgG2a were significantly enhanced by AE, QB-90 and Quil-A compared to control group on day 56. The magnitude of enhancement was statistically equivalent for QB-90 and Quil-A. The cellular response was evaluated through DTH and analysis of IFN-γ and IL-2 mRNA levels using in vitro reestimulated splenocytes. Results indicated that AE and QB-90 were capable of stimulating the generation of Th1 cells against the administered antigen to the same extent as Quil-A. Mucosal immune response was enhanced by the vaccine adjuvanted with QB-90 as demonstrated by increases of specific IgA titers in bile, feces and vaginal washings, yielding comparable or higher titers than Quil-A. The results obtained indicate that saponins from Q. brasiliensis are potent adjuvants of specific cellular and humoral immune responses and represent a viable option to Quil-A.

  1. Intensified environmental surveillance supporting the response to wild poliovirus type 1 silent circulation in Israel, 2013.

    Science.gov (United States)

    Manor, Y; Shulman, L M; Kaliner, E; Hindiyeh, M; Ram, D; Sofer, D; Moran-Gilad, J; Lev, B; Grotto, I; Gamzu, R; Mendelson, E

    2014-02-20

    An emergency response was triggered by recovery of wild poliovirus type 1 (WPV1) of the South Asia (SOAS) lineage from sewage in southern Israel in April 2013 during routine environmental surveillance. Public health risk assessment necessitated intensification of environmental surveillance in order to facilitate countrywide monitoring of WPV1-SOAS circulation. This involved increasing sampling frequency and broadening the geographical area, for better coverage of the population at risk, as well as modifying sewage testing algorithms to accommodate a newly developed WPV1-SOAS-specific quantitative real-time RT-PCR assay for screening of RNA extracted directly from sewage concentrates, in addition to standard virus isolation. Intensified surveillance in 74 sites across Israel between 1 February and 31 August 2013 documented a sustained high viral load of WPV1-SOAS in sewage samples from six Bedouin settlements and two cities with Jewish and Arab populations in the South district. Lower viral loads and intermittent detection were documented in sampling sites representing 14 mixed communities in three of the five health districts in central and northern Israel. Environmental surveillance plays a fundamental role in routine monitoring of WPV circulation in polio-free countries. The rapid assay specific for the circulating strain facilitated implementation of intensified surveillance and informed the public health response and decision-making.

  2. Molecular Tectonic Model of Virus Structural Transitions: the Putative Cell Entry States of Poliovirus

    Science.gov (United States)

    Belnap, David M.; Filman, David J.; Trus, Benes L.; Cheng, Naiqian; Booy, Frank P.; Conway, James F.; Curry, Stephen; Hiremath, Chaitanya N.; Tsang, Simon K.; Steven, Alasdair C.; Hogle, James M.

    2000-01-01

    Upon interacting with its receptor, poliovirus undergoes conformational changes that are implicated in cell entry, including the externalization of the viral protein VP4 and the N terminus of VP1. We have determined the structures of native virions and of two putative cell entry intermediates, the 135S and 80S particles, at ∼22-Å resolution by cryo-electron microscopy. The 135S and 80S particles are both ∼4% larger than the virion. Pseudoatomic models were constructed by adjusting the beta-barrel domains of the three capsid proteins VP1, VP2, and VP3 from their known positions in the virion to fit the 135S and 80S reconstructions. Domain movements of up to 9 Å were detected, analogous to the shifting of tectonic plates. These movements create gaps between adjacent subunits. The gaps at the sites where VP1, VP2, and VP3 subunits meet are plausible candidates for the emergence of VP4 and the N terminus of VP1. The implications of these observations are discussed for models in which the externalized components form a transmembrane pore through which viral RNA enters the infected cell. PMID:10627545

  3. Mathematical model of adherent Vero cell growth and poliovirus production in animal component free medium.

    Science.gov (United States)

    Ursache, Ramona V; Thomassen, Yvonne E; van Eikenhorst, Gerco; Verheijen, Peter J T; Bakker, Wilfried A M

    2015-03-01

    Sabin-IPV (or sIPV, inactivated polio vaccine based on attenuated Sabin strains) is anticipated to replace the oral polio vaccine for the endgame in polio eradication. Optimization of sIPV production will lead to a better economically feasible vaccine. To assist process optimization, we studied Sabin type 1 poliovirus (PV) infection kinetics on Vero cells in controlled bioreactor vessels. The aim of our study was to develop a descriptive mathematical model able to capture the dynamics of adherent Vero cell growth and PV infection kinetics in animal component free medium. The model predicts the cell density, metabolites profiles, and viral yields in time. We found that the multiplicity of infection (MOI) and the time of infection (TOI) within the investigated range did not affect maximal PV yields, but they did affect the process time. The latter may be reduced by selecting a low TOI and a high MOI. Additionally, we present a correlation between viral titers and D-antigen, a measure for immunogenicity, of Sabin type 1 PV. The developed model is adequate for further studies of the cell metabolism and infection kinetics and may be used to identify control strategies to increase viral productivity. Increased viral yields reduce costs of polio vaccines with large implications on public health.

  4. An Introduction to Poliovirus: Pathogenesis, Vaccination, and the Endgame for Global Eradication.

    Science.gov (United States)

    Minor, Philip D

    2016-01-01

    Poliomyelitis is caused by poliovirus, which is a positive strand non-enveloped virus that occurs in three distinct serotypes (1, 2, and 3). Infection is mainly by the fecal-oral route and can be confined to the gut by antibodies induced either by vaccine, previous infection or maternally acquired. Vaccines include the live attenuated strains developed by Sabin and the inactivated vaccines developed by Salk; the live attenuated vaccine (Oral Polio Vaccine or OPV) has been the main tool in the Global Program of Polio eradication of the World Health Organisation. Wild type 2 virus has not caused a case since 1999 and type 3 since 2012 and eradication seems near. However most infections are entirely silent so that sophisticated environmental surveillance may be needed to ensure that the virus has been eradicated, and the live vaccine can sometimes revert to virulent circulating forms under conditions that are not wholly understood. Cessation of vaccination is therefore an increasingly important issue and inactivated polio vaccine (IPV) is playing a larger part in the end game.

  5. Frequency of isolation of polioviruses and non polio enteroviruses from patients with acute flaccid paralysis, enterovirus infection and children from groups at risk

    Directory of Open Access Journals (Sweden)

    N. I. Romanenkova

    2012-01-01

    Full Text Available The article describes the frequency of isolation of polioviruses and non polio enteroviruses from different categories of the investigated children. The percentage of detection of polioviruses from the patients with acute flaccid paralysis was lower than that from the children from groups at risk. Among the patients with the enterovirus infection the polioviruses were rarely revealed. The frequency of isolation of non polio enteroviruses from these patients was significantly higher than that from the other categories of investigated persons. The improvement of poliomyelitis surveillance and the reinforcement of virological surveillance of children from groups at risk and those with enterovirus infection will provide the important data for Global Polio Eradication Initiative and the maintenance of polio free status of the Russian Federation.

  6. Immunogenicity and safety of combined adsorbed low-dose diphtheria, tetanus and inactivated poliovirus vaccine (REVAXIS®) versus combined diphtheria, tetanus and inactivated poliovirus vaccine (DT Polio®) given as a booster dose at 6 years of age

    Science.gov (United States)

    Gajdos, Vincent; Soubeyrand, Benoit; Vidor, Emmanuel; Richard, Patrick; Boyer, Julie; Sadorge, Christine

    2011-01-01

    This randomized, comparative, phase-IIIb study conducted in France aimed to demonstrate whether seroprotection against diphtheria, tetanus and poliomyelitis 1 month after a single dose of REVAXIS (low-dose diphtheria) is non-inferior to seroprotection 1 month after a single dose of DT Polio (standard-dose diphtheria), both vaccines being given as a second booster to healthy children at 6 years of age. Children were randomly assigned to receive a single intramuscular dose of REVAXIS or DT Polio. Primary endpoints were the 1-month post-booster seroprotection rates for diphtheria, tetanus and poliovirus type-1, -2 and -3 antigens. Secondary endpoints were immunogenicity and safety observations. Of 788 children screened, 760 were randomized: REVAXIS group, 384 children; DT Polio group, 376 children. No relevant difference in demographic characteristics at baseline was observed between REVAXIS and DT Polio groups. Noninferiority of REVAXIS compared with DT Polio for seroprotection was demonstrated against diphtheria (respectively 98.6% and 99.3%), tetanus (respectively 99.6% and 100%) and poliovirus antigens (100% for each types in both groups). No allergic reactions to REVAXIS were reported. A benefit/risk ratio in favor of REVAXIS was suggested by the trend towards a better tolerability of REVAXIS compared with DT Polio regarding the rate of severe solicited injection-site reactions. The results support the use of REVAXIS as a booster at 6 years of age in infants who previously received a three-dose primary series within the first 6 months of life and a first booster including diphtheria, tetanus and poliovirus vaccine(s) given before 2 years of age. PMID:21441781

  7. The role of supplementary environmental surveillance to complement acute flaccid paralysis surveillance for wild poliovirus in Pakistan – 2011–2013

    Science.gov (United States)

    Burns, Cara C.; Sharif, Salmaan; Gary, Howard E.; Iber, Jane; Henderson, Elizabeth; Malik, Farzana; Zahoor Zaidi, Syed Sohail; Shaukat, Shahzad; Rehman, Lubna; Pallansch, Mark A.; Orenstein, Walter A.

    2017-01-01

    Background More than 99% of poliovirus infections are non-paralytic and therefore, not detected by acute flaccid paralysis (AFP) surveillance. Environmental surveillance (ES) can detect circulating polioviruses from sewage without relying on clinical presentation. With extensive ES and continued circulation of polioviruses, Pakistan presents a unique opportunity to quantify the impact of ES as a supplement to AFP surveillance on overall completeness and timeliness of poliovirus detection. Methods Genetic, geographic and temporal data were obtained for all wild poliovirus (WPV) isolates detected in Pakistan from January 2011 through December 2013. We used viral genetics to assess gaps in AFP surveillance and ES as measured by detection of ‘orphan viruses’ (≥1.5% different in VP1 capsid nucleotide sequence). We compared preceding detection of closely related circulating isolates (≥99% identity) detected by AFP surveillance or ES to determine which surveillance system first detected circulation before the presentation of each polio case. Findings A total of 1,127 WPV isolates were detected by AFP surveillance and ES in Pakistan from 2011–2013. AFP surveillance and ES combined exhibited fewer gaps (i.e., % orphan viruses) in detection than AFP surveillance alone (3.3% vs. 7.7%, respectively). ES detected circulation before AFP surveillance in nearly 60% of polio cases (200 of 346). For polio cases reported from provinces conducting ES, ES detected circulation nearly four months sooner on average (117.6 days) than did AFP surveillance. Interpretation Our findings suggest ES in Pakistan is providing earlier, more sensitive detection of wild polioviruses than AFP surveillance alone. Overall, targeted ES through strategic selection of sites has important implications in the eradication endgame strategy. PMID:28742803

  8. A second gene for the African green monkey poliovirus receptor that has no putative N-glycosylation site in the functional N-terminal immunoglobulin-like domain.

    OpenAIRE

    Koike, S.; Ise, I; Sato, Y; Yonekawa, H; Gotoh, O; Nomoto, A

    1992-01-01

    Using cDNA of the human poliovirus receptor (PVR) as a probe, two types of cDNA clones of the monkey homologs were isolated from a cDNA library prepared from an African green monkey kidney cell line. Either type of cDNA clone rendered mouse L cells permissive for poliovirus infection. Homologies of the amino acid sequences deduced from these cDNA sequences with that of human PVR were 90.2 and 86.4%, respectively. These two monkey PVRs were found to be encoded in two different loci of the geno...

  9. Serological survey on immunity status against polioviruses in children and adolescents living in a border region, Apulia (Southern Italy).

    Science.gov (United States)

    Tafuri, Silvio; Prato, Rosa; Martinelli, Domenico; Calvario, Agata; Bozzi, Anna; Labianca, Michele; Patti, Annamaria; Lopalco, Pietro Luigi; Germinario, Cinzia

    2008-10-30

    In 1988 the World Health Assembly adopted the goal to eradicate poliomyelitis by routine immunization using Oral Polio Vaccine (OPV). On 21 June 2002 the WHO European Region was declared polio-free. In 2008 poliomyelitis is still endemic in 4 countries (Nigeria, India, Pakistan, and Afghanistan), where 1201 new cases were registered in 2007; 107 sporadic cases were also notified in countries where poliovirus is not endemic. The aim of this work was to verify the level of antipoliomyelitis immunity status in children and adolescents in the Apulia region (south of Italy), which may be considered a border region due to its position. 704 blood specimens from a convenience sample were collected in six laboratories. The age of subjects enrolled was 0-15 years. The immunity against poliomyelitis was evaluated by neutralizing antibody titration in tissue culture microplates. Seropositivity (neutralising antibodies titre > or = 8) for polioviruses 1, 2 and 3 was detected in 100%, 99.8% and 99.4% of collected sera. Antibody titres were not lower in subjects who received either four doses of inactivated polio vaccine (IPV) or a sequential schedule consisting of two doses of IPV and two of oral polio vaccine than in subjects who received four doses of OPV. These results confirmed current data of vaccine coverage for poliomyelitis: during the last ten years in Apulia, the coverage in 24 months old children was more than 90%. The high level of immunization found confirms the effectiveness both of the sequential schedule IPV-OPV and of the schedule all-IPV. Apulia region has to face daily arrivals of refugees and remains subject to the risk of the importation of poliovirus from endemic areas. Surveys aimed at determining anti-polio immunity in subpopulations as well as in the general population should be carried out.

  10. Characteristics of an environmentally monitored prolonged type 2 vaccine derived poliovirus shedding episode that stopped without intervention.

    Directory of Open Access Journals (Sweden)

    Tapani Hovi

    Full Text Available Vaccine derived poliovirus (VDPV type 2 strains strongly divergent from the corresponding vaccine strain, Sabin 2, were repeatedly isolated from sewage in Slovakia over a period of 22 months in 2003-2005. Cell cultures of stool specimens from known immune deficient patients and from an identified putative source population of 500 people failed to identify the potential excretor(s of the virus. The occurrence of VDPV in sewage stopped without any intervention. No paralytic cases were reported in Slovakia during the episode. According to a GenBank search and similarity plotting-analysis, the closest known relative of the first isolate PV2/03/SVK/E783 through all main sections of the genome was the type 2 poliovirus Sabin strain, with nucleotide identities in 5'UTR, P1, P2, P3, and 3'UTR parts of the genome of 88.6, 85.9, 87.3, 88.5, and 94.0 percent, respectively. Phenotypic properties of selected Slovakian aVDPV strains resembled those of VDPV strains isolated from immune deficient individuals with prolonged PV infection (iVDPV, including antigenic changes and moderate neurovirulence in the transgenic mouse model. One hundred and two unique VP1 coding sequences were determined from VDPV strains isolated from 34 sewage specimens. Nucleotide differences from Sabin 2 in the VP1 coding region ranged from 12.5 to 15.6 percent, and reached a maximum of 9.6 percent between the VDPV strains under study. Most of the nucleotide substitutions were synonymous but as many as 93 amino acid positions out of 301 in VP1 showed substitutions. We conclude that (1 individuals with prolonged poliovirus infection are not as rare as suggested by the studies on immune deficient patients known to the health care systems and (2 genetic divergence of VDPV strains may remain extensive during years long replication in humans.

  11. Implementation of coordinated global serotype 2 oral poliovirus vaccine cessation: risks of potential non-synchronous cessation.

    Science.gov (United States)

    Duintjer Tebbens, Radboud J; Hampton, Lee M; Thompson, Kimberly M

    2016-05-26

    The endgame for polio eradication involves coordinated global cessation of oral poliovirus vaccine (OPV) with cessation of serotype 2 OPV (OPV2 cessation) implemented in late April and early May 2016 and cessation of serotypes 1 and 3 OPV (OPV13 cessation) currently planned for after 2018. The logistics associated with globally switching all use of trivalent OPV (tOPV) to bivalent OPV (bOPV) represent a significant undertaking, which may cause some complications, including delays that lead to different timing of the switch across shared borders. Building on an integrated global model for long-term poliovirus risk management, we consider the expected vulnerability of different populations to transmission of OPV2-related polioviruses as a function of time following the switch. We explore the relationship between the net reproduction number (Rn) of OPV2 at the time of the switch and the time until OPV2-related viruses imported from countries still using OPV2 can establish transmission. We also analyze some specific situations modeled after populations at high potential risk of circulating serotype 2 vaccine-derived poliovirus (cVDPV2) outbreaks in the event of a non-synchronous switch. Well-implemented tOPV immunization activities prior to the tOPV to bOPV switch (i.e., tOPV intensification sufficient to prevent the creation of indigenous cVDPV2 outbreaks) lead to sufficient population immunity to transmission to cause die-out of any imported OPV2-related viruses for over 6 months after the switch in all populations in the global model. Higher Rn of OPV2 at the time of the switch reduces the time until imported OPV2-related viruses can establish transmission and increases the time during which indigenous OPV2-related viruses circulate. Modeling specific connected populations suggests a relatively low vulnerability to importations of OPV2-related viruses that could establish transmission in the context of a non-synchronous switch from tOPV to bOPV, unless the gap

  12. The in vitro antiviral property of Azadirachta indica polysaccharides for poliovirus.

    Science.gov (United States)

    Faccin-Galhardi, Ligia Carla; Yamamoto, Kristie Aimi; Ray, Sayani; Ray, Bimalendu; Carvalho Linhares, Rosa Elisa; Nozawa, Carlos

    2012-06-26

    Azadirachta indica A. Juss, popularly known as neem, has been extensively used in Ayurvedic medicine by Indian population for over 2000 years. It is used traditionally for the healing of various diseases. Natural products and their derivatives provide an excellent source for new anti-viral drugs. The present study aims at evaluating the activity of two polysaccharides (P1 and P2) isolated from the leaves of Azadirachta indica and their chemical sulfated derivatives (P1S and P2S) against poliovirus type 1 (PV-1). The cytotoxicity of the compounds was analyzed by MTT and the antiviral effect was determined by plaque reduction assay in different protocols. The polysaccharides did not show any cytotoxic effects on HEp-2 cells at the highest tested concentration (200 μg/ml) and exhibited significant antiviral activity with inhibitory concentrations (IC₅₀) of 80 μg/ml, 37.5 μg/ml, 77.5 μg/ml, and 12.1 μg/ml for P1, P1S, P2 and P2S, respectively, and the selectivity indexes (SI) ranged from 18 to 131.9. The compounds demonstrated better inhibitory effect when added concomitantly with the virus infection with a dose-dependent curve inhibition. Lesser effect was observed when the compounds were added after viral infection and the least effect at pre-treatment. We suggested that the polysaccharides obtained from Azadirachta indica act against PV-1 by inhibiting the initial stage of viral replication. Importantly, original polysaccharides showed better virucidal effect than their sulfated derivatives at all tested concentrations. This study provides a scientific basis for the past and present ethnomedical uses of this plant.

  13. Safety of diphtheria, tetanus, acellular pertussis and inactivated poliovirus (DTaP-IPV) vaccine.

    Science.gov (United States)

    Daley, Matthew F; Yih, W Katherine; Glanz, Jason M; Hambidge, Simon J; Narwaney, Komal J; Yin, Ruihua; Li, Lingling; Nelson, Jennifer C; Nordin, James D; Klein, Nicola P; Jacobsen, Steven J; Weintraub, Eric

    2014-05-23

    In 2008, a diphtheria, tetanus, acellular pertussis, and inactivated poliovirus combined vaccine (DTaP-IPV) was licensed for use in children 4 through 6 years of age. While pre-licensure studies did not demonstrate significant safety concerns, the number vaccinated in these studies was not sufficient to examine the risk of uncommon but serious adverse events. To assess the risk of serious adverse events following DTaP-IPV vaccination. The study was conducted from January 2009 through September 2012 in the Vaccine Safety Datalink (VSD) project. In the VSD, electronic vaccination and encounter data are updated and aggregated weekly as part of ongoing surveillance activities. Based on previous reports and biologic plausibility, eight potential adverse events were monitored: meningitis/encephalitis; seizures; stroke; Guillain-Barré syndrome; Stevens-Johnson syndrome; anaphylaxis; serious allergic reactions other than anaphylaxis; and serious local reactions. Adverse event rates in DTaP-IPV recipients were compared to historical incidence rates in the VSD population prior to 2009. Sequential probability ratio testing was used to analyze the data on a weekly basis. During the study period, 201,116 children received DTaP-IPV vaccine. Ninety-seven percent of DTaP-IPV recipients also received other vaccines on the same day, typically measles-mumps-rubella and varicella vaccines. There was no statistically significant increased risk of any of the eight pre-specified adverse events among DTaP-IPV recipients when compared to historical incidence rates. In this safety surveillance study of more than 200,000 DTaP-IPV vaccine recipients, there was no evidence of increased risk for any of the pre-specified adverse events monitored. Continued surveillance of DTaP-IPV vaccine safety may be warranted to monitor for rare adverse events, such as Guillain-Barré syndrome. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Transferrin Receptor 1 Facilitates Poliovirus Permeation of Mouse Brain Capillary Endothelial Cells.

    Science.gov (United States)

    Mizutani, Taketoshi; Ishizaka, Aya; Nihei, Coh-Ichi

    2016-02-05

    As a possible route for invasion of the CNS, circulating poliovirus (PV) in the blood is believed to traverse the blood-brain barrier (BBB), resulting in paralytic poliomyelitis. However, the underlying mechanism is poorly understood. In this study, we demonstrated that mouse transferrin receptor 1 (mTfR1) is responsible for PV attachment to the cell surface, allowing invasion into the CNS via the BBB. PV interacts with the apical domain of mTfR1 on mouse brain capillary endothelial cells (MBEC4) in a dose-dependent manner via its capsid protein (VP1). We found that F-G, G-H, and H-I loops in VP1 are important for this binding. However, C-D, D-E, and E-F loops in VP1-fused Venus proteins efficiently penetrate MBEC4 cells. These results imply that the VP1 functional domain responsible for cell attachment is different from that involved in viral permeation of the brain capillary endothelium. We observed that co-treatment of MBEC4 cells with excess PV particles but not dextran resulted in blockage of transferrin transport into cells. Using the Transwell in vitro BBB model, transferrin co-treatment inhibited permeation of PV into MBEC4 cells and delayed further viral permeation via mTfR1 knockdown. With mTfR1 as a positive mediator of PV-host cell attachment and PV permeation of MBEC4 cells, our results indicate a novel role of TfR1 as a cellular receptor for human PV receptor/CD155-independent PV invasion of the CNS. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. Improved poliovirus D-antigen yields by application of different Vero cell cultivation methods.

    Science.gov (United States)

    Thomassen, Yvonne E; Rubingh, Olaf; Wijffels, René H; van der Pol, Leo A; Bakker, Wilfried A M

    2014-05-19

    Vero cells were grown adherent to microcarriers (Cytodex 1; 3 g L(-1)) using animal component free media in stirred-tank type bioreactors. Different strategies for media refreshment, daily media replacement (semi-batch), continuous media replacement (perfusion) and recirculation of media, were compared with batch cultivation. Cell densities increased using a feed strategy from 1×10(6) cells mL(-1) during batch cultivation to 1.8, 2.7 and 5.0×10(6) cells mL(-1) during semi-batch, perfusion and recirculation, respectively. The effects of these different cell culture strategies on subsequent poliovirus production were investigated. Increased cell densities allowed up to 3 times higher D-antigen levels when compared with that obtained from batch-wise Vero cell culture. However, the cell specific D-antigen production was lower when cells were infected at higher cell densities. This cell density effect is in good agreement with observations for different cell lines and virus types. From the evaluated alternative culture methods, application of a semi-batch mode of operations allowed the highest cell specific D-antigen production. The increased product yields that can easily be reached using these higher cell density cultivation methods, showed the possibility for better use of bioreactor capacity for the manufacturing of polio vaccines to ultimately reduce vaccine cost per dose. Further, the use of animal-component-free cell- and virus culture media shows opportunities for modernization of human viral vaccine manufacturing. Copyright © 2014. Published by Elsevier Ltd.

  16. Adsorption characteristics of an enteric virus-binding protein to norovirus, rotavirus and poliovirus

    Directory of Open Access Journals (Sweden)

    Imai Takahiro

    2011-12-01

    Full Text Available Abstract Background Water contamination with human enteric viruses has posed human health risks all over the world. Reasonable and facile methodologies for recovering and quantifying infectious enteric viruses in environmental samples are needed to address the issues of waterborne viral infectious diseases. In this study, a bacterial protein that has a binding capability with several enteric viruses is discovered, and its binding characteristics were investigated for utilizing it as a viral adsorbent in virus recovery and detection technologies. Results A gene of an enteric virus-binding protein (EVBP, derived from a monomer of a bacterial chaperon protein GroEL, was successfully acquired from a genomic DNA library of activated sludge microorganisms with nested PCR. Equilibrium dissociation constants between EVBP and norovirus-like particles (NoVLPs of genotypes GI.7 and GII.4, estimated with quartz crystal microbalance method, were 240 and 210 nM, respectively. These values of equilibrium dissociation constant imply that the binding affinity between EVBP and NoVLPs is 1 to 3-log weaker than that in general antigen-antibody interactions, but about 2-log stronger than that in weak specific interactions of proteins with cations and organic polymers. The adsorptions of EVBP to norovirus, group A rotavirus and poliovirus type 1 were found to be significant in enzyme-linked immunosorbent assay. Meanwhile, the binding of native GroEL tetradecamer to viral particles was weaker than that of EVBP, presumably because of a steric hindrance. The small molecule of EVBP could have an advantage in the access to the surface of viral particles with rugged structure. Conclusions EVBP that has a broad binding spectrum to enteric viruses was newly discovered. The broad binding characteristic of EVBP would allow us to utilize it as a novel adsorbent for detecting diverse enteric viruses in clinical and environmental samples.

  17. Demonstration in vitro that eucaryotic initiation factor 3 is active but that a cap-binding protein complex is inactive in poliovirus-infected HeLa cells.

    Science.gov (United States)

    Etchison, D; Hansen, J; Ehrenfeld, E; Edery, I; Sonenberg, N; Milburn, S; Hershey, J W

    1984-01-01

    Protein synthesis initiation factor preparations from poliovirus-infected HeLa cells have reduced ability to initiate translation on capped mRNA. The defect in initiation factors has been variously attributed to inactivation of eucaryotic initiation factor 3 (eIF3), eIF4B, or a cap-binding protein (CBP) complex. We have developed a series of in vitro protein synthesis assays to show that eIF3 is active but a CBP complex activity is inactivated after poliovirus infection. eIF3 activity, when determined in the presence of purified CBP complex, is present in sucrose gradients of factors from both infected and uninfected cells. CBP complex activity, determined in the presence of eIF3 from poliovirus-infected cells, is present in uninfected cells only and comigrates on sucrose gradient with an activity which restores the ability of crude initiation factors from infected cells to translate capped globin mRNA. This is the first demonstration by a fractionated translation system that an activity which is attributable to CBP complex is inactivated in poliovirus-infected cells. The results also indicate that eIF3 is undetectable or has greatly reduced activity in the absence of CBP complex. Images PMID:6088805

  18. Primary vaccination of adults with reduced antigen-content diphtheria-tetanus-acellular pertussis or dTpa-inactivated poliovirus vaccines compared to diphtheria-tetanus-toxoid vaccines.

    NARCIS (Netherlands)

    Theeten, H.; Rumke, H.C.; Hoppener, F.J.; Vilatimo, R.; Narejos, S.; Damme, P. van; Hoet, B.

    2007-01-01

    OBJECTIVE: To evaluate immunogenicity and reactogenicity of primary vaccination with reduced-antigen-content diphtheria-tetanus-acellular pertussis (dTpa) or dTpa-inactivated poliovirus (dTpa-IPV) vaccine compared to diphtheria-tetanus-toxoid vaccines (Td) in adults > or = 40 years of age without

  19. Differences in female-male mortality after high-titre measles vaccine and association with subsequent vaccination with diphtheria-tetanus-pertussis and inactivated poliovirus

    DEFF Research Database (Denmark)

    Aaby, Peter; Jensen, Henrik; Samb, Badara

    2003-01-01

    Females given high-titre measles vaccine (HTMV) have high mortality; diphtheria-tetanus-pertussis (DTP) vaccination might be associated with increased female mortality. We aimed to assess whether DTP or inactivated poliovirus (IPV) administered after HTMV was associated with increased female...

  20. The evaluation of a physical method for the quantification of inactivated poliovirus particles and its relationship to D-antigenicity and potency testing in rats.

    NARCIS (Netherlands)

    T.R. Doel; A.D.M.E. Osterhaus (Albert); A.L. van Wezel; G. van Steenis (Bert)

    1984-01-01

    textabstractThe use of a density gradient procedure for the quantification of intact, inactivated poliovirus particles in vaccine preparations is described. The procedure is both sensitive and highly reproducible and the results correlate with those of potency tests in rats and with D-antigen

  1. Evolution of type 2 vaccine derived poliovirus lineages. Evidence for codon-specific positive selection at three distinct locations on capsid wall.

    Directory of Open Access Journals (Sweden)

    Tapani Hovi

    Full Text Available Partial sequences of 110 type 2 poliovirus strains isolated from sewage in Slovakia in 2003-2005, and most probably originating from a single dose of oral poliovirus vaccine, were subjected to a detailed genetic analysis. Evolutionary patterns of these vaccine derived poliovirus strains (SVK-aVDPV2 were compared to those of type 1 and type 3 wild poliovirus (WPV lineages considered to have a single seed strain origin, respectively. The 102 unique SVK-aVDPV VP1 sequences were monophyletic differing from that of the most likely parental poliovirus type 2/Sabin (PV2 Sabin by 12.5-15.6%. Judging from this difference and from the rate of accumulation of synonymous transversions during the 22 month observation period, the relevant oral poliovirus vaccine dose had been administered to an unknown recipient more than 12 years earlier. The patterns of nucleotide substitution during the observation period differed from those found in the studied lineages of WPV1 or 3, including a lower transition/transversion (Ts/Tv bias and strikingly lower Ts/Tv rate ratios at the 2(nd codon position for both purines and pyrimidines. A relatively low preference of transitions at the 2(nd codon position was also found in the large set of VP1 sequences of Nigerian circulating (cVDPV2, as well as in the smaller sets from the Hispaniola cVDPV1 and Egypt cVDPV2 outbreaks, and among aVDPV1and aVDPV2 strains recently isolated from sewage in Finland. Codon-wise analysis of synonymous versus non-synonymous substitution rates in the VP1 sequences suggested that in five codons, those coding for amino acids at sites 24, 144, 147, 221 and 222, there may have been positive selection during the observation period. We conclude that pattern of poliovirus VP1 evolution in prolonged infection may differ from that found in WPV epidemics. Further studies on sufficiently large independent datasets are needed to confirm this suggestion and to reveal its potential significance.

  2. Natural type 3/type 2 intertypic vaccine-related poliovirus recombinants with the first crossover sites within the VP1 capsid coding region.

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    Yong Zhang

    Full Text Available BACKGROUND: Ten uncommon natural type 3/type 2 intertypic poliovirus recombinants were isolated from stool specimens from nine acute flaccid paralysis case patients and one healthy vaccinee in China from 2001 to 2008. PRINCIPAL FINDINGS: Complete genomic sequences revealed their vaccine-related genomic features and showed that their first crossover sites were randomly distributed in the 3' end of the VP1 coding region. The length of donor Sabin 2 sequences ranged from 55 to 136 nucleotides, which is the longest donor sequence reported in the literature for this type of poliovirus recombination. The recombination resulted in the introduction of Sabin 2 neutralizing antigenic site 3a (NAg3a into a Sabin 3 genomic background in the VP1 coding region, which may have been altered by some of the type 3-specific antigenic properties, but had not acquired any type 2-specific characterizations. NAg3a of the Sabin 3 strain seems atypical; other wild-type poliovirus isolates that have circulated in recent years have sequences of NAg3a more like the Sabin 2 strain. CONCLUSIONS: 10 natural type 3/type 2 intertypic VP1 capsid-recombinant polioviruses, in which the first crossover sites were found to be in the VP1 coding region, were isolated and characterized. In spite of the complete replacement of NAg3a by type 2-specific amino acids, the serotypes of the recombinants were not altered, and they were totally neutralized by polyclonal type 3 antisera but not at all by type 2 antisera. It is possible that recent type 3 wild poliovirus isolates may be a recombinant having NAg3a sequences derived from another strain during between 1967 and 1980, and the type 3/type 2 recombination events in the 3' end of the VP1 coding region may result in a higher fitness.

  3. Combinations of Quality and Frequency of Immunization Activities to Stop and Prevent Poliovirus Transmission in the High-Risk Area of Northwest Nigeria.

    Directory of Open Access Journals (Sweden)

    Radboud J Duintjer Tebbens

    Full Text Available Frequent supplemental immunization activities (SIAs with the oral poliovirus vaccine (OPV represent the primary strategy to interrupt poliovirus transmission in the last endemic areas.Using a differential-equation based poliovirus transmission model tailored to high-risk areas in Nigeria, we perform one-way and multi-way sensitivity analyses to demonstrate the impact of different assumptions about routine immunization (RI and the frequency and quality of SIAs on population immunity to transmission and persistence or emergence of circulating vaccine-derived polioviruses (cVDPVs after OPV cessation.More trivalent OPV use remains critical to avoid serotype 2 cVDPVs. RI schedules with or without inactivated polio vaccine (IPV could significantly improve population immunity if coverage increases well above current levels in under-vaccinated subpopulations. Similarly, the impact of SIAs on overall population immunity and cVDPV risks depends on their ability to reach under-vaccinated groups (i.e., SIA quality. Lower SIA coverage in the under-vaccinated subpopulation results in a higher frequency of SIAs needed to maintain high enough population immunity to avoid cVDPVs after OPV cessation.National immunization program managers in northwest Nigeria should recognize the benefits of increasing RI and SIA quality. Sufficiently improving RI coverage and improving SIA quality will reduce the frequency of SIAs required to stop and prevent future poliovirus transmission. Better information about the incremental costs to identify and reach under-vaccinated children would help determine the optimal balance between spending to increase SIA and RI quality and spending to increase SIA frequency.

  4. Recombination between Poliovirus and Coxsackie A Viruses of Species C: A Model of Viral Genetic Plasticity and Emergence

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    Francis Delpeyroux

    2011-08-01

    Full Text Available Genetic recombination in RNA viruses was discovered many years ago for poliovirus (PV, an enterovirus of the Picornaviridae family, and studied using PV or other picornaviruses as models. Recently, recombination was shown to be a general phenomenon between different types of enteroviruses of the same species. In particular, the interest for this mechanism of genetic plasticity was renewed with the emergence of pathogenic recombinant circulating vaccine-derived polioviruses (cVDPVs, which were implicated in poliomyelitis outbreaks in several regions of the world with insufficient vaccination coverage. Most of these cVDPVs had mosaic genomes constituted of mutated poliovaccine capsid sequences and part or all of the non-structural sequences from other human enteroviruses of species C (HEV-C, in particular coxsackie A viruses. A study in Madagascar showed that recombinant cVDPVs had been co-circulating in a small population of children with many different HEV-C types. This viral ecosystem showed a surprising and extensive biodiversity associated to several types and recombinant genotypes, indicating that intertypic genetic recombination was not only a mechanism of evolution for HEV-C, but an usual mode of genetic plasticity shaping viral diversity. Results suggested that recombination may be, in conjunction with mutations, implicated in the phenotypic diversity of enterovirus strains and in the emergence of new pathogenic strains. Nevertheless, little is known about the rules and mechanisms which govern genetic exchanges between HEV-C types, as well as about the importance of intertypic recombination in generating phenotypic variation. This review summarizes our current knowledge of the mechanisms of evolution of PV, in particular recombination events leading to the emergence of recombinant cVDPVs.

  5. Relação entre a patogenicidade de Schistosoma mansoni em camundongos e a susceptibilidade do molusco vetor: I. Infecciosidade das cercárias e carga de vermes Relationship between the pathogenicity of Schistosoma mansoni in mice and the susceptibility of the vector mollusc: I. Cercariae infectivity and worm burden

    Directory of Open Access Journals (Sweden)

    Eliana Maria Zanotti-Magalhães

    1991-10-01

    Full Text Available Foram pesquisadas as possíveis influências que os mecanismos imunes do molusco poderiam exercer no desenvolvimento dos esporocistos e no comportamento do verme adulto no hospedeiro vertebrado. Utilizaram-se duas linhagens de S. mansoni (BH e SJ, selecionadas para o caráter susceptibilidade e mantidas, respectivamente, em Biomphalaria glabrata e Biomphalaria tenagophila, seus hospedeiros invertebrados naturais. Formaram-se grupos experimentais de camundongos infectados com cercárias oriundas de moluscos das duas espécies, pertencentes às gerações P, F1, F2, F3 e F4. Foram calculadas as taxas de infecção dos moluscos, número de cercárias penetrantes e o número de esquistossomos adultos nos roedores. Concluiu-se que a maior susceptibilidade de B. tenagophila determinou maior capacidade das cercárias em se tornarem vermes adultos. A maior susceptibilidade de B. glabrata originou maior capacidade de penetração das cercárias.The possible influence of the immune mechanisms of the molluscs on the developmente of the sporocysts and the resultant behavior of the adult worm in the vertebrate host were studied. Two strains of Schistosoma mansoni (BH and SJ were used. These were genetically selected for their susceptibility and maintained, respectively, in Biomphalaria glabrata and Biomphalaria tenegophila, the natural invertebrate hosts. Experimental groups of mice infected with cercariae proceeding from the two species of molluscs, belonging to generations P, F1 F2, F3 and F4, were formed. The infection rates of the snails, the number of the penetrant cercariae and the worm burden in mice were evaluated. It was concluded that the higher susceptibility of Biomphalaria tenagophila results in a greater ability on the part of the cercarial to develop into adult worms. The higher susceptibility of B. glabrata results in greater power of penetration into mice tegument on the part of the cercariae.

  6. Higher susceptibility of spontaneous and NNK-induced lung neoplasms in connexin 43 deficient CD1 × AJ F1 mice: paradoxical expression of connexin 43 during lung carcinogenesis.

    Science.gov (United States)

    Fukumasu, Heidge; Avanzo, Jose L; Sanches, Daniel S; Mennecier, Gregory; Mori, Claudia M C; Dagli, Maria L Z

    2013-07-01

    Connexins (Cxs) are proteins that form the communicating gap junctions, and reportedly have a role in carcinogenesis. Here, we evaluated the importance of Connexin43 (Cx43) in spontaneous and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung carcinogenesis. Male wild-type (Cx43(+/+) ) and hemizygote (Cx43(+/-) ) CD1 × AJ F1 mice were injected with NNK or saline. After 60 weeks mice were euthanized; lung nodules were counted, measured, and fixed in formalin or snap frozen. Immunohistochemistry for Cx43 and Beta-catenin (β-catenin) was performed and Cx43 mRNA expression was evaluated by real-time PCR. Cx43 deletion significantly increased the incidence and number of spontaneous nodules in the CD1 × AJ F1 mice and the number of gross lesions and the aggressiveness of lesions in NNK-treated mice. Cx43 mRNA increased significantly and was correlated with the aggressiveness of tumors, although lesions from Cx43(+/-) mice expressed less Cx43 RNAm than their counterparts. Lung parenchyma presented a Cx43 immunostaining pattern with points or plaques between cells. In hyperplasias and adenomas, Cx43 was found in the membrane and in cytoplasm. Malignant lesions presented increased Cx43 in cytoplasm and a few membrane spots of immunostaining. β-catenin was weakly expressed in lung parenchyma. Though hyperplasias presented some cells with nuclear β-catenin, NNK-induced tumors contained a higher number of this staining pattern. Also, no difference in β-catenin occurred between both genotypes independently of the histological grade. In summary, our results indicate that Cx43 acts as a tumor suppressor gene in early lung tumorigenesis and loses this property in advanced carcinogenesis. Therefore, Cxs are better classified as conditional tumor suppressors. Copyright © 2012 Wiley Periodicals, Inc.

  7. Association of cap-binding protein with eucaryotic initiation factor 3 in initiation factor preparations from uninfected and poliovirus-infected HeLa cells.

    Science.gov (United States)

    Hansen, J; Etchison, D; Hershey, J W; Ehrenfeld, E

    1982-04-01

    Extracts from poliovirus-infected HeLa cells are unable to translate vesicular stomatitis virus or cellular mRNAs in vitro, probably reflecting the poliovirus-induced inhibition of host cell protein synthesis which occurs in vivo. Crude initiation factors from uninfected HeLa cells are able to restore translation of vesicular stomatitis virus mRNA in infected cell lysates. This restoring activity separates into the 0 to 40% ammonium sulfate fractional precipitate of ribosomal salt wash. Restoring activity is completely lacking in the analogous fractions prepared from poliovirus-infected cells. The 0 to 40% ammonium sulfate precipitates from both uninfected and infected cells contain eucaryotic initiation factor 3 (eIF-3), eIf-4B, and the cap-binding protein (CBP), which is detected by means of a cross-linking assay, as well as other proteins. The association of eIF-3 and cap binding protein was examined. The 0 to 40% ammonium sulfate precipitate of ribosomal salt wash from uninfected and infected cells was sedimented in sucrose gradients. Each fraction was examined for the presence of eIF-3 antigens by an antibody blot technique and for the presence of the CBP by cross-linking to cap-labeled mRNAs. From uninfected cells, a major proportion of the CBP cosedimented with eIF-3; however, none of the CBP from infected cells sedimented with eIF-3. The results suggest that the association of the CBP with eIF-3 into a functional complex may have been disrupted during the course of poliovirus infection.

  8. Age dependent course of EAE in Aire-/- mice.

    Science.gov (United States)

    Aharoni, Rina; Aricha, Revital; Eilam, Raya; From, Ido; Mizrahi, Keren; Arnon, Ruth; Souroujon, Miriam C; Fuchs, Sara

    2013-09-15

    This study explores the consequences of deficiency in the autoimmune regulator (Aire) on the susceptibility to experimental autoimmune encephalomyelitis (EAE). Increased susceptibility to EAE was found in Aire knockout (KO) compared to wild type (WT) in 6month old mice. In contrast, 2month old Aire KO mice were less susceptible to EAE than WT mice, and this age-related resistance correlated with elevated proportions of T regulatory (Treg) cells in their spleen and brain. Combined with our previous findings in experimental autoimmune myasthenia gravis, we suggest an age-related association between Aire and Treg cells in the susceptibility to autoimmunity. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. PAPEL DEL LABORATORIO NACIONAL DE POLIOVIRUS EN EL PROGRAMA DE ERRADICACIÖN Y VIGILANCIA DE LA POLIOMIELITIS

    Directory of Open Access Journals (Sweden)

    Gloria Trallero

    2013-01-01

    Full Text Available El Laboratorio Nacional de Poliovirus (LNP coordina la Red Española de Vigilancia de Parálisis Flácida Aguda desde 1998 y caracteriza los poliovirus (PV y otros enterovirus detectados, utilizando métodos de cultivo celular y moleculares. Durante 1998-2012 se estudiaron por la Red un total de 110.725 (70.046+40.679 muestras clínicas, resultando positivas para enterovirus 8.804 (8%, entre las que 241 se caracterizaron como PV. La caracterización intratípica demostró que todos los PV eran vacunales excep- to las muestras correspondientes a un caso importado de poliomielitis postvacunal y sus contactos, que fueron caracterizados como PV2 derivado de vacuna. En el LNP se ha realizado el serotipado y la caracterización intratípica de todos los PV aislados en España de cualquier síndrome. Con ello se ha demostrado que el PV salvaje no ha circulado en nuestro país durante los 15 años que recoge este trabajo y eso condujo a la firma del Acta de la “Erradicación de la Poliomielitis en España” por parte de la OMS en 2001 y a la “Certificación de la Erradicación Europea como libre de circulación de PV salvaje”el 21 de junio de 2002 . En la actualidad sólo 3 países presentan transmisión endémica de PV salvaje (Pakistán, Afganistán y Nigeria y hasta que no se haya conseguido la erradicación a nivel mundial, España debe mantener la infraestructura creada en el Plan de Erradicación de la Poliomielitis y continuar con la vigilancia e inmunización. También el Programa de Contención de los PV salvajes en los laboratorios debe seguir en activo para evitar reintroducciones accidentales.

  10. Introduction of inactivated poliovirus vaccine leading into the polio eradication endgame strategic plan; Hangzhou, China, 2010-2014.

    Science.gov (United States)

    Liu, Yan; Wang, Jun; Liu, Shijun; Du, Jian; Wang, Liang; Gu, Wenwen; Xu, Yuyang; Zuo, Shuyan; Xu, Erping; An, Zhijie

    2017-03-01

    China's Expanded Program on Immunization (EPI) has provided 4 doses of oral poliovirus vaccine (OPV) since the 1970s. Inactivated poliovirus vaccine (IPV) became available in 2010 in Hangzhou as a private-sector, parent-chosen alternative to OPV. In 2015, WHO recommended that countries with all-OPV vaccination schedules introduce at least one dose of IPV, to mitigate risk associated with the withdrawal of type 2 OPV. We analyzed polio vaccine coverage and utilization in Hangzhou to determine patterns of IPV use and the occurrence of vaccine-associated paralytic polio (VAPP) in the various patterns identified. Children born between 2010 and 2014 and registered in Hangzhou's Immunization Information System (HZIIS) were included. VAPP cases were detected through the acute flaccid paralysis surveillance system. We used descriptive epidemiological methods to determine IPV and OPV usage patterns and VAPP occurrence. HZIIS data from 566,894 children were analyzed. Coverage levels of polio vaccine were greater than 92% for each birth cohort. Percentages of children using OPV-only, IPV-only, and IPV/OPV sequential schedules were 70.57%, 27.01% and 2.41%, respectively. IPV-only schedule utilization increased by birth cohort regardless of geographical area or whether the child was locally-born. The highest use of an all-IPV schedule (79.85%) was among urban, locally-born children in the 2014 birth cohort. Five VAPP cases were identified during the study years; all cases occurred following the first polio vaccine dose, which was always OPV for the cases. Type 2 vaccine virus was isolated from 2 VAPP cases, and type 2 and type 3 vaccine virus was isolated from one VAPP case. The incidence of VAPP in the 2010-2014 birth cohorts was 3.76 per 1million doses of OPV. Children in Hangzhou had high polio vaccination coverage. IPV-only schedule use increased by year, and was highest in urban areas among locally-born children. All cases of VAPP were associated with the first dose of OPV

  11. A statistical model of the international spread of wild poliovirus in Africa used to predict and prevent outbreaks.

    Directory of Open Access Journals (Sweden)

    Kathleen M O'Reilly

    2011-10-01

    Full Text Available Outbreaks of poliomyelitis in African countries that were previously free of wild-type poliovirus cost the Global Polio Eradication Initiative US$850 million during 2003-2009, and have limited the ability of the program to focus on endemic countries. A quantitative understanding of the factors that predict the distribution and timing of outbreaks will enable their prevention and facilitate the completion of global eradication.Children with poliomyelitis in Africa from 1 January 2003 to 31 December 2010 were identified through routine surveillance of cases of acute flaccid paralysis, and separate outbreaks associated with importation of wild-type poliovirus were defined using the genetic relatedness of these viruses in the VP1/2A region. Potential explanatory variables were examined for their association with the number, size, and duration of poliomyelitis outbreaks in 6-mo periods using multivariable regression analysis. The predictive ability of 6-mo-ahead forecasts of poliomyelitis outbreaks in each country based on the regression model was assessed. A total of 142 genetically distinct outbreaks of poliomyelitis were recorded in 25 African countries, resulting in 1-228 cases (median of two cases. The estimated number of people arriving from infected countries and <5-y childhood mortality were independently associated with the number of outbreaks. Immunisation coverage based on the reported vaccination history of children with non-polio acute flaccid paralysis was associated with the duration and size of each outbreak, as well as the number of outbreaks. Six-month-ahead forecasts of the number of outbreaks in a country or region changed over time and had a predictive ability of 82%.Outbreaks of poliomyelitis resulted primarily from continued transmission in Nigeria and the poor immunisation status of populations in neighbouring countries. From 1 January 2010 to 30 June 2011, reduced transmission in Nigeria and increased incidence in reinfected

  12. Susceptibility to malignant hyperthermia

    NARCIS (Netherlands)

    Snoeck, Marcus Matheus Johannes

    2004-01-01

    In this thesis the author studied the diagnostic procedures for susceptibility to malignant hyperthermia (MH), with special emphasis upon refining the biological diagnostic test and improving protocols and guidelines for investigation of MH susceptibility. MH is a pharmacogenetic disease of skeletal

  13. Radioimmunological detection of type-specific antibodies against polioviruses 1, 2 and 3 as well as the B4 Coxsackie virus. Radioimmunologischer Nachweis typenspezifischer Antikoerper gegen Poliovirus 1, 2 und 3 und gegen Coxsackievirus B4

    Energy Technology Data Exchange (ETDEWEB)

    Hartung Goetze, C.F.

    1985-06-27

    A simple radioimmunological procedure is described in which the qualitative and quantitative determination of serum antibodies against polioviruses 1, 2 and 3 and against the B4 Coxsackie virus is based on adsorption chromatography. It is comparable to the neutralisation test as regards sensitivity and specifity and has the additional advantage of being the faster, simplier and cheaper of those two methods. The radioactive labelling of the virsuses was achieved with types of 32 P or 3 H that had favourable half-lives and would thus permit the labelled compounds to be stored for prolonged periods of time. The immunological statuses and antibody titres of sera obtained from 45 female volunteers, where the vaccinations against polymyelitis had mostly been carried out by the oral route, showed remarkably little changes, which was evident from the fact that the proportion of study participants found to have antibodies against all three serological types was 91% in 1970 and still as large at 89% in 1983. When a total of 1016 sera were screened for Coxsackie virus B4, no age dependency could be determined for the age range between 5 and 35 years, nor were there any differences seen between the individual residential areas. (TRV).

  14. Relação entre patogenicidade do Schistosoma mansoni em camundongos e susceptibilidade do molusco vetor. IV - Infecciosidade dos miracidios Relationship between the pathogenicity of Schistosoma mansoni in mice and the susceptibility of the vector mollusk. IV - Infectiousness of the miracídia

    Directory of Open Access Journals (Sweden)

    Eliana Maria Zanotti-Magalhães

    1997-10-01

    ão selecionados, conclui-se que a maior patogenicidade do S. mansoni, oriundo de moluscos mais susceptíveis, implica maior capacidade de infecção desses miracídios.OBJECTIVE: The infection ability of miracidia of BH and SJ strains of S. mansoni, obtained from mice infected with cercariae taken from Biomphalaria glabrata and Biomphalaria tenagophila, genetically selected for susceptibility is compared with the infection ability of miracidia obtained from mice infected with larvae from non-selected mollusks. MATERIAL AND METHOD: Progeny of S. mansoni resulting from successive infections of selected mollusk sproduced various generations of selected miracidia. Selecion of B. glabrata and B. tengophila was carried out by autofertilization of mollusks susceptible to the BH and SJ strains of S. mansoni. Five generations of mollusks (from parental down to F4, were used in the experiment. Tests for the infectiousness of the miracidia used 10 larvae; susceptibility was checked starting on day 30 after infection, for 90 days, through observation for the presence of cercariae. RESULTS: The results showed that susceptibility of the selected mollusks in the face of the respective sympatric strains was not altered by the selection process of S. mansoni. However F4 miracidia of the BH strain were more infectant for non-selected B. glabrata than parental miracidia of the same strain. Miracidia of BH and SJ strains, parental generation, and BH strain, F3 generation, showed the same infectiousness in selected B. glabrata. Nevertheless, these mollusks had distinct infection rates from allopatric selected miracidia (SJ strain, F4 generation. The generation of successive infections of S. mansoni SJ in selected B. tenagophila resulted in the adaptation of the worm strain to the species of mollusk. B. tenagophila was never susceptible to the BH strain, even when selected mollusks and trematodes were employed. The susceptibility/infectiousness of the pair B. tenagophila-SJ S. mansoni strain was only

  15. Anti-poliovirus activity of Baccharis dracunculifolia and propolis by cell viability determination and real-time PCR.

    Science.gov (United States)

    Búfalo, M C; Figueiredo, A S; de Sousa, J P B; Candeias, J M G; Bastos, J K; Sforcin, J M

    2009-11-01

    The aim of this work was to evaluate the antiviral activities of Baccharis dracunculifolia (extract and essential oil), propolis and some isolated compounds (caffeic and cinnamic acids) against poliovirus type 1 (PV1) replication in HEp-2 cells. Three different protocols (pre-, simultaneous and post-treatments) were used to verify the effect of addition time of the variables on PV1 replication by crystal violet method and relative viral RNA quantification by real-time PCR for analysing in which step of virus replication the variables could interfere. Data revealed that the B. dracunculifolia showed the best antiviral activity percentage in the simultaneous treatment, as well as lower relative viral quantification by real-time PCR. Variables might block partially the viral entry within cells, affect the steps of viral cycle replication into cells, or lead to RNA degradation before the virus entry into cells or after their release to the supernatant. Baccharis dracunculifolia is the most important botanical source of the south-eastern Brazilian propolis, and its potential for the development of new phytotherapeutic medicines has been investigated. Propolis is commonly used for its antimicrobial and immunomodulatory activities. Nevertheless, B. dracunculifolia and propolis effects on PV1 have not been investigated yet.

  16. Intradermal Administration of Fractional Doses of Inactivated Poliovirus Vaccine: A Dose-Sparing Option for Polio Immunization.

    Science.gov (United States)

    Okayasu, Hiromasa; Sein, Carolyn; Chang Blanc, Diana; Gonzalez, Alejandro Ramirez; Zehrung, Darin; Jarrahian, Courtney; Macklin, Grace; Sutter, Roland W

    2017-07-01

    A fractional dose of inactivated poliovirus vaccine (fIPV) administered by the intradermal route delivers one fifth of the full vaccine dose administered by the intramuscular route and offers a potential dose-sparing strategy to stretch the limited global IPV supply while further improving population immunity. Multiple studies have assessed immunogenicity of intradermal fIPV compared with the full intramuscular dose and demonstrated encouraging results. Novel intradermal devices, including intradermal adapters and disposable-syringe jet injectors, have also been developed and evaluated as alternatives to traditional Bacillus Calmette-Guérin needles and syringes for the administration of fIPV. Initial experience in India, Pakistan, and Sri Lanka suggests that it is operationally feasible to implement fIPV vaccination on a large scale. Given the available scientific data and operational feasibility shown in early-adopter countries, countries are encouraged to consider introducing a fIPV strategy into their routine immunization and supplementary immunization activities. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

  17. Crystal Structure of Poliovirus 3CD Protein: Virally Encoded Protease and Precursor to the RNA-Dependent RNA Polymerase

    Energy Technology Data Exchange (ETDEWEB)

    Marcotte,L.; Wass, A.; Gohara, D.; Pathak, H.; Arnold, J.; Filman, D.; Cameron, C.; Hogle, J.

    2007-01-01

    Poliovirus 3CD is a multifunctional protein that serves as a precursor to the protease 3Cpro and the viral polymerase 3Dpol and also plays a role in the control of viral replication. Although 3CD is a fully functional protease, it lacks polymerase activity. We have solved the crystal structures of 3CD at a 3.4- Angstroms resolution and the G64S fidelity mutant of 3Dpol at a 3.0- Angstroms resolution. In the 3CD structure, the 3C and 3D domains are joined by a poorly ordered polypeptide linker, possibly to facilitate its cleavage, in an arrangement that precludes intramolecular proteolysis. The polymerase active site is intact in both the 3CD and the 3Dpol G64S structures, despite the disruption of a network proposed to position key residues in the active site. Therefore, changes in molecular flexibility may be responsible for the differences in fidelity and polymerase activities. Extensive packing contacts between symmetry-related 3CD molecules and the approach of the 3C domain's N terminus to the VPg binding site suggest how 3Dpol makes biologically relevant interactions with the 3C, 3CD, and 3BCD proteins that control the uridylylation of VPg during the initiation of viral replication. Indeed, mutations designed to disrupt these interfaces have pronounced effects on the uridylylation reaction in vitro.

  18. Cryo-Electron Microscopy Reconstruction Shows Poliovirus 135S Particles Poised for Membrane Interaction and RNA Release

    Science.gov (United States)

    Butan, Carmen; Filman, David J.

    2014-01-01

    During infection, binding of mature poliovirus to cell surface receptors induces an irreversible expansion of the capsid, to form an infectious cell-entry intermediate particle that sediments at 135S. In these expanded virions, the major capsid proteins (VP1 to VP3) adopt an altered icosahedral arrangement to open holes in the capsid at 2-fold and quasi-3-fold axes, and internal polypeptides VP4 and the N terminus of VP1, which can bind membranes, become externalized. Cryo-electron microscopy images for 117,330 particles were collected using Leginon and reconstructed using FREALIGN. Improved rigid-body positioning of major capsid proteins established reliably which polypeptide segments become disordered or rearranged. The virus-to-135S transition includes expansion of 4%, rearrangements of the GH loops of VP3 and VP1, and disordering of C-terminal extensions of VP1 and VP2. The N terminus of VP1 rearranges to become externalized near its quasi-3-fold exit, binds to rearranged GH loops of VP3 and VP1, and attaches to the top surface of VP2. These details improve our understanding of subsequent stages of infection, including endocytosis and RNA transfer into the cytoplasm. PMID:24257617

  19. Crystal Structure of Poliovirus 3CD Protein: Virally Encoded Protease and Precursor to the RNA-Dependent RNA Polymerase▿

    Science.gov (United States)

    Marcotte, Laura L.; Wass, Amanda B.; Gohara, David W.; Pathak, Harsh B.; Arnold, Jamie J.; Filman, David J.; Cameron, Craig E.; Hogle, James M.

    2007-01-01

    Poliovirus 3CD is a multifunctional protein that serves as a precursor to the protease 3Cpro and the viral polymerase 3Dpol and also plays a role in the control of viral replication. Although 3CD is a fully functional protease, it lacks polymerase activity. We have solved the crystal structures of 3CD at a 3.4-Å resolution and the G64S fidelity mutant of 3Dpol at a 3.0-Å resolution. In the 3CD structure, the 3C and 3D domains are joined by a poorly ordered polypeptide linker, possibly to facilitate its cleavage, in an arrangement that precludes intramolecular proteolysis. The polymerase active site is intact in both the 3CD and the 3Dpol G64S structures, despite the disruption of a network proposed to position key residues in the active site. Therefore, changes in molecular flexibility may be responsible for the differences in fidelity and polymerase activities. Extensive packing contacts between symmetry-related 3CD molecules and the approach of the 3C domain's N terminus to the VPg binding site suggest how 3Dpol makes biologically relevant interactions with the 3C, 3CD, and 3BCD proteins that control the uridylylation of VPg during the initiation of viral replication. Indeed, mutations designed to disrupt these interfaces have pronounced effects on the uridylylation reaction in vitro. PMID:17251299

  20. Early priming with inactivated poliovirus vaccine (IPV) and intradermal fractional dose IPV administered by a microneedle device: A randomized controlled trial.

    Science.gov (United States)

    Anand, Abhijeet; Zaman, K; Estívariz, Concepción F; Yunus, Mohammad; Gary, Howard E; Weldon, William C; Bari, Tajul I; Steven Oberste, M; Wassilak, Steven G; Luby, Stephen P; Heffelfinger, James D; Pallansch, Mark A

    2015-11-27

    Inactivated poliovirus vaccine (IPV) introduction and phased oral poliovirus vaccine (OPV) cessation are essential for eradication of polio. Healthy 6-week old infants in Bangladesh were randomized to one of five study arms: receipt of trivalent OPV (tOPV) or bivalent OPV (bOPV) at ages 6, 10 and 14 weeks, intramuscular IPV or intradermal one-fifth fractional dose IPV (f-IPV) at ages 6 and 14 weeks, or f-IPV at ages 6 and 14 weeks with bOPV at age 10 weeks (f-IPV/bOPV). All participants received tOPV at age 18 weeks. Of 975 infants randomized, 95% (922) completed follow-up. Type 1 seroconversion after 3 doses at 6, 10 and 14 weeks was higher with bOPV compared with tOPV (99% vs 94%, p=0.019). Seroconversions to types 1 and 3 after 2 IPV doses at ages 6 and 14 weeks were no different than after 3 doses of tOPV or bOPV at ages 6, 10 and 14 weeks. A priming response, seroconversion 1 week after IPV at 14 weeks among those who did not seroconvert after IPV at 6 weeks, was observed against poliovirus types 1, 2 and 3 in 91%, 84% and 97%, respectively. Compared with IPV, f-IPV failed non-inferiority tests for seroconversion with 1 or 2 doses and priming after 1 dose. The findings demonstrate considerable priming with IPV at age 6 weeks, comparable immunogenicity of tOPV and bOPV, and inferior immunogenicity of one-fifth f-IPV compared with IPV. If IPV induced priming at age 6 weeks is similar to that at age 14 weeks, IPV could be administered at a younger age and possibly with a higher coverage. Published by Elsevier Ltd.

  1. Surfactant protein D is proatherogenic in mice

    DEFF Research Database (Denmark)

    Sorensen, Grith L; Madsen, Jens; Kejling, Karin

    2006-01-01

    -/-) mice. Atherogenesis involves both inflammation and lipid deposition, and we investigated the role of SP-D in the development of atherosclerosis. SP-D synthesis was localized to vascular endothelial cells. Atherosclerotic lesion areas were 5.6-fold smaller in the aortic roots in Spd-/- mice compared...... with wild-type C57BL/6N mice on an atherogenic diet. HDL cholesterol (HDL-C) was significantly elevated in Spd-/- mice. Treatment of Spd-/- mice with a recombinant fragment of human SP-D resulted in decreases of HDL-C (21%) as well as total cholesterol (26%), and LDL cholesterol (28%). Plasma TNF......-alpha was reduced in Spd-/- mice (45% difference). SP-D was proatherogenic in the mouse model used. The effect is likely to be due to the observed disturbances of plasma lipid metabolism and alteration of the inflammatory process, which underlie the reduced susceptibility to atherosclerosis in Spd-/- mice....

  2. Interference of Monovalent, Bivalent, and Trivalent Oral Poliovirus Vaccines on Monovalent Rotavirus Vaccine Immunogenicity in Rural Bangladesh.

    Science.gov (United States)

    Emperador, Devy M; Velasquez, Daniel E; Estivariz, Concepcion F; Lopman, Ben; Jiang, Baoming; Parashar, Umesh; Anand, Abhijeet; Zaman, Khalequ

    2016-01-15

    Trivalent oral poliovirus vaccine (OPV) is known to interfere with monovalent rotavirus vaccine (RV1) immunogenicity. The interference caused by bivalent and monovalent OPV formulations, which will be increasingly used globally in coming years, has not been examined. We conducted a post hoc analysis to assess the effect of coadministration of different OPV formulations on RV1 immunogenicity. Healthy infants in Matlab, Bangladesh, were randomized to receive 3 doses of monovalent OPV type 1 or bivalent OPV types 1 and 3 at either 6, 8, and 10 or 6, 10, and 14 weeks of age or trivalent OPV at 6, 10, and 14 weeks of age. All infants received 2 doses of RV1 at about 6 and 10 weeks of age. Concomitant administration was defined as RV1 and OPV given on the same day; staggered administration as RV1 and OPV given ≥1 day apart. Rotavirus seroconversion was defined as a 4-fold rise in immunoglobulin A titer from before the first RV1 dose to ≥3 weeks after the second RV1 dose. There were no significant differences in baseline RV1 immunogenicity among the 409 infants included in the final analysis. Infants who received RV1 and OPV concomitantly, regardless of OPV formulation, were less likely to seroconvert (47%; 95% confidence interval, 39%-54%) than those who received both vaccines staggered ≥1 day (63%; 57%-70%; P < .001). For staggered administration, we found no evidence that the interval between RV1 and OPV administration affected RV1 immunogenicity. Coadministration of monovalent, bivalent, or trivalent OPV seems to lower RV1 immunogenicity. NCT01633216. Published by Oxford University Press for the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  3. Kinetics of Poliovirus Shedding following Oral Vaccination as Measured by Quantitative Reverse Transcription-PCR versus Culture

    Science.gov (United States)

    Begum, Sharmin; Uddin, Md Jashim; Platts-Mills, James A.; Liu, Jie; Kirkpatrick, Beth D.; Chowdhury, Anwarul H.; Jamil, Khondoker M.; Haque, Rashidul; Petri, William A.; Houpt, Eric R.

    2014-01-01

    Amid polio eradication efforts, detection of oral polio vaccine (OPV) virus in stool samples can provide information about rates of mucosal immunity and allow estimation of the poliovirus reservoir. We developed a multiplex one-step quantitative reverse transcription-PCR (qRT-PCR) assay for detection of OPV Sabin strains 1, 2, and 3 directly in stool samples with an external control to normalize samples for viral quantity and compared its performance with that of viral culture. We applied the assay to samples from infants in Dhaka, Bangladesh, after the administration of trivalent OPV (tOPV) at weeks 14 and 52 of life (on days 0 [pre-OPV], +4, +11, +18, and +25 relative to vaccination). When 1,350 stool samples were tested, the sensitivity and specificity of the quantitative PCR (qPCR) assay were 89 and 91% compared with culture. A quantitative relationship between culture+/qPCR+ and culture−/qPCR+ stool samples was observed. The kinetics of shedding revealed by qPCR and culture were similar. qPCR quantitative cutoffs based on the day +11 or +18 stool samples could be used to identify the culture-positive shedders, as well as the long-duration or high-frequency shedders. Interestingly, qPCR revealed that a small minority (7%) of infants contributed the vast majority (93 to 100%) of the total estimated viral excretion across all subtypes at each time point. This qPCR assay for OPV can simply and quantitatively detect all three Sabin strains directly in stool samples to approximate shedding both qualitatively and quantitatively. PMID:25378579

  4. Ambiguous Role of Interleukin-12 in Yersinia enterocolitica Infection in Susceptible and Resistant Mouse Strains

    Science.gov (United States)

    Bohn, Erwin; Schmitt, Edgar; Bielfeldt, Claudia; Noll, Annette; Schulte, Ralf; Autenrieth, Ingo B.

    1998-01-01

    Endogenous interleukin-12 (IL-12) mediates protection against Yersinia enterocolitica in C57BL/6 mice by triggering gamma interferon (IFN-γ) production in NK and CD4+ T cells. Administration of exogenous IL-12 confers protection against yersiniae in Yersinia-susceptible BALB/c mice but exacerbates yersiniosis in resistant C57BL/6 mice. Therefore, we wanted to dissect the different mechanisms exerted by IL-12 during Yersinia infections by using different models of Yersinia-resistant and -susceptible mice, including resistant C57BL/6 mice, susceptible BALB/c mice, intermediate-susceptible wild-type 129/Sv mice, 129/Sv IFN-γ-receptor-deficient (IFN-γR−/−) mice and C57BL/6 tumor necrosis factor (TNF) receptor p55 chain-deficient (TNFR p55−/−) mice. IFN-γR−/− mice turned out to be highly susceptible to infection by Y. enterocolitica compared with IFN-γR+/+ mice. Administration of IL-12 was protective in IFN-γR+/+ mice but not in IFN-γR−/− mice, suggesting that IFN-γR-induced mechanisms are essential for IL-12-induced resistance against yersiniae. BALB/c mice could be rendered Yersinia resistant by administration of anti-CD4 antibodies or by administration of IL-12. In contrast, C57BL/6 mice could be rendered more resistant by administration of transforming growth factor β (TGF-β). Furthermore, IL-12-triggered toxic effects in C57BL/6 mice were abrogated by coadministration of TGF-β. While administration of IL-12 alone increased TNF-α levels, administration of TGF-β or TGF-β plus IL-12 decreased both TNF-α and IFN-γ levels in Yersinia-infected C57BL/6 mice. Moreover, IL-12 did not induce toxicity in Yersinia-infected TNFR p55−/− mice, suggesting that TNF-α accounts for IL-12-induced toxicity. Taken together, IL-12 may induce different effector mechanisms in BALB/c and C57BL/6 mice resulting either in protection or exacerbation. These results are important for understanding the critical balance of proinflammatory and regulatory

  5. Neuroanatomic Differences Associated With Stress Susceptibility and Resilience.

    Science.gov (United States)

    Anacker, Christoph; Scholz, Jan; O'Donnell, Kieran J; Allemang-Grand, Rylan; Diorio, Josie; Bagot, Rosemary C; Nestler, Eric J; Hen, René; Lerch, Jason P; Meaney, Michael J

    2016-05-15

    We examined the neurobiological mechanisms underlying stress susceptibility using structural magnetic resonance imaging and diffusion tensor imaging to determine neuroanatomic differences between stress-susceptible and resilient mice. We also examined synchronized anatomic differences between brain regions to gain insight into the plasticity of neural networks underlying stress susceptibility. C57BL/6 mice underwent 10 days of social defeat stress and were subsequently tested for social avoidance. For magnetic resonance imaging, brains of stressed (susceptible, n = 11; resilient, n = 8) and control (n = 12) mice were imaged ex vivo at 56 µm resolution using a T2-weighted sequence. We tested for behavior-structure correlations by regressing social avoidance z-scores against local brain volume. For diffusion tensor imaging, brains were scanned with a diffusion-weighted fast spin echo sequence at 78 μm isotropic voxels. Structural covariance was assessed by correlating local volume between brain regions. Social avoidance correlated negatively with local volume of the cingulate cortex, nucleus accumbens, thalamus, raphe nuclei, and bed nucleus of the stria terminals. Social avoidance correlated positively with volume of the ventral tegmental area (VTA), habenula, periaqueductal gray, cerebellum, hypothalamus, and hippocampal CA3. Fractional anisotropy was increased in the hypothalamus and hippocampal CA3. We observed synchronized anatomic differences between the VTA and cingulate cortex, hippocampus and VTA, hippocampus and cingulate cortex, and hippocampus and hypothalamus. These correlations revealed different structural covariance between brain regions in susceptible and resilient mice. Stress-integrative brain regions shape the neural architecture underlying individual differences in susceptibility and resilience to chronic stress. Copyright © 2016. Published by Elsevier Inc.

  6. Population Immunity against Serotype-2 Poliomyelitis Leading up to the Global Withdrawal of the Oral Poliovirus Vaccine: Spatio-temporal Modelling of Surveillance Data.

    Directory of Open Access Journals (Sweden)

    Margarita Pons-Salort

    2016-10-01

    Full Text Available Global withdrawal of serotype-2 oral poliovirus vaccine (OPV2 took place in April 2016. This marked a milestone in global polio eradication and was a public health intervention of unprecedented scale, affecting 155 countries. Achieving high levels of serotype-2 population immunity before OPV2 withdrawal was critical to avoid subsequent outbreaks of serotype-2 vaccine-derived polioviruses (VDPV2s.In August 2015, we estimated vaccine-induced population immunity against serotype-2 poliomyelitis for 1 January 2004-30 June 2015 and produced forecasts for April 2016 by district in Nigeria and Pakistan. Population immunity was estimated from the vaccination histories of children 70% population immunity among children <36 mo old. Districts with lower immunity were clustered in northeastern Nigeria and northwestern Pakistan. The accuracy of immunity estimates was limited by the small numbers of non-polio AFP cases in some districts, which was reflected by large uncertainty intervals. Forecasted improvements in immunity for April 2016 were robust to the uncertainty in estimates of baseline immunity (January-June 2015, vaccine coverage, and vaccine efficacy.Immunity against serotype-2 poliomyelitis was forecasted to improve in April 2016 compared to the first half of 2015 in Nigeria and Pakistan. These analyses informed the endorsement of OPV2 withdrawal in April 2016 by the WHO Strategic Advisory Group of Experts on Immunization.

  7. The Structure of the Poliovirus 135S Cell Entry Intermediate at 10-Angstrom Resolution Reveals the Location of an Externalized Polypeptide That Binds to Membranes†

    Science.gov (United States)

    Bubeck, Doryen; Filman, David J.; Cheng, Naiqian; Steven, Alasdair C.; Hogle, James M.; Belnap, David M.

    2005-01-01

    Poliovirus provides a well-characterized system for understanding how nonenveloped viruses enter and infect cells. Upon binding its receptor, poliovirus undergoes an irreversible conformational change to the 135S cell entry intermediate. This transition involves shifts of the capsid protein β barrels, accompanied by the externalization of VP4 and the N terminus of VP1. Both polypeptides associate with membranes and are postulated to facilitate entry by forming a translocation pore for the viral RNA. We have calculated cryo-electron microscopic reconstructions of 135S particles that permit accurate placement of the β barrels, loops, and terminal extensions of the capsid proteins. The reconstructions and resulting models indicate that each N terminus of VP1 exits the capsid though an opening in the interface between VP1 and VP3 at the base of the canyon that surrounds the fivefold axis. Comparison with reconstructions of 135S particles in which the first 31 residues of VP1 were proteolytically removed revealed that the externalized N terminus is located near the tips of propeller-like features surrounding the threefold axes rather than at the fivefold axes, as had been proposed in previous models. These observations have forced a reexamination of current models for the role of the 135S particle in transmembrane pore formation and suggest testable alternatives. PMID:15919927

  8. Catching a Virus in the Act of RNA Release: a Novel Poliovirus Uncoating Intermediate Characterized by Cryo-Electron Microscopy▿ §

    Science.gov (United States)

    Levy, Hazel C.; Bostina, Mihnea; Filman, David J.; Hogle, James M.

    2010-01-01

    Poliovirus infection requires that the particle undergo a series of conformational transitions that lead to cell entry and genome release. In an effort to understand the conformational changes associated with the release of the RNA genome, we have used cryo-electron microscopy to characterize the structure of the 80S “empty” particles of poliovirus that are thought to represent the final product of the cell entry pathway. Using two-dimensional classification methods, we show that preparations of 80S particles contain at least two structures, which might represent snapshots from a continuous series of conformers. Using three-dimensional reconstruction methods, we have solved the structure of two distinct forms at subnanometric resolution, and we have built and refined pseudoatomic models into the reconstructions. The reconstructions and the derived models demonstrate that the two structural forms are both slightly expanded, resulting in partial disruption of interprotomer interfaces near their particle 2-fold axes, which may represent the site where RNA is released. The models demonstrate that each of the two 80S structures has undergone a unique set of movements of the capsid proteins, associated with rearrangement of flexible loops and amino-terminal extensions that participate in contacts between protomers, between pentamers, and with the viral RNA. PMID:20181687

  9. Single particle cryoelectron tomography characterization of the structure and structural variability of poliovirus-receptor-membrane complex at 30-Angstroms resolution

    Science.gov (United States)

    Bostina, Mihnea; Bubeck, Doryen; Schwartz, Cindi; Nicastro, Daniela; Filman, David J.; Hogle, James M.

    2007-01-01

    As a long-term goal we want to use cryoelectron tomography to understand how non-enveloped viruses, such as picornaviruses, enter cells and translocate their genomes across membranes. To this end, we developed new image-processing tools using an in vitro system to model viral interactions with membranes. The complex of poliovirus with its membrane-bound receptors was reconstructed by averaging multiple sub-tomograms, thereby producing three-dimensional maps of surprisingly high resolution (30Å). Recognizable images of the complex could be produced by averaging as few as 20 copies. Additionally, model-free reconstructions of free poliovirus particles, clearly showing the major surface features, could be calculated from 60 virions. All calculations were designed to avoid artifacts caused by missing information typical for tomographic data (“missing wedge”). To investigate structural and conformational variability we applied a principal component analysis classification to specific regions. We show that the missing wedge causes a bias in classification, and that this bias can be minimized by supplementation with data from the Fourier transform of the averaged structure. After classifying images of the receptor into groups with high similarity, we were able to see differences in receptor density consistent with the known variability in receptor glycosylation. PMID:17897840

  10. Activation of double-stranded RNA-activated protein kinase in HeLa cells after poliovirus infection does not result in increased phosphorylation of eucaryotic initiation factor-2.

    Science.gov (United States)

    Ransone, L J; Dasgupta, A

    1987-01-01

    Protein kinase activity in general is stimulated at least 5- to 10-fold in ribosomal salt wash preparations from poliovirus-infected HeLa cells compared with those from mock-infected cells. The stimulation of kinase activity is manifested by increased phosphorylation of ribosome-associated polypeptides having approximate molecular weights of 135,000, 120,000, 85,000, 68,000, 65,000, 40,000, 28,000, 25,000, and 21,000. The Mr 68,000 phosphoprotein is structurally identical to the interferon-induced, double-stranded RNA-activated protein kinase (P1) which phosphorylates the alpha subunit of eucaryotic initiation factor-2 (eIF-2). A similar protein of Mr 68,000 is more phosphorylated in poliovirus-infected cells than in mock-infected cells. Increased phosphorylation of P1 protein in poliovirus-infected cells, however, does not result in an increased phosphorylation of the alpha subunit of endogenous or exogenously added eIF-2, both in vitro and in vivo. These results suggest that a mechanism must exist in poliovirus-infected HeLa cells which prevents further phosphorylation of eIF-2 by the activated kinase. Images PMID:3033310

  11. Genetic susceptibility of periodontitis

    NARCIS (Netherlands)

    Laine, M.L.; Crielaard, W.; Loos, B.G.

    2012-01-01

    In this systematic review, we explore and summarize the peer-reviewed literature on putative genetic risk factors for susceptibility to aggressive and chronic periodontitis. A comprehensive literature search on the PubMed database was performed using the keywords ‘periodontitis’ or ‘periodontal

  12. Fourie susceptible.pmd

    African Journals Online (AJOL)

    Prof. Adipala Ekwamu

    a number of cultivars exhibited field resistance to halo blight and bacterial brown spot, all cultivars were more or less susceptible to .... Cerillos. Alubia. I. 91. 57. Kranskop. Red speckled sugar. II. 97. 63. OPS-RS1. Red speckled sugar. II. 96. 63. OPS-RS2. Red speckled sugar. I. 100. 61. OPS-RS3. Red speckled sugar. II. 97.

  13. Differential GR Expression and Translocation in the Hippocampus Mediates Susceptibility vs. Resilience to Chronic Social Defeat Stress

    Directory of Open Access Journals (Sweden)

    Qiu-Qin Han

    2017-05-01

    Full Text Available While social stress exposure is a common risk factor for affective disorders, most individuals exposed to it can maintain normal physical and psychological functioning. However, factors that determine susceptibility vs. resilience to social stress remain unclear. Here, the resident-intruder model of social defeat was used as a social stressor in male C57BL/6J mice to investigate the difference between susceptibility and resilience. As depression is often characterized by hyperactivity of the hypothalamic-pituitary-adrenal (HPA axis, we conducted the present study to further investigate the individual differences in the HPA axis response and glucocorticoid receptor (GR protein expression and translocation between susceptible mice and resilient mice. We found that hypercortisolemia, induced by social defeat stress occurred in susceptible mice, but not in resilient mice. Moreover, susceptible mice exhibited significantly less GR protein expression and nuclear translocation in the hippocampus than resilient mice. Treatment with escitalopram could decrease the serum corticosterone (CORT, increase GR protein expression as well as nuclear translocation in the hippocampus and ultimately reverse social withdrawal behaviors in susceptible mice. These results indicate that the up-regulation of GR and the enhancement of GR nuclear translocation in the hippocampus play an important role in resilience to chronic social defeat stress.

  14. A Susceptible Mouse Model for Zika Virus Infection.

    Directory of Open Access Journals (Sweden)

    Stuart D Dowall

    2016-05-01

    Full Text Available Zika virus (ZIKV is a mosquito-borne pathogen which has recently spread beyond Africa and into Pacific and South American regions. Despite first being detected in 1947, very little information is known about the virus, and its spread has been associated with increases in Guillain-Barre syndrome and microcephaly. There are currently no known vaccines or antivirals against ZIKV infection. Progress in assessing interventions will require the development of animal models to test efficacies; however, there are only limited reports on in vivo studies. The only susceptible murine models have involved intracerebral inoculations or juvenile animals, which do not replicate natural infection. Our report has studied the effect of ZIKV infection in type-I interferon receptor deficient (A129 mice and the parent strain (129Sv/Ev after subcutaneous challenge in the lower leg to mimic a mosquito bite. A129 mice developed severe symptoms with widespread viral RNA detection in the blood, brain, spleen, liver and ovaries. Histological changes were also striking in these animals. 129Sv/Ev mice developed no clinical symptoms or histological changes, despite viral RNA being detectable in the blood, spleen and ovaries, albeit at lower levels than those seen in A129 mice. Our results identify A129 mice as being highly susceptible to ZIKV and thus A129 mice represent a suitable, and urgently required, small animal model for the testing of vaccines and antivirals.

  15. A Susceptible Mouse Model for Zika Virus Infection.

    Science.gov (United States)

    Dowall, Stuart D; Graham, Victoria A; Rayner, Emma; Atkinson, Barry; Hall, Graham; Watson, Robert J; Bosworth, Andrew; Bonney, Laura C; Kitchen, Samantha; Hewson, Roger

    2016-05-01

    Zika virus (ZIKV) is a mosquito-borne pathogen which has recently spread beyond Africa and into Pacific and South American regions. Despite first being detected in 1947, very little information is known about the virus, and its spread has been associated with increases in Guillain-Barre syndrome and microcephaly. There are currently no known vaccines or antivirals against ZIKV infection. Progress in assessing interventions will require the development of animal models to test efficacies; however, there are only limited reports on in vivo studies. The only susceptible murine models have involved intracerebral inoculations or juvenile animals, which do not replicate natural infection. Our report has studied the effect of ZIKV infection in type-I interferon receptor deficient (A129) mice and the parent strain (129Sv/Ev) after subcutaneous challenge in the lower leg to mimic a mosquito bite. A129 mice developed severe symptoms with widespread viral RNA detection in the blood, brain, spleen, liver and ovaries. Histological changes were also striking in these animals. 129Sv/Ev mice developed no clinical symptoms or histological changes, despite viral RNA being detectable in the blood, spleen and ovaries, albeit at lower levels than those seen in A129 mice. Our results identify A129 mice as being highly susceptible to ZIKV and thus A129 mice represent a suitable, and urgently required, small animal model for the testing of vaccines and antivirals.

  16. Vial usage, device dead space, vaccine wastage, and dose accuracy of intradermal delivery devices for inactivated poliovirus vaccine (IPV).

    Science.gov (United States)

    Jarrahian, Courtney; Rein-Weston, Annie; Saxon, Gene; Creelman, Ben; Kachmarik, Greg; Anand, Abhijeet; Zehrung, Darin

    2017-03-27

    Intradermal delivery of a fractional dose of inactivated poliovirus vaccine (IPV) offers potential benefits compared to intramuscular (IM) delivery, including possible cost reductions and easing of IPV supply shortages. Objectives of this study were to assess intradermal delivery devices for dead space, wastage generated by the filling process, dose accuracy, and total number of doses that can be delivered per vial. Devices tested included syringes with staked (fixed) needles (autodisable syringes and syringes used with intradermal adapters), a luer-slip needle and syringe, a mini-needle syringe, a hollow microneedle device, and disposable-syringe jet injectors with their associated filling adapters. Each device was used to withdraw 0.1-mL fractional doses from single-dose IM glass vials which were then ejected into a beaker. Both vial and device were weighed before and after filling and again after expulsion of liquid to record change in volume at each stage of the process. Data were used to calculate the number of doses that could potentially be obtained from multidose vials. Results show wide variability in dead space, dose accuracy, overall wastage, and total number of doses that can be obtained per vial among intradermal delivery devices. Syringes with staked needles had relatively low dead space and low overall wastage, and could achieve a greater number of doses per vial compared to syringes with a detachable luer-slip needle. Of the disposable-syringe jet injectors tested, one was comparable to syringes with staked needles. If intradermal delivery of IPV is introduced, selection of an intradermal delivery device can have a substantial impact on vaccine wasted during administration, and thus on the required quantity of vaccine that needs to be purchased. An ideal intradermal delivery device should be not only safe, reliable, accurate, and acceptable to users and vaccine recipients, but should also have low dead space, high dose accuracy, and low overall

  17. The tumor spectrum in FHIT-deficient mice

    Science.gov (United States)

    Zanesi, Nicola; Fidanza, Vincenzo; Fong, Louise Y.; Mancini, Rita; Druck, Teresa; Valtieri, Mauro; Rüdiger, Thomas; McCue, Peter A.; Croce, Carlo M.; Huebner, Kay

    2001-01-01

    Mice carrying one inactivated Fhit allele (Fhit +/− mice) are highly susceptible to tumor induction by N-nitrosomethylbenzylamine, with 100% of Fhit +/− mice exhibiting tumors of the forestomach/squamocolumnar junction vs. 25% of Fhit +/+ controls. In the current study a single N-nitrosomethylbenzylamine dose was administered to Fhit +/+, +/−, and −/− mice to compare carcinogen susceptibility in +/- and −/− Fhit-deficient mice. At 29 weeks after treatment, 7.7% of wild-type mice had tumors. Of the Fhit −/− mice 89.5% exhibited tumors (average 3.3 tumors/mouse) of the forestomach and squamocolumnar junction; half of the −/− mice had medium (2 mm diameter) to large (>2 mm) tumors. Of the Fhit +/− mice 78% exhibited tumors (average 2.4 tumors/mouse) and 22% showed medium to large tumors. Untreated Fhit-deficient mice have been observed for up to 2 years for spontaneous tumors. Fhit +/− mice (average age 21 mo) exhibit an average of 0.94 tumors of different types; Fhit −/− mice (average age 16 mo) also showed an array of tumors (average 0.76 tumor/mouse). The similar spontaneous and induced tumor spectra observed in mice with one or both Fhit alleles inactivated suggests that Fhit may be a one-hit tumor suppressor gene in some tissues. PMID:11517343

  18. Genetic Susceptibility to Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Sanja Kovacic

    2012-01-01

    Full Text Available Atherosclerosis is a complex multifocal arterial disease involving interactions of multiple genetic and environmental factors. Advances in techniques of molecular genetics have revealed that genetic ground significantly influences susceptibility to atherosclerotic vascular diseases. Besides further investigations of monogenetic diseases, candidate genes, genetic polymorphisms, and susceptibility loci associated with atherosclerotic diseases have been identified in recent years, and their number is rapidly increasing. This paper discusses main genetic investigations fields associated with human atherosclerotic vascular diseases. The paper concludes with a discussion of the directions and implications of future genetic research in arteriosclerosis with an emphasis on prospective prediction from an early age of individuals who are predisposed to develop premature atherosclerosis as well as to facilitate the discovery of novel drug targets.

  19. Marijuana Usage and Hypnotic Susceptibility

    Science.gov (United States)

    Franzini, Louis R.; McDonald, Roy D.

    1973-01-01

    Anonymous self-reported drug usage data and hypnotic susceptibility scores were obtained from 282 college students. Frequent marijuana users (more than 10 times) showed greater susceptibility to hypnosis than nonusers. (Author)

  20. Murine glomerular transcriptome links endothelial cell-specific molecule-1 deficiency with susceptibility to diabetic nephropathy.

    Directory of Open Access Journals (Sweden)

    Xiaoyi Zheng

    Full Text Available Diabetic nephropathy (DN is the leading cause of kidney disease; however, there are no early biomarkers and no cure. Thus, there is a large unmet need to predict which individuals will develop nephropathy and to understand the molecular mechanisms that govern this susceptibility. We compared the glomerular transcriptome from mice with distinct susceptibilities to DN at four weeks after induction of diabetes, but before histologic injury, and identified differential regulation of genes that modulate inflammation. From these genes, we identified endothelial cell specific molecule-1 (Esm-1, as a glomerular-enriched determinant of resistance to DN. Glomerular Esm-1 mRNA and protein were lower in DN-susceptible, DBA/2, compared to DN-resistant, C57BL/6, mice. We demonstrated higher Esm-1 secretion from primary glomerular cultures of diabetic mice, and high glucose was sufficient to increase Esm-1 mRNA and protein secretion in both strains of mice. However, induction was significantly attenuated in DN-susceptible mice. Urine Esm-1 was also significantly higher only in DN-resistant mice. Moreover, using intravital microscopy and a biomimetic microfluidic assay, we showed that Esm-1 inhibited rolling and transmigration in a dose-dependent manner. For the first time we have uncovered glomerular-derived Esm-1 as a potential non-invasive biomarker of DN. Esm-1 inversely correlates with disease susceptibility and inhibits leukocyte infiltration, a critical factor in protecting the kidney from DN.

  1. Coverage estimates and patterns of inactivated poliovirus vaccine (IPV) use prior to and during the polio eradication endgame, Jinan City, China, 2010–2015

    Science.gov (United States)

    Chang, Caiyun; Zhang, Ji; Zhou, Jingwen; Cao, Ruoming; Song, Kaijun; Liu, Chong; Zhang, Xianhui; Geng, Xingyi; Liu, Xiaoxue; Li, Chuanbin

    2016-01-01

    ABSTRACT Background: Use of inactivated poliovirus vaccine (IPV) in Jinan during the polio eradication endgame has not been previously documented. Two IPV-containing vaccines were made available as an option for Jinan parents in 2009. We describe coverage levels and patterns of use of IPV over time using data from the Jinan Childhood Immunization Information Management System (JNCIIMS). Methods: Children born between January 2010 and December 2014 who were registered in JNCIIMS were included in this study. Vaccination records were obtained from JNCIIMS on April 30, 2015. JNCIIMS distinguishes among available poliovirus vaccines; doses administered data were used to describe IPV usage over time. We identified the polio vaccination sequences used by children in the 2012 and 2013 birth cohorts. Coverage estimates were analyzed by birth cohort and migration status. We developed 3 categories for analysis: “resident child,” “migrant child” and “other child” according to migration status. Results: In total, 12,354 (11.7%) IPV, 5,893(5.6%) DTP-IPV-Hib vaccine and 87,054(82.7%) OPV doses were administered to children in the 2010 to 2014 birth cohorts. The proportion of children using an IPV-only schedule increased each year, consistent with the introduction of IPV that is called for by the Polio Eradication Endgame Strategic Plan 2013–2018. During this time, 4.7% children used a schedule containing both IPV and oral poliovirus vaccine (OPV). In the 2012 to 2013 birth cohorts, 14.4% children used an IPV-only schedule; 5.7% children used a sequential schedule, and 79.9% used OPV-only schedule. Use of IPV only schedules was higher among migrant children than among resident children. Among those sequential schedule using both IPV and OPV, 87.2% children used IPV for the first dose and 12.8% used OPV for the first dose. Conclusions: JNCIIMS provided a mechanism for tracking IPV and OPV vaccination patterns, and showed areas in need of improvement. Ensuring

  2. Coverage estimates and patterns of inactivated poliovirus vaccine (IPV) use prior to and during the polio eradication endgame, Jinan City, China, 2010-2015.

    Science.gov (United States)

    Chang, Caiyun; Zhang, Ji; Zhou, Jingwen; Cao, Ruoming; Song, Kaijun; Liu, Chong; Zhang, Xianhui; Geng, Xingyi; Liu, Xiaoxue; Li, Chuanbin

    2016-11-01

    Use of inactivated poliovirus vaccine (IPV) in Jinan during the polio eradication endgame has not been previously documented. Two IPV-containing vaccines were made available as an option for Jinan parents in 2009. We describe coverage levels and patterns of use of IPV over time using data from the Jinan Childhood Immunization Information Management System (JNCIIMS). Children born between January 2010 and December 2014 who were registered in JNCIIMS were included in this study. Vaccination records were obtained from JNCIIMS on April 30, 2015. JNCIIMS distinguishes among available poliovirus vaccines; doses administered data were used to describe IPV usage over time. We identified the polio vaccination sequences used by children in the 2012 and 2013 birth cohorts. Coverage estimates were analyzed by birth cohort and migration status. We developed 3 categories for analysis: "resident child," "migrant child" and "other child" according to migration status. In total, 12,354 (11.7%) IPV, 5,893(5.6%) DTP-IPV-Hib vaccine and 87,054(82.7%) OPV doses were administered to children in the 2010 to 2014 birth cohorts. The proportion of children using an IPV-only schedule increased each year, consistent with the introduction of IPV that is called for by the Polio Eradication Endgame Strategic Plan 2013-2018. During this time, 4.7% children used a schedule containing both IPV and oral poliovirus vaccine (OPV). In the 2012 to 2013 birth cohorts, 14.4% children used an IPV-only schedule; 5.7% children used a sequential schedule, and 79.9% used OPV-only schedule. Use of IPV only schedules was higher among migrant children than among resident children. Among those sequential schedule using both IPV and OPV, 87.2% children used IPV for the first dose and 12.8% used OPV for the first dose. JNCIIMS provided a mechanism for tracking IPV and OPV vaccination patterns, and showed areas in need of improvement. Ensuring appropriately sequenced IPV and OPV supports reduction of risk of vaccine

  3. Mitotic arrest in teratoma susceptible fetal male germ cells.

    Directory of Open Access Journals (Sweden)

    Patrick S Western

    Full Text Available Formation of germ cell derived teratomas occurs in mice of the 129/SvJ strain, but not in C57Bl/6 inbred or CD1 outbred mice. Despite this, there have been few comparative studies aimed at determining the similarities and differences between teratoma susceptible and non-susceptible mouse strains. This study examines the entry of fetal germ cells into the male pathway and mitotic arrest in 129T2/SvJ mice. We find that although the entry of fetal germ cells into mitotic arrest is similar between 129T2/SvJ, C57Bl/6 and CD1 mice, there were significant differences in the size and germ cell content of the testis cords in these strains. In 129T2/SvJ mice germ cell mitotic arrest involves upregulation of p27(KIP1, p15(INK4B, activation of RB, the expression of male germ cell differentiation markers NANOS2, DNMT3L and MILI and repression of the pluripotency network. The germ-line markers DPPA2 and DPPA4 show reciprocal repression and upregulation, respectively, while FGFR3 is substantially enriched in the nucleus of differentiating male germ cells. Further understanding of fetal male germ cell differentiation promises to provide insight into disorders of the testis and germ cell lineage, such as testis tumour formation and infertility.

  4. Inhibition of translation in cells infected with a poliovirus 2Apro mutant correlates with phosphorylation of the alpha subunit of eucaryotic initiation factor 2.

    Science.gov (United States)

    O'Neill, R E; Racaniello, V R

    1989-01-01

    A poliovirus type 2 Lansing mutant was constructed by inserting 6 base pairs into the 2Apro region of an infectious cDNA clone, resulting in the addition of a leucine and threonine into the polypeptide sequence. The resulting small-plaque mutant, 2A-2, had a reduced viral yield in HeLa cells and synthesized viral proteins inefficiently. Infection with the mutant did not lead to specific inhibition of host cell protein synthesis early in infection, and this defect was attributed to a failure to induce cleavage of the cap-binding complex protein p220. At late times after infection with the mutant virus, both cellular and viral protein syntheses were severely inhibited. To explain this global inhibition of protein synthesis, the phosphorylation state of the alpha subunit of eucaryotic initiation factor 2 (eIF-2 alpha) was examined. eIF-2 alpha was phosphorylated in both R2-2A-2- and wild-type-virus-infected cells, indicating that poliovirus does not encode a function that blocks phosphorylation of eIF-2 alpha. The kinetics and extent of eIF-2 alpha phosphorylation correlated with the production of double-stranded RNA in infected cells, suggesting that eIF-2 alpha is phosphorylated by P1/eIF-2 alpha kinase. When HeLa cells were infected with R2-2A-2 in the presence of 2-aminopurine, a protein kinase inhibitor, much higher virus titers were produced, cleavage of p220 occurred, and host cell protein synthesis was specifically inhibited. Since phosphorylation of eIF-2 alpha was not inhibited by 2-aminopurine, we propose that 2-aminopurine rescues the ability of R2-2A-2 to induce cleavage of p220 by inhibition of a second as yet unidentified kinase. Images PMID:2555543

  5. Concomitant administration of diphtheria, tetanus, acellular pertussis and inactivated poliovirus vaccine derived from Sabin strains (DTaP-sIPV) with pentavalent rotavirus vaccine in Japanese infants.

    Science.gov (United States)

    Tanaka, Yoshiyuki; Yokokawa, Ruriko; Rong, Han Shi; Kishino, Hiroyuki; Stek, Jon E; Nelson, Margaret; Lawrence, Jody

    2017-06-03

    Rotavirus is the leading cause of severe acute gastroenteritis in infants and young children. Most children are infected with rotavirus, and the health and economic burdens of rotavirus gastroenteritis on healthcare systems and families are considerable. In 2012 pentavalent rotavirus vaccine (RV5) and diphtheria, tetanus, acellular pertussis and inactivated poliovirus vaccine derived from Sabin strains (DTaP-sIPV) were licensed in Japan. We examined the immunogenicity and safety of DTaP-sIPV when administrated concomitantly with RV5 in Japanese infants. A total of 192 infants 6 to 11 weeks of age randomized to Group 1 (N = 96) received DTaP-sIPV and RV5 concomitantly, and Group 2 (N = 96) received DTaP-sIPV and RV5 separately. Antibody titer to diphtheria toxin, pertussis antigens (PT and FHA), tetanus toxin, and poliovirus type 1, 2, and 3 were measured at 4 to 6 weeks following 3-doses of DTaP-sIPV. Seroprotection rates for all components of DTaP-sIPV were 100% in both groups, and the geometric mean titers for DTaP-sIPV in Group 1 were comparable to Group 2. Incidence of systemic AEs (including diarrhea, vomiting, fever, and nasopharyngitis) were lower in Group 1 than in Group 2. All vaccine-related AEs were mild or moderate in intensity. There were no vaccine-related serious AEs, no deaths, and no cases of intussusception during the study. Concomitant administration of DTaP-sIPV and RV5 induced satisfactory immune responses to DTaP-sIPV and acceptable safety profile. The administration of DTaP-sIPV given concomitantly with RV5 is expected to facilitate compliance with the vaccination schedule and improve vaccine coverage in Japanese infants.

  6. Risk of febrile seizures and epilepsy after vaccination with diphtheria, tetanus, acellular pertussis, inactivated poliovirus, and Haemophilus influenzae type B.

    Science.gov (United States)

    Sun, Yuelian; Christensen, Jakob; Hviid, Anders; Li, Jiong; Vedsted, Peter; Olsen, Jørn; Vestergaard, Mogens

    2012-02-22

    Vaccination with whole-cell pertussis vaccine carries an increased risk of febrile seizures, but whether this risk applies to the acellular pertussis vaccine is not known. In Denmark, acellular pertussis vaccine has been included in the combined diphtheria-tetanus toxoids-acellular pertussis-inactivated poliovirus-Haemophilus influenzae type b (DTaP-IPV-Hib) vaccine since September 2002. To estimate the risk of febrile seizures and epilepsy after DTaP-IPV-Hib vaccination given at 3, 5, and 12 months. A population-based cohort study of 378,834 children who were born in Denmark between January 1, 2003, and December 31, 2008, and followed up through December 31, 2009; and a self-controlled case series (SCCS) study based on children with febrile seizures during follow-up of the cohort. Hazard ratio (HR) of febrile seizures within 0 to 7 days (0, 1-3, and 4-7 days) after each vaccination and HR of epilepsy after first vaccination in the cohort study. Relative incidence of febrile seizures within 0 to 7 days (0, 1-3, and 4-7 days) after each vaccination in the SCCS study. A total of 7811 children were diagnosed with febrile seizures before 18 months, of whom 17 were diagnosed within 0 to 7 days after the first (incidence rate, 0.8 per 100,000 person-days), 32 children after the second (1.3 per 100,000 person-days), and 201 children after the third (8.5 per 100,000 person-days) vaccinations. Overall, children did not have higher risks of febrile seizures during the 0 to 7 days after the 3 vaccinations vs a reference cohort of children who were not within 0 to 7 days of vaccination. However, a higher risk of febrile seizures was found on the day of the first (HR, 6.02; 95% CI, 2.86-12.65) and on the day of the second (HR, 3.94; 95% CI, 2.18-7.10), but not on the day of the third vaccination (HR, 1.07; 95% CI, 0.73-1.57) vs the reference cohort. On the day of vaccination, 9 children were diagnosed with febrile seizures after the first (5.5 per 100,000 person-days), 12

  7. Influence of age of mice on the susceptibility to murine ...

    African Journals Online (AJOL)

    Nancy Kamau

    activity, 185 kBq/ mM, Amersham International. PLC, Buckingshire, England). Cells were harvested after a further 18 h of incubation and the incorporated isotope was measured by liquid scintillation counting. Results were expressed as the differential counts per minute (∆ cpm) of. ConA or SWAP stimulated cultures - cpm of.

  8. Magnetic susceptibilities of minerals

    Science.gov (United States)

    Rosenblum, Sam; Brownfield, I.K.

    2000-01-01

    Magnetic separation of minerals is a topic that is seldom reported in the literature for two reasons. First, separation data generally are byproducts of other projects; and second, this study requires a large amount of patience and is unusually tedious. Indeed, we suspect that most minerals probably are never investigated for this property. These data are timesaving for mineralogists who concentrate mono-mineralic fractions for chemical analysis, age dating, and for other purposes. The data can certainly be used in the ore-beneficiation industries. In some instances, magnetic-susceptibility data may help in mineral identification, where other information is insufficient. In past studies of magnetic separation of minerals, (Gaudin and Spedden, 1943; Tille and Kirkpatrick, 1956; Rosenblum, 1958; Rubinstein and others, 1958; Flinter, 1959; Hess, 1959; Baker, 1962; Meric and Peyre, 1963; Rojas and others, 1965; and Duchesne, 1966), the emphasis has been on the ferromagnetic and paramagnetic ranges of extraction. For readers interested in the history of magnetic separation of minerals, Krumbein and Pettijohn (1938, p. 344-346) indicated nine references back to 1848. The primary purpose of this paper is to report the magnetic-susceptibility data on as many minerals as possible, similar to tables of hardness, specific gravity, refractive indices, and other basic physical properties of minerals. A secondary purpose is to demonstrate that the total and best extraction ranges are influenced by the chemistry of the minerals. The following notes are offered to help avoid problems in separating a desired mineral concentrate from mixtures of mineral grains.

  9. Alcohol increases hypnotic susceptibility.

    Science.gov (United States)

    Semmens-Wheeler, Rebecca; Dienes, Zoltán; Duka, Theodora

    2013-09-01

    One approach to hypnosis suggests that for hypnotic experience to occur frontal lobe activity must be attenuated. For example, cold control theory posits that a lack of awareness of intentions is responsible for the experience of involuntariness and/or the subjective reality of hypnotic suggestions. The mid-dorso-lateral prefrontal cortex and the ACC are candidate regions for such awareness. Alcohol impairs frontal lobe executive function. This study examined whether alcohol affects hypnotisability. We administered 0.8 mg/kg of alcohol or a placebo to 32 medium susceptible participants. They were subsequently hypnotised and given hypnotic suggestions. All participants believed they had received some alcohol. Participants in the alcohol condition were more susceptible to hypnotic suggestions than participants in the placebo condition. Impaired frontal lobe activity facilitates hypnotic responding, which supports theories postulating that attenuation of executive function facilitates hypnotic response, and contradicts theories postulating that hypnotic response involves enhanced inhibitory, attentional or other executive function. Copyright © 2013. Published by Elsevier Inc.

  10. Individual Genetic Susceptibility

    Energy Technology Data Exchange (ETDEWEB)

    Eric J. Hall

    2008-12-08

    Risk estimates derived from epidemiological studies of exposed populations, as well as the maximum permissible doses allowed for occupational exposure and exposure of the public to ionizing radiation are all based on the assumption that the human population is uniform in its radiosensitivity, except for a small number of individuals, such as ATM homozygotes who are easily identified by their clinical symptoms. The hypothesis upon which this proposal is based is that the human population is not homogeneous in radiosensitiviry, but that radiosensitive sub-groups exist which are not easy to identify. These individuals would suffer an increased incidence of detrimental radiation effects, and distort the shape of the dose response relationship. The radiosensitivity of these groups depend on the expression levels of specific proteins. The plan was to investigate the effect of 3 relatively rare, high penetrate genes available in mice, namely Atm, mRad9 & Brca1. The purpose of radiation protection is to prevent! deterministic effects of clinical significance and limit stochastic effects to acceptable levels. We plan, therefore to compare with wild type animals the radiosensitivity of mice heterozygous for each of the genes mentioned above, as well as double heterozygotes for pairs of genes, using two biological endpoints: a) Ocular cataracts as an important and relevant deterministic effect, and b) Oncogenic transformation in cultured embryo fibroblasts, as a surrogate for carcinogenesis, the most relevant stochastic effect.

  11. Genetic selection for coping style predicts stressor susceptibility

    OpenAIRE

    Veenema, AH; Meijer, OC; de Kloet, ER; Koolhaas, JM

    2003-01-01

    Genetically selected aggressive (SAL) and nonaggressive (LAL) male wild house-mice which show distinctly different coping styles, also display a differential regulation of the hypothalamic-pituitary-adrenal axis after exposure to an acute stressor. To test the hypothesis that coping style predicts stressor susceptibility, the present study examined line differences in response to a chronic stressor. Chronic psychosocial stress was evoked using two paradigms. In the first paradigm, a SAL or LA...

  12. Chlorine gas exposure increases susceptibility to invasive lung fungal infection.

    Science.gov (United States)

    Gessner, Melissa A; Doran, Stephen F; Yu, Zhihong; Dunaway, Chad W; Matalon, Sadis; Steele, Chad

    2013-06-01

    Chlorine (Cl₂) is a highly irritating and reactive gas with potential occupational and environmental hazards. Acute exposure to Cl₂ induces severe epithelial damage, airway hyperreactivity, impaired alveolar fluid clearance, and pulmonary edema in the presence of heightened inflammation and significant neutrophil accumulation in the lungs. Herein, we investigated whether Cl₂ exposure affected the lung antimicrobial immune response leading to increased susceptibility to opportunistic infections. Mice exposed to Cl₂ and challenged intratracheally 24 h thereafter with the opportunistic mold Aspergillus fumigatus demonstrated an >500-fold increase in A. fumigatus lung burden 72 h postchallenge compared with A. fumigatus mice exposed to room air. Cl₂-exposed A. fumigatus challenged mice also demonstrated significantly higher lung resistance following methacholine challenge and increased levels of plasma proteins (albumin and IgG) in the bronchoalveolar lavage fluid. Despite enhanced recruitment of inflammatory cells to the lungs of Cl₂-exposed A. fumigatus challenged mice, these cells (>60% of which were neutrophils) demonstrated a profound impairment in generating superoxide. Significantly higher A. fumigatus burden in the lungs of Cl₂ exposed mice correlated with enhanced production of IL-6, TNF-α, CXCL1, CCL2, and CCL3. Surprisingly, however, Cl₂-exposed A. fumigatus challenged mice had a specific impairment in the production of IL-17A and IL-22 in the lungs compared with mice exposed to room air and challenged with A. fumigatus. In summary, our results indicate that Cl₂ exposure markedly impairs the antimicrobial activity and inflammatory reactivity of myeloid cells in the lung leading to increased susceptibility to opportunistic pathogens.

  13. Graphene susceptibility in Holstein model

    Energy Technology Data Exchange (ETDEWEB)

    Mousavi, Hamze, E-mail: hamze.mousavi@gmail.co [Department of Physics, Razi University, Kermanshah (Iran, Islamic Republic of); Nano Science and Nano Technology Research Center, Razi University, Kermanshah (Iran, Islamic Republic of)

    2011-06-15

    We study the effects of the electron-phonon interaction on the temperature dependence of the orbital magnetic susceptibility of monolayer graphene. We use the linear response theory and Green's function formalism within the Holstein Hamiltonian model. The results show that the effects of the electron-phonon interaction on the susceptibility of graphene sheet have different behaviors in two temperature regions. In the low temperature region, susceptibility increases when the electron-phonon coupling strength increases. On the other hand, the susceptibility reduces with increasing the electron-phonon coupling strength in the high temperature region. - Highlights: Effect of electron-phonon interaction on the susceptibility of graphene is studied. Linear response theory and Green's function technique in Holstein model are used. Effect of electron-phonon on susceptibility has different behaviors in two temperature regions.

  14. Topological susceptibility from slabs

    Energy Technology Data Exchange (ETDEWEB)

    Bietenholz, Wolfgang [Instituto de Ciencias Nucleares, Universidad Nacional Autónoma de México, A.P. 70-543, Distrito Federal, C.P. 04510 (Mexico); Forcrand, Philippe de [Institute for Theoretical Physics, ETH Zürich,CH-8093 Zürich (Switzerland); CERN, Physics Department, TH Unit, CH-1211 Geneva 23 (Switzerland); Gerber, Urs [Instituto de Ciencias Nucleares, Universidad Nacional Autónoma de México, A.P. 70-543, Distrito Federal, C.P. 04510 (Mexico); Instituto de Física y Matemáticas, Universidad Michoacana de San Nicolás de Hidalgo,Edificio C-3, Apdo. Postal 2-82, Morelia, Michoacán, C.P. 58040 (Mexico)

    2015-12-14

    In quantum field theories with topological sectors, a non-perturbative quantity of interest is the topological susceptibility χ{sub t}. In principle it seems straightforward to measure χ{sub t} by means of Monte Carlo simulations. However, for local update algorithms and fine lattice spacings, this tends to be difficult, since the Monte Carlo history rarely changes the topological sector. Here we test a method to measure χ{sub t} even if data from only one sector are available. It is based on the topological charges in sub-volumes, which we denote as slabs. Assuming a Gaussian distribution of these charges, this method enables the evaluation of χ{sub t}, as we demonstrate with numerical results for non-linear σ-models.

  15. Topological Susceptibility from Slabs

    CERN Document Server

    Bietenholz, Wolfgang; Gerber, Urs

    2015-01-01

    In quantum field theories with topological sectors, a non-perturbative quantity of interest is the topological susceptibility chi_t. In principle it seems straightforward to measure chi_t by means of Monte Carlo simulations. However, for local update algorithms and fine lattice spacings, this tends to be difficult, since the Monte Carlo history rarely changes the topological sector. Here we test a method to measure chi_t even if data from only one sector are available. It is based on the topological charges in sub-volumes, which we denote as slabs. Assuming a Gaussian distribution of these charges, this method enables the evaluation of chi_t, as we demonstrate with numerical results for non-linear sigma-models.

  16. Safety and immunogenicity of inactivated poliovirus vaccine when given with measles-rubella combined vaccine and yellow fever vaccine and when given via different administration routes: a phase 4, randomised, non-inferiority trial in The Gambia.

    Science.gov (United States)

    Clarke, Ed; Saidu, Yauba; Adetifa, Jane U; Adigweme, Ikechukwu; Hydara, Mariama Badjie; Bashorun, Adedapo O; Moneke-Anyanwoke, Ngozi; Umesi, Ama; Roberts, Elishia; Cham, Pa Modou; Okoye, Michael E; Brown, Kevin E; Niedrig, Matthias; Chowdhury, Panchali Roy; Clemens, Ralf; Bandyopadhyay, Ananda S; Mueller, Jenny; Jeffries, David J; Kampmann, Beate

    2016-08-01

    The introduction of the inactivated poliovirus vaccine (IPV) represents a crucial step in the polio eradication endgame. This trial examined the safety and immunogenicity of IPV given alongside the measles-rubella and yellow fever vaccines at 9 months and when given as a full or fractional dose using needle and syringe or disposable-syringe jet injector. We did a phase 4, randomised, non-inferiority trial at three periurban government clinics in west Gambia. Infants aged 9-10 months who had already received oral poliovirus vaccine were randomly assigned to receive the IPV, measles-rubella, and yellow fever vaccines, singularly or in combination. Separately, IPV was given as a full intramuscular or fractional intradermal dose by needle and syringe or disposable-syringe jet injector at a second visit. The primary outcomes were seroprevalence rates for poliovirus 4-6 weeks post-vaccination and the rate of seroconversion between baseline and post-vaccination serum samples for measles, rubella, and yellow fever; and the post-vaccination antibody titres generated against each component of the vaccines. We did a per-protocol analysis with a non-inferiority margin of 10% for poliovirus seroprevalence and measles, rubella, and yellow fever seroconversion, and (1/3) log2 for log2-transformed antibody titres. This trial is registered with ClinicalTrials.gov, number NCT01847872. Between July 10, 2013, and May 8, 2014, we assessed 1662 infants for eligibility, of whom 1504 were enrolled into one of seven groups for vaccine interference and one of four groups for fractional dosing and alternative route of administration. The rubella and yellow fever antibody titres were reduced by co-administration but the seroconversion rates achieved non-inferiority in both cases (rubella, -4·5% [95% CI -9·5 to -0·1]; yellow fever, 1·2% [-2·9 to 5·5]). Measles and poliovirus responses were unaffected (measles, 6·8% [95% CI -1·4 to 14·9]; poliovirus serotype 1, 1·6% [-6·7 to 4·7

  17. Susceptibility of laboratory rodents to Trichinella papuae.

    Science.gov (United States)

    Sadaow, Lakkhana; Intapan, Pewpan M; Boonmars, Thidarut; Morakote, Nimit; Maleewong, Wanchai

    2013-12-01

    Members of the genus Trichinella are small nematodes that can infect a wide range of animal hosts. However, their infectivity varies depending on the parasite and host species combination. In this study, we examined the susceptibility of 4 species of laboratory rodents, i.e., mice, rats, hamsters, and gerbils to Trichinella papuae, an emerging non-encapsulated Trichinella species. Trichinella spiralis and Trichinella pseudospiralis were also included in this study for comparison. Fifteen animals of each rodent species were infected orally with 100 muscle larvae of each Trichinella species. Intestinal worm burden was determined at day 6 and 10 post-inoculation (PI). The numbers of muscle larvae were examined at day 45 PI. The reproductive capacity index (RCI) of the 3 Trichinella species in different rodent hosts was determined. By day 6 PI, 33.2-69.6% of the inoculated larvae of the 3 Trichinella species became adult worms in the small intestines of the host animals. However, in rats, more than 96% of adult worms of all 3 Trichinella species were expelled from the gut by day 10 PI. In gerbils, only 4.8-18.1% of adult worms were expelled by day 10 PI. In accordance with the intestinal worm burden and the persistence of adults, the RCI was the highest in gerbils with values of 241.5±41.0 for T. papuae, 432.6±48 for T. pseudospiralis, and 528.6±20.6 for T. spiralis. Hamsters ranked second and mice ranked third in susceptibility in terms of the RCI, Rats yielded the lowest parasite RCI for all 3 Trichinella species. Gerbils may be an alternative laboratory animal for isolation and maintenance of Trichinella spp.

  18. Effects of Social Defeat Stress on Sleep in Mice

    Directory of Open Access Journals (Sweden)

    Fiona Henderson

    2017-11-01

    Full Text Available Stress plays a key role in the development of psychiatric disorders and has a negative impact on sleep integrity. In mice, chronic social defeat stress (CSDS is an ethologically valid model of stress-related disorders but little is known about its effects on sleep regulation. Here, we investigated the immediate and long-term effects of 10 consecutive days of social defeat (SD on vigilance states in C57Bl/6J male mice. Social behavior was assessed to identify susceptible mice, i.e., mice that develop long-lasting social avoidance, and unsusceptible mice. Sleep-wake stages in mice of both groups were analyzed by means of polysomnographic recordings at baseline, after the first, third, and tenth stress sessions and on the 5th recovery day (R5 following the 10-day CSDS. In susceptible mice, each SD session produced biphasic changes in sleep-wake states that were preserved all along 10-day CSDS. These sessions elicited a short-term enhancement of wake time while rapid eye-movement (REM sleep was strongly inhibited. Concomitantly, delta power was increased during non REM (NREM sleep. During the following dark period, an increase in total sleep time, as well as wake fragmentation, were observed after each analyzed SD session. Similar changes were observed in unsusceptible mice. At R5, elevated high-frequency EEG activity, as observed in insomniacs, emerged during NREM sleep in both susceptible and unsusceptible groups suggesting that CSDS impaired sleep quality. Furthermore, susceptible but not unsusceptible mice displayed stress-anticipatory arousal during recovery, a common feature of anxiety disorders. Altogether, our findings show that CSDS has profound impacts on vigilance states and further support that sleep is tightly regulated by exposure to stressful events. They also revealed that susceptibility to chronic psychological stress is associated with heightened arousal, a physiological feature of stress vulnerability.

  19. Microwave susceptibility experiments

    Energy Technology Data Exchange (ETDEWEB)

    McConaghy, C.

    1984-05-29

    In certain experimental environments, systems can be affected or damaged by microwave pulses. I have conducted tests at LLNL to understand the phenomenology of microwave susceptibility of system components and subsystem components. To date, my experiments have concentrated on bipolar transistors, similar to what might be used in discrete analog circuits, and on CMOS RAM chips, which might be used in a computer memory system. I observed a decrease in failure energies for both the transistor and the integrated curcuit as I shortened the microwave pulse width. An S band (2.86 GHz) transmit/receive (T/R) tube has also been tested both at S band and at X band (8.16 GHz). The S band pulse had limitations in rise-time from zero power, which had an effect on the amount of power that could be transmitted through the T/R tube, as much as 0.7% of the incident power passed through the tube. All tests were conducted in closed-waveguide or coax test-fixtures, in contrast to the anechoic chambers utilized by other experimenters. I have used both S band and X band Klystron generators. For very high power (greater than 1 MW), I used an additional pulse-compression cavity at S band. Other subsystem components such as an X band mixer and an X band T/R tube will be tested in the future. 8 references.

  20. [Antimicrobial susceptibility cumulative reports].

    Science.gov (United States)

    Canut-Blasco, Andrés; Calvo, Jorge; Rodríguez-Díaz, Juan Carlos; Martínez-Martínez, Luis

    2016-10-01

    Cumulative reports on antimicrobial susceptibility tests data are important for selecting empirical treatments, as an educational tool in programs on antimicrobial use, and for establishing breakpoints defining clinical categories. These reports should be based on data validated by clinical microbiologists using diagnostic samples (not surveillance samples). In order to avoid a bias derived from including several isolates obtained from the same patient, it is recommended that, for a defined period, only the first isolate is counted. A minimal number of isolates per species should be presented: a figure of >=30 isolates is statistically acceptable. The report is usually presented in a table format where, for each cell, information on clinically relevant microorganisms-antimicrobial agents is presented. Depending on particular needs, multiple tables showing data related to patients, samples, services or special pathogens can be prepared. Copyright © 2015 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  1. Community transmission of type 2 poliovirus after cessation of trivalent oral polio vaccine in Bangladesh: an open-label cluster-randomised trial and modelling study.

    Science.gov (United States)

    Taniuchi, Mami; Famulare, Michael; Zaman, Khalequ; Uddin, Md Jashim; Upfill-Brown, Alexander M; Ahmed, Tahmina; Saha, Parimalendu; Haque, Rashidul; Bandyopadhyay, Ananda S; Modlin, John F; Platts-Mills, James A; Houpt, Eric R; Yunus, Mohammed; Petri, William A

    2017-10-01

    Trivalent oral polio vaccine (tOPV) was replaced worldwide from April, 2016, by bivalent types 1 and 3 oral polio vaccine (bOPV) and one dose of inactivated polio vaccine (IPV) where available. The risk of transmission of type 2 poliovirus or Sabin 2 virus on re-introduction or resurgence of type 2 poliovirus after this switch is not understood completely. We aimed to assess the risk of Sabin 2 transmission after a polio vaccination campaign with a monovalent type 2 oral polio vaccine (mOPV2). We did an open-label cluster-randomised trial in villages in the Matlab region of Bangladesh. We randomly allocated villages (clusters) to either: tOPV at age 6 weeks, 10 weeks, and 14 weeks; or bOPV at age 6 weeks, 10 weeks, and 14 weeks and either one dose of IPV at age 14 weeks or two doses of IPV at age 14 weeks and 18 weeks. After completion of enrolment, we implemented an mOPV2 vaccination campaign that targeted 40% of children younger than 5 years, regardless of enrolment status. The primary outcome was Sabin 2 incidence in the 10 weeks after the campaign in per-protocol infants who did not receive mOPV2, as assessed by faecal shedding of Sabin 2 by reverse transcriptase quantitative PCR (RT-qPCR). The effect of previous immunity on incidence was also investigated with a dynamical model of poliovirus transmission to observe prevalence and incidence of Sabin 2 virus. This trial is registered at ClinicalTrials.gov, number NCT02477046. Between April 30, 2015, and Jan 14, 2016, individuals from 67 villages were enrolled to the study. 22 villages (300 infants) were randomly assigned tOPV, 23 villages (310 infants) were allocated bOPV and one dose of IPV, and 22 villages (329 infants) were assigned bOPV and two doses of IPV. Faecal shedding of Sabin 2 in infants who did not receive the mOPV2 challenge did not differ between children immunised with bOPV and one or two doses of IPV and those who received tOPV (15 of 252 [6%] vs six of 122 [4%]; odds ratio [OR] 1·29, 95% CI 0

  2. Isolamento e identificação intratípica de cêpas de poliovirus associadas com a administração de vacina Sabin Isolation and intratypical identification on poliovirus strains following the administration of Sabin vaccine

    Directory of Open Access Journals (Sweden)

    José Alberto Neves Candeias

    1969-12-01

    Full Text Available Estudou-se a taxa de excreção de enterovírus em dois grupos de crianças de 1 a 4 anos de idade, que receberam várias doses de vacina Sabin. No primeiro grupo a colheita de fezes foi feita 60 dias após a administração da última dose de vacina e no segundo grupo, passados somente 15 dias. No primeiro grupo as porcentagens de isolamento de poliovírus e outros enterovírus foram, respectivamente, de 12,12% e 13,63%. já no segundo, estas porcentagens foram de 37,61% e 9,17%. Em ambos os grupos foram isolados os três tipos sorológicos de poliovírus. As taxas de isolamentos de poliovírus e outros enterovírus não se mostraram estatìsticamente diferentes, em ambos os grupos, quando relacionadas com o número de doses de vacina recebidas - duas ou menos doses e três ou mais doses. A identificação intratípica das cêpas de poliovirus isoladas foi feita pelos "marcadores" RCT40 e ds. Das 8 cêpas isoladas do primeiro grupo, 6 foram identificadas como intermediárias e 2 como cêpas naturais. Estas 2 cêpas foram isoladas das duas únicas crianças que não tinham sido vacinadas contra a poliomielite. Das 41 cêpas isoladas do segundo grupo, 8 foram caracterizadas como intermediárias e 33 como ceêpas tipicamente vacinais.The author studied the incidence of enterovirus excretion in 2 groups of children aged between 1 and 4 years, who had been given varying doses of Sabin polio vaccine. In the first group faeces were collected 60 days and in the second group 15 days after the last dose of vaccine had been given. In the first group 12,12% yielded poliovirus and 13,63% yielded "other enteroviruses"; in the second group the percentages were 37,61% and 9,17%. In both groups all three serological types of poliovirus were isolated. The previous vaccination status of the children in both groups, whether vaccinated with two or less or three or more doses, did not have a statistically significant effect on the subsequent virus isolations. The

  3. Anticorpos neutralizantes contra poliovírus em soros de recém-nascidos antes e após imunização em massa da população brasileira de zero a cinco anos de idade. São Paulo, Brasil (1980 Neutralizing antibodies for poliovirus in newborn children sera before and after mass immunization of Brazilian population from one to five years old, São Paulo — Brazil, 1980

    Directory of Open Access Journals (Sweden)

    Rudolf Uri Hutzler

    1984-04-01

    Full Text Available Foram colhidas amostras de sangue de 178 recém-nascidos (RN em berçários de hospital localizado no Município de São Paulo. Noventa crianças foram puncionadas antes do primeiro "Dia Nacional de Vacinação Contra a Poliomielite" e as outras 88, após o segundo "Dia Nacional de Vacinação Contra a Poliomielite", realizados em 1980. Nessas campanhas foram imunizadas as crianças com idade de zero a cinco anos, em todo o Brasil. No presente trabalho pesquisou-se os títulos de anticorpos neutralizantes contra poliovírus nos dois grupos de recém-nascidos. Após a imunização em massa verificou-se que a taxa de recém-nascidos triplo suscetíveis decresceu de 8,9% para 4,5%, enquanto que o aumento observado do triplo imunes foi de 38,9% para 52,3%; essas diferenças mostraram-se estatisticamente significantes ao nível de 5,0%. A proporção de recém-nascidos, com títulos de anticorpos neutralizantes contra poliovírus iguais ou maiores do que 8, aumentou após as campanhas de imunização, quando passaram de 68,9% para 81,8%, de 73,3% para 83,0% e de 57,8% para 70,5%, respectivamente, para os sorotipos 1, 2 e 3. Essas diferenças mostraram se estatisticamente significantes, ao nível de 5,0%, em relação aos poliovírus 1 e 3.Blood samples from 178 new-born children in the nurseries of hospital located in São Paulo Municipality were examined. The samples from 90 children were obtained before "The First National Day For Poliomyelitis Vaccination" and 88 were analysed after "The Second National Day For Poliomyelitis Vaccination", both of them achieved in 1980. During these vaccination campaigns, it was observed that the number of children susceptible for three poliovirus serotypes decreased from 8.9% to 4.5%; on the other hand, there was an increase in immunized children for the three serotypes from 38.9% to 52.3%. These differences were statis- tically significative at level of 5.0%. After mass immunization, an increase in relation to

  4. [Antimicrobial susceptibility in Chile 2012].

    Science.gov (United States)

    Cifuentes-D, Marcela; Silva, Francisco; García, Patricia; Bello, Helia; Briceño, Isabel; Calvo-A, Mario; Labarca, Jaime

    2014-04-01

    Bacteria antimicrobial resistance is an uncontrolled public health problem that progressively increases its magnitude and complexity. The Grupo Colaborativo de Resistencia, formed by a join of experts that represent 39 Chilean health institutions has been concerned with bacteria antimicrobial susceptibility in our country since 2008. In this document we present in vitro bacterial susceptibility accumulated during year 2012 belonging to 28 national health institutions that represent about 36% of hospital discharges in Chile. We consider of major importance to report periodically bacteria susceptibility so to keep the medical community updated to achieve target the empirical antimicrobial therapies and the control measures and prevention of the dissemination of multiresistant strains.

  5. pso.ATION AND ANTIMICROBIAL SUSCEPTIBILITY

    African Journals Online (AJOL)

    isolates vere made using standard methods, Antibiotic susceptibility tests against commonly prescribed ... Acute otitis media is rapid with short .... sensitivity tests. Antimicrobial susceptibility tests: The antimicrobial susceptibility patterns of major Gram positive and negative bacterial isolates obtained from clinical specimens.

  6. Lack of a Functioning P2X7 Receptor Leads to Increased Susceptibility to Toxoplasmic Ileitis.

    Directory of Open Access Journals (Sweden)

    Catherine M Miller

    Full Text Available Oral infection of C57BL/6J mice with the protozoan parasite Toxoplasma gondii leads to a lethal inflammatory ileitis.Mice lacking the purinergic receptor P2X7R are acutely susceptible to toxoplasmic ileitis, losing significantly more weight than C57BL/6J mice and exhibiting much greater intestinal inflammatory pathology in response to infection with only 10 cysts of T. gondii. This susceptibility is not dependent on the ability of P2X7R-deficient mice to control the parasite, which they accomplish just as efficiently as C57BL/6J mice. Rather, susceptibility is associated with elevated ileal concentrations of pro-inflammatory cytokines, reactive nitrogen intermediates and altered regulation of elements of NFκB activation in P2X7R-deficient mice.Our data support the thesis that P2X7R, a well-documented activator of pro-inflammatory cytokine production, also plays an important role in the regulation of intestinal inflammation.

  7. Aire deficiency causes increased susceptibility to streptozotocin-induced murine type 1 diabetes.

    Science.gov (United States)

    Hässler, S; Peltonen, L; Sandler, S; Winqvist, O

    2008-06-01

    Aire-deficient mice are a model of the human monogenic disorder autoimmune polyendocrine syndrome type I (APS I) characterized by a progressive autoimmune destruction of multiple endocrine glands such as the adrenal cortex, the parathyroids and the beta-cells of the pancreas. The disease is caused by mutations in the autoimmune regulator (AIRE) gene, a putative transcription factor expressed in thymic medullary epithelial cells and in antigen-presenting cells of the myeloid lineage in peripheral lymphoid organs. As Aire(-/-) mice do not spontaneously develop endocrinopathies, we wanted to evaluate the autoimmune multiple low-dose streptozotocin (MLDSTZ) diabetes model in Aire(-/-) mice. Surprisingly, Aire heterozygote mice were most susceptible to MLDSTZ-induced diabetes, whereas Aire(-/-) mice displayed an intermediate sensitivity to diabetes. Furthermore, Aire(-/-) macrophages produced higher levels of TNF-alpha and lower levels of IL-10 following streptozotocin stimulation, and Aire(-/-) mice developed a higher frequency of islet cells autoantibodies as a sign of increased activation. However, the number of islet infiltrating F4/80(+) Aire(-/-) macrophages was significantly decreased which was attributed to an increased susceptibility to streptozotocin cytotoxicity of Aire(-/-) macrophages. In conclusion, Aire(-/-) macrophages display an increased activation after STZ stimuli, but suffer from increased susceptibility to STZ cytotoxicity. These results support an important function of Aire in the control of peripheral tolerance through myeloid antigen-presenting cells.

  8. Hypnotic susceptibility and dream characteristics.

    Science.gov (United States)

    Zamore, N; Barrett, D

    1989-11-01

    This study examined the relationship of hypnotic susceptibility to a variety of dream characteristics and types of dream content. A Dream Questionnaire was constructed synthesizing Gibson's dream inventory and Hilgard's theoretical conceptions of hypnosis. Employing the Harvard Group Scale of Hypnotic Susceptibility and the Field Inventory for evaluating hypnotic response, several dream dimensions correlated significantly with hypnotizability. For subjects as a whole, the strongest correlates were the frequency of dreams which they believed to be precognitive and out-of-body dreams. Ability to dream on a chosen topic also correlated significantly with hypnotic susceptibility for both genders. For females only, there was a negative correlation of hypnotic susceptibility to flying dreams. Absorption correlated positively with dream recall, ability to dream on a chosen topic, reports of conflict resolution in dreams, creative ideas occurring in dreams, amount of color in dreams, pleasantness of dreams, bizarreness of dreams, flying dreams and precognitive dreams.

  9. Replication of echo virus type 25 JV-4 reference strain and wild type strains in MRC5 cells compared with that of poliovirus type 1.

    Science.gov (United States)

    Bailly, J L; Chambon, M; Peigue-Lafeuille, H; Charbonné, F

    1994-01-01

    In echo virus type 25/JV-4 the shut off of host cell protein synthesis took significantly longer and the kinetics of the synthesis of viral proteins and viral RNA occurred much later than in the poliovirus. However, these characteristics impaired neither polyprotein processing nor virus production in the JV-4 strain. In contrast the two wild strains M.1262 and Th.222 had a lower virus yield than strain JV-4. The presence of a high Mr protein in the pattern of viral proteins of wild strains suggested that a defect in the polyprotein processing was responsible for the decreased virus yield. The infectious cycle of strain Th.222 differed from that of strains JV-4 and M.1262 in the rapid inhibition of host cell translation and the extent of viral protein synthesis. The sensitivity to actinomycin D was also investigated. Strain M.1262 was found to be insensitive. The virus yield of strains JV-4 and Th.222 was three- and fourfold lower respectively in the presence of actinomycin D. This sensitivity to the antibiotic was observed during viral RNA synthesis in strain JV-4 and during viral protein synthesis in strain Th.222. These results suggest that cellular factors are involved in the replication of echo virus type 25 strains in MRC5 cells.

  10. Radioiodide uptake in brain, CSF, thyroid, and salivary glands of audiogenic seizure mice

    Energy Technology Data Exchange (ETDEWEB)

    Engstrom, F.L.; Chow, S.Y.; Kemp, J.W.; Woodbury, D.M.

    1984-08-01

    DBA/2J (DBA) mice are susceptible to audiogenic seizures (ASs) in an age-dependent manner. Anion transport as measured by radioiodide uptake was determined in thyroid gland, salivary gland, skeletal muscle, cerebral cortex, cerebellum, brainstem, and CSF from these mice at various ages. Anion transport was also determined in C57BL/6J(C57) mice, an AS-resistant strain. In thyroid, DBA mice had an enhanced ability to concentrate iodide at 21 days of age when they have maximal AS susceptibility, as compared with the same-aged C57 mice. This difference in thyroid function was less marked at 40 days of age, when DBA mice are less AS susceptible, and was absent at 110 days of age, when DBA mice are AS resistant. In brain, differences in iodide uptake were also noted between these two strains of mice at 21 days of age. DBA mice had an increased concentration of iodide in CSF, an indication that they have a defect in the transport of iodide out of the CSF across the choroid plexus. In addition, DBA mice had a lower ratio of cerebral cortex to CSF iodide, which suggests that DBA mice have a defect in the transport of this anion into cerebral cortical cells from brain interstitial fluid. These differences in iodide transport in brain decreased with age as the AS susceptibility of DBA mice decreased. These results suggest a relation between anion transport in thyroid gland, cerebral cortex, and choroid plexus and AS susceptibility in DBA mice at 21 days of age.

  11. Ancestral susceptibility to colorectal cancer

    Czech Academy of Sciences Publication Activity Database

    Huhn, S.; Pardini, Barbara; Naccarati, Alessio; Vodička, Pavel (ed.); Hemminki, K.; Försti, A.

    2012-01-01

    Roč. 27, č. 2 (2012), s. 197-204 ISSN 0267-8357 R&D Projects: GA ČR GA310/07/1430; GA ČR GAP304/10/1286 Grant - others:EU FP7(XE) HEALTH-F4-2007-200767 Institutional research plan: CEZ:AV0Z50390512 Keywords : cancer susceptibility * molecular epidemiology * genetic susceptibility Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.500, year: 2012

  12. Transfer of innate resistance and susceptibility to Leishmania donovani infection in mouse radiation bone marrow chimaeras

    Energy Technology Data Exchange (ETDEWEB)

    Crocker, P.R.; Blackwell, J.M.; Bradley, D.J. (London School of Hygiene and Tropical Medicine (UK))

    1984-07-01

    Reciprocal radiation bone marrow chimaeras were made between H-2-compatible strains of mice innately resistant or susceptible to visceral leishmaniasis. In initial experiments, susceptibility but not resistance to Leishmania donovani could be transferred with donor bone marrow into irradiated recipients. In subsequent experiments it was possible to transfer both resistance and susceptibility. This was achieved either by selecting more radiosensitive mouse strains as susceptible recipients, or alternatively by increasing the irradiation dose for the susceptible recipients used in the initial experiments. Using the higher irradiation dose, successful transfer of resistance and susceptibility between congenic mice carrying the Lshsup(r) and Lshsup(s) alleles on the more radioresistant B10 genetic background provided firm evidence that the results obtained in this study were specifically related to expression of the Lsh gene. It is concluded that Lsh gene-controlled resistance and susceptibility to L. donovani is determined by bone marrow-derived cells. The cell type(s) involved is likely to be of the macrophage lineage.

  13. Susceptibility of the wild-derived inbred CAST/Ei mouse to infection by orthopoxviruses analyzed by live bioluminescence imaging

    Energy Technology Data Exchange (ETDEWEB)

    Americo, Jeffrey L.; Sood, Cindy L.; Cotter, Catherine A.; Vogel, Jodi L.; Kristie, Thomas M.; Moss, Bernard, E-mail: bmoss@nih.gov; Earl, Patricia L., E-mail: pearl@nih.gov

    2014-01-20

    Classical inbred mice are extensively used for virus research. However, we recently found that some wild-derived inbred mouse strains are more susceptible than classical strains to monkeypox virus. Experiments described here indicated that the 50% lethal dose of vaccinia virus (VACV) and cowpox virus (CPXV) were two logs lower in wild-derived inbred CAST/Ei mice than classical inbred BALB/c mice, whereas there was little difference in the susceptibility of the mouse strains to herpes simplex virus. Live bioluminescence imaging was used to follow spread of pathogenic and attenuated VACV strains and CPXV virus from nasal passages to organs in the chest and abdomen of CAST/Ei mice. Luminescence increased first in the head and then simultaneously in the chest and abdomen in a dose-dependent manner. The spreading kinetics was more rapid with VACV than CPXV although the peak photon flux was similar. These data suggest advantages of CAST/Ei mice for orthopoxvirus studies. - Highlights: • Wild-derived inbred CAST/Ei mice are susceptible to vaccinia virus and cowpox virus. • Morbidity and mortality from orthopoxviruses are greater in CAST/Ei than BALB/c mice. • Morbidity and mortality from herpes simplex virus type 1 are similar in both mice. • Imaging shows virus spread from nose to lungs, abdominal organs and brain. • Vaccinia virus spreads more rapidly than cowpox virus.

  14. Insufficient Innate Immunity Contributes to the Susceptibility of the Castaneous Mouse to Orthopoxvirus Infection.

    Science.gov (United States)

    Earl, Patricia L; Americo, Jeffrey L; Moss, Bernard

    2017-10-01

    The castaneous (CAST) mouse, a wild-derived inbred strain, is highly susceptible to orthopoxvirus infection by intranasal and systemic routes. The 50% lethal intraperitoneal dose of vaccinia virus (VACV) was 3 PFU for CAST mice, whereas BALB/c mice survived 106 PFU. At all times and in all organs analyzed, virus titers were higher in CAST than in BALB/c mice. In individual CAST mice, luciferase-expressing VACV was seen to replicate rapidly leading to death, whereas virus levels increased for a few days and then declined in BALB/c mice. Increases in gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) were delayed and low in CAST mice compared to BALB/c mice following VACV infection or poly(I-C) inoculation, consistent with differences in innate immune responses. In addition, naive CAST mice had considerably lower numbers of NK and T cells than BALB/c mice. The percentage of IFN-γ-producing CD4+ and CD8+ T cells increased following infection of CAST mice only after considerable virus spread, and the absolute cell numbers remained low. Administration of exogenous IFN-γ or -α to CAST mice before or during the first days of infection suppressed virus replication and prolonged survival, allowing the mice to make adaptive CD4+ and CD8+ T cell responses that were necessary to clear the virus after cessation of interferon treatment. Thus, insufficient innate cytokine and cellular immune responses contribute to the unique susceptibility of CAST mice to VACV, whereas the adaptive immune response can be protective only if virus replication is suppressed during the first several days of infection.IMPORTANCE Most inbred mouse strains are relatively resistant to orthopoxviruses. The castaneous (CAST) mouse is a notable exception, exhibiting extreme vulnerability to monkeypox virus, cowpox virus, and vaccinia virus and thus providing a unique model for studying pathogenicity, immunity, vaccines, and antiviral drugs. To fully utilize the CAST mouse for such

  15. Immune cells from SR/CR mice induce the regression of established tumors in BALB/c and C57BL/6 mice

    DEFF Research Database (Denmark)

    Koch, Janne; Hau, Jann; Pravsgaard Christensen, Jan

    2013-01-01

    of resistance to EL-4 lymphoma cells and J774A.1 monocyte-macrophage cancer cells. The cancer resistance against S180 sarcoma cells could be transferred to susceptible non-resistant BALB/c mice as well as C57BL/6 mice after depletion of both CD4+/CD8+ leukocytes and B-cells from SR/CR mice. In the responding...... recipient mice, the cancer disappeared gradually following infiltration of a large number of polymorphonuclear granulocytes and remarkably few lymphocytes in the remaining tumor tissues. This study confirmed that the in vivo growth and spread of cancer cells depend on a complex interplay between the cancer...... mice could be transferred to inhibit S180 cancer cell growth in susceptible recipient mice support the vision of an efficient and adverse event free immunotherapy in future selected cancer types....

  16. Microbicide excipients can greatly increase susceptibility to genital herpes transmission in the mouse

    Directory of Open Access Journals (Sweden)

    Sun Mianmian

    2010-11-01

    Full Text Available Abstract Background Several active ingredients proposed as vaginal microbicides have been shown paradoxically to increase susceptibility to infection in mouse genital herpes (HSV-2 vaginal susceptibility models and in clinical trials. In addition, "inactive ingredients" (or excipients used in topical products to formulate and deliver the active ingredient might also cause epithelial toxicities that increase viral susceptibility. However, excipients have not previously been tested in susceptibility models. Methods Excipients commonly used in topical products were formulated in a non-toxic vehicle (the "HEC universal placebo", or other formulations as specified. Twelve hours after exposure to the excipient or a control treatment, mice were challenged with a vaginal dose of HSV-2, and three days later were assessed for infection by vaginal lavage culture to assess susceptibility. Results The following excipients markedly increased susceptibility to HSV-2 after a single exposure: 5% glycerol monolaurate (GML formulated in K-Y® Warming Jelly, 5% GML as a colloidal suspension in phosphate buffered saline, K-Y Warming Jelly alone, and both of its humectant/solvent ingredients (neat propylene glycol and neat PEG-8. For excipients formulated in the HEC vehicle, 30% glycerin significantly increased susceptibility, and a trend toward increased HSV-2 susceptibility was observed after 10% glycerin, and 0.1% disodium EDTA, but not after 0.0186% disodium EDTA. The following excipients did not increase susceptibility: 10% propylene glycol, 0.18%, methylparaben plus 0.02% propylparaben, and 1% benzyl alcohol. Conclusions As reported with other surfactants, the surfactant/emulsifier GML markedly increased susceptibility to HSV-2. Glycerin at 30% significantly increased susceptibility, and, undiluted propylene glycol and PEG-8 greatly increased susceptibility.

  17. Susceptibility Genes in Thyroid Autoimmunity

    Directory of Open Access Journals (Sweden)

    Yoshiyuki Ban

    2005-01-01

    Full Text Available The autoimmune thyroid diseases (AITD are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions that are linked with AITD, and in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD and Hashimoto's thyroiditis (HT and some are common to both the diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4 and thyroid specific genes (e.g. TSHR, Tg. Most likely, these loci interact and their interactions may influence disease phenotype and severity.

  18. Mind the gap: glucocorticoids modulate hippocampal glutamate tone underlying individual differences in stress susceptibility.

    Science.gov (United States)

    Nasca, C; Bigio, B; Zelli, D; Nicoletti, F; McEwen, B S

    2015-06-01

    Why do some individuals succumb to stress and develop debilitating psychiatric disorders, whereas others adapt well in the face of adversity? There is a gap in understanding the neural bases of individual differences in the responses to environmental factors on brain development and functions. Here, using a novel approach for screening an inbred population of laboratory animals, we identified two subpopulations of mice: susceptible mice that show mood-related abnormalities compared with resilient mice, which cope better with stress. This approach combined with molecular and behavioral analyses, led us to recognize, in hippocampus, presynaptic mGlu2 receptors, which inhibit glutamate release, as a stress-sensitive marker of individual differences to stress-induced mood disorders. Indeed, genetic mGlu2 deletion in mice results in a more severe susceptibility to stress, mimicking the susceptible mouse sub-population. Furthermore, we describe an underlying mechanism by which glucocorticoids, acting via mineralocorticoid receptors (MRs), decrease resilience to stress via downregulation of mGlu2 receptors. We also provide a mechanistic link between MRs and an epigenetic control of the glutamatergic synapse that underlies susceptibility to stressful experiences. The approach and the epigenetic allostasis concept introduced here serve as a model for identifying individual differences based upon biomarkers and underlying mechanisms and also provide molecular features that may be useful in translation to human behavior and psychopathology.

  19. Pulmonary exposure to particles during pregnancy causes increased neonatal asthma susceptibility

    DEFF Research Database (Denmark)

    Fedulov, Alexey V; Leme, Adriana; Yang, Zhiping

    2008-01-01

    Maternal immune responses can promote allergy development in offspring, as shown in a model of increased susceptibility to asthma in babies of ovalbumin (OVA)-sensitized and -challenged mother mice. We investigated whether inflammatory responses to air pollution particles (diesel exhaust particles...

  20. EXPERIMENTAL-INFECTION IN MICE WITH BACILLUS-LICHENIFORMIS

    DEFF Research Database (Denmark)

    Agerholm, J.S.; Jensen, H.E.; Jensen, N.E.

    1995-01-01

    The pathogenicity of Bacillus licheniformis was assessed in normal and immunodepressed BALB/c mice. The animals were challenged intravenously with 4 x 10(7) colony forming units of B, licheniformis (ATCC 14580) and both normal and immunodepressed mice were susceptible. However, the infection was ...... could be identified in tissue sections by immunostaining. Immunohistochemically, B, licheniformis was demonstrated in hepatic and pulmonic macrophages, and from some animals the bacteria were also reisolated....

  1. Ac magnetic susceptibility study of in vivo nanoparticle biodistribution

    Energy Technology Data Exchange (ETDEWEB)

    Gutierrez, L; Veintemillas-Verdaguer, S; Serna, C J; Morales, M P [Instituto de Ciencia de Materiales de Madrid, ICMM-CSIC, Sor Juana Ines de la Cruz 3, Cantoblanco 28049, Madrid (Spain); MejIas, R; Barber, D F [Centro Nacional de BiotecnologIa, CNB-CSIC, Darwin 3, Cantoblanco 28049, Madrid (Spain); Lazaro, F J, E-mail: lucia@icmm.csic.es [Departamento de Ciencia y Tecnologia de Materiales y Fluidos, Universidad de Zaragoza, Maria de Luna 3, 50018, Zaragoza (Spain)

    2011-06-29

    We analysed magnetic nanoparticle biodistribution, before and after cytokine conjugation, in a mouse model by ac susceptibility measurements of the corresponding resected tissues. Mice received repeated intravenous injections of nanoparticle suspension for two weeks and they were euthanized 1 h after the last injection. In general, only 10% of the total injected nanoparticles after multiple exposures were found in tissues. The rest of the particles may probably be metabolized or excreted by the organism. Our findings indicate that the adsorption of interferon to DMSA-coated magnetic nanoparticles changes their biodistribution, reducing the presence of nanoparticles in lungs and therefore their possible toxicity. The specific targeting of the particles to tumour tissues by the use of an external magnetic field has also been studied. Magnetic nanoparticles were observed by transmission electron microscopy in the targeted tissue and quantified by ac magnetic susceptibility.

  2. Inherited susceptibility and radiation exposure

    Energy Technology Data Exchange (ETDEWEB)

    Little, J.B. [Harvard School of Public Health, Boston, MA (United States)

    1997-03-01

    There is continuing concern that some people in the general population may have genetic makeups that place them at particularly high risk for radiation-induced cancer. The existence of such a susceptible subpopulation would have obvious implications for the estimation of risks of radiation exposure. Although it has been long known that familial aggregations of cancer do sometimes occur, recent evidence suggests that a general genetic predisposition to cancer does not exist; most cancers occur sporadically. On the other hand, nearly 10% of the known Mendelian genetic disorders are associated with cancer. A number of these involve a familial predisposition to cancer, and some are characterized by an enhanced susceptibility to the induction of cancer by various physical and chemical carcinogens, including ionizing radiation. Such increased susceptibility will depend on several factors including the frequency of the susceptibility gene in the population and its penetrance, the strength of the predisposition, and the degree to which the cancer incidence in susceptible individuals may be increased by the carcinogen. It is now known that these cancer-predisposing genes may be responsible not only for rare familial cancer syndromes, but also for a proportion of the common cancers. Although the currently known disorders can account for only a small fraction of all cancers, they serve as models for genetic predisposition to carcinogen-induced cancer in the general population. In the present report, the author describes current knowledge of those specific disorders that are associated with an enhanced predisposition to radiation-induced cancer, and discusses how this knowledge may bear on the susceptibility to radiation-induced cancer in the general population and estimates of the risk of radiation exposure.

  3. Salmonella Meningitis Associated with Monocyte Infiltration in Mice.

    Science.gov (United States)

    Bauler, Timothy J; Starr, Tregei; Nagy, Toni A; Sridhar, Sushmita; Scott, Dana; Winkler, Clayton W; Steele-Mortimer, Olivia; Detweiler, Corrella S; Peterson, Karin E

    2017-01-01

    In the current study, we examined the ability of Salmonella enterica serovar Typhimurium to infect the central nervous system and cause meningitis following the natural route of infection in mice. C57BL/6J mice are extremely susceptible to systemic infection by Salmonella Typhimurium because of loss-of-function mutations in Nramp1 (SLC11A1), a phagosomal membrane protein that controls iron export from vacuoles and inhibits Salmonella growth in macrophages. Therefore, we assessed the ability of Salmonella to disseminate to the central nervous system (CNS) after oral infection in C57BL/6J mice expressing either wild-type (resistant) or mutant (susceptible) alleles of Nramp1. In both strains, oral infection resulted in focal meningitis and ventriculitis with recruitment of inflammatory monocytes to the CNS. In susceptible Nramp1-/- mice, there was a direct correlation between bacteremia and the number of bacteria in the brain, which was not observed in resistant Nramp1+/+ mice. A small percentage of Nramp1+/+ mice developed severe ataxia, which was associated with high bacterial loads in the CNS as well as clear histopathology of necrotizing vasculitis and hemorrhage in the brain. Thus, Nramp1 is not essential for Salmonella entry into the CNS or neuroinflammation, but may influence the mechanisms of CNS entry as well as the severity of meningitis. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  4. pitting corrosion susceptibility pitting corrosion susceptibility of aisi ...

    African Journals Online (AJOL)

    eobe

    Abstract. The susceptibility of austenitic (AISI 301) stainless steel to pitting corrosion was evaluated in sodium chloride. (NaCl) solutions ... AISI 301 steel suffers from pitting corrosion in all the investigated solutions. AISI 301 steel suffers from ..... [1] Ijeomah, M.N.C. Elements of Corrosion and Protection. Theory, Auto Century ...

  5. Age-related changes in arthritis susceptibility and severity in a murine model of rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    Nemeth Peter

    2009-06-01

    Full Text Available Abstract Background Rheumatoid arthritis (RA most often begins in females in the fourth-fifth decade of their life, suggesting that the aging of the immune system (immunosenescence has a major role in this disease. Therefore, in the present study, we sought to investigate the effect of age on arthritis susceptibility in BALB/c mice using the proteoglycan (PG-induced arthritis (PGIA model of RA. Results We have found that young, 1-month-old female BALB/c mice are resistant to the induction of PGIA, but with aging they become susceptible. PG-induced T cell responses decline with age, whereas there is a shift toward Th1 cytokines. An age-dependent decrease in T cell number is associated with an increased ratio of the memory phenotype, and lower CD28 expression. Antigen-presenting cells shifted from macrophages and myeloid dendritic cells in young mice toward B cells in older mice. The regulatory/activated T cell ratio decreases in older mice after PG injections indicating impaired regulation of the immune response. Conclusion We conclude that immunosenescence could alter arthritis susceptibility in a very complex manner including both adaptive and innate immunities, and it cannot be determined by a single trait. Cumulative alterations in immunoregulatory functions closely resemble human disease, which makes this systemic autoimmune arthritis model of RA even more valuable.

  6. Magnetic Susceptability Measurements in Superconductors

    Science.gov (United States)

    Kim, Jason; Mallory, Kendall; Seim, Ryan

    2000-04-01

    A new undergraduate research facility in magnetic susceptability measurements on superconductors is being developed at the University of Northern Colorado. Initial data measurements of the magnetic susceptability of various superconductors will be presented. These measurements were obtained with a liquid helium/nitrogen dewar that was reassembled for use in this project. The cryostat consists of two separate dewars, the first of which contains liquid nitrogen, the second, liquid helium. The liquid nitrogen dewar is used to keep the helium bath from evaporating off too quickly. Data on the evaporation rates of the two liquids will also be presented.

  7. Preparation for global introduction of inactivated poliovirus vaccine: safety evidence from the US Vaccine Adverse Event Reporting System, 2000-12.

    Science.gov (United States)

    Iqbal, Shahed; Shi, Jing; Seib, Katherine; Lewis, Paige; Moro, Pedro L; Woo, Emily J; Shimabukuro, Tom; Orenstein, Walter A

    2015-10-01

    Safety data from countries with experience in the use of inactivated poliovirus vaccine (IPV) are important for the global polio eradication strategy to introduce IPV into the immunisation schedules of all countries. In the USA, IPV has been included in the routine immunisation schedule since 1997. We aimed to analyse adverse events after IPV administration reported to the US Vaccine Adverse Event Reporting System (VAERS). We analysed all VAERS data associated with IPV submitted between Jan 1, 2000, and Dec 31, 2012, either as individual or as combination vaccines, for all age and sex groups. We analysed the number and event type (non-serious, non-fatal serious, and death reports) of individual reports, and explored the most commonly coded event terms to describe the adverse event. We classified death reports according to previously published body-system categories (respiratory, cardiovascular, neurological, gastrointestinal, other infectious, and other non-infectious) and reviewed death reports to identify the cause of death. We classified sudden infant death syndrome as a separate cause of death considering previous concerns about sudden infant syndrome after vaccines. We used empirical Bayesian data mining methods to identify disproportionate reporting of adverse events for IPV compared with other vaccines. Additional VAERS data from 1991 to 2000 were analysed to compare the safety profiles of IPV and oral poliovirus vaccine (OPV). Of the 41,792 adverse event reports submitted, 39,568 (95%) were for children younger than 7 years. 38,381 of the reports for children in this age group (97%) were for simultaneous vaccination with IPV and other vaccines (most commonly pneumococcal and acellular pertussis vaccines), whereas standalone IPV vaccines accounted for 0·5% of all reports. 34,880 reports were for non-serious events (88%), 3905 reports were for non-fatal serious events (10%), and 783 reports were death reports (2%). Injection-site erythema was the most

  8. Lack of the pattern recognition molecule mannose-binding lectin increases susceptibility to influenza A virus infection

    Directory of Open Access Journals (Sweden)

    Hartshorn Kevan L

    2010-12-01

    Full Text Available Abstract Background Mannose-binding lectin (MBL, a pattern recognition innate immune molecule, inhibits influenza A virus infection in vitro. MBL deficiency due to gene polymorphism in humans has been associated with infection susceptibility. These clinical observations were confirmed by animal model studies, in which mice genetically lacking MBL were susceptible to certain pathogens, including herpes simplex virus 2. Results We demonstrate that MBL is present in the lung of naïve healthy wild type (WT mice and that MBL null mice are more susceptible to IAV infection. Administration of recombinant human MBL (rhMBL reverses the infection phenotype, confirming that the infection susceptibility is MBL-mediated. The anti-viral mechanisms of MBL include activation of the lectin complement pathway and coagulation, requiring serum factors. White blood cells (WBCs in the lung increase in WT mice compared with MBL null mice on day 1 post-infection. In contrast, apoptotic macrophages (MΦs are two-fold higher in the lung of MBL null mice compared with WT mice. Furthermore, MBL deficient macrophages appear to be susceptible to apoptosis in vitro. Lastly, soluble factors, which are associated with lung injury, are increased in the lungs of MBL null mice during IAV infection. These results suggest that MBL plays a key role against IAV infection. Conclusion MBL plays a key role in clearing IAV and maintaining lung homeostasis. In addition, our findings also suggest that MBL deficiency maybe a risk factor in IAV infection and MBL may be a useful adjunctive therapy for IAV infection.

  9. Absence of IFN-γ increases brain pathology in experimental autoimmune encephalomyelitis-susceptible DRB1*0301.DQ8 HLA transgenic mice through secretion of proinflammatory cytokine IL-17 and induction of pathogenic monocytes/microglia into the central nervous system.

    Science.gov (United States)

    Mangalam, Ashutosh K; Luo, Ningling; Luckey, David; Papke, Louisa; Hubbard, Alyssa; Wussow, Arika; Smart, Michele; Giri, Shailendra; Rodriguez, Moses; David, Chella

    2014-11-15

    Multiple sclerosis is an inflammatory, demyelinating disease of the CNS of presumed autoimmune origin. Of all the genetic factors linked with multiple sclerosis, MHC class II molecules have the strongest association. Generation of HLA class II transgenic (Tg) mice has helped to elucidate the role of HLA class II genes in chronic inflammatory and demyelinating diseases. We have shown that the human HLA-DRB1*0301 gene predisposes to proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE), whereas HLA-DQβ1*0601 (DQ6) was resistant. We also showed that the DQ6 molecule protects from EAE in DRB1*0301.DQ6 double-Tg mice by producing anti-inflammatory IFN-γ. HLA-DQβ1*0302 (DQ8) Tg mice were also resistant to PLP(91-110)-induced EAE, but production of proinflammatory IL-17 exacerbated disease in DRB1*0301.DQ8 mice. To further confirm the role of IFN-γ in protection, we generated DRB1*0301.DQ8 mice lacking IFN-γ (DRB1*0301.DQ8.IFN-γ(-/-)). Immunization with PLP(91-110) peptide caused atypical EAE in DRB1*0301.DQ8.IFN-γ(-/-) mice characterized by ataxia, spasticity, and dystonia, hallmarks of brain-specific disease. Severe brain-specific inflammation and demyelination in DRB1*0301.DQ8.IFN-γ(-/-) mice with minimal spinal cord pathology further confirmed brain-specific pathology. Atypical EAE in DRB1*0301.DQ8.IFN-γ(-/-) mice was associated with increased encephalitogenicity of CD4 T cells and their ability to produce greater levels of IL-17 and GM-CSF compared with DRB1*0301.DQ8 mice. Further, areas with demyelination showed increased presence of CD68(+) inflammatory cells, suggesting an important role for monocytes/microglia in causing brain pathology. Thus, our study supports a protective role for IFN-γ in the demyelination of brain through downregulation of IL-17/GM-CSF and induction of neuroprotective factors in the brain by monocytes/microglial cells. Copyright © 2014 by The American Association of Immunologists, Inc.

  10. IFNγ influences type I interferon response and susceptibility to Theiler's virus-induced demyelinating disease.

    Science.gov (United States)

    Bowen, Jenna L; Olson, Julie K

    2013-08-01

    Theiler's murine encephalomyelitis virus (TMEV) induces a demyelinating disease in susceptible SJL mice that has similarities to multiple sclerosis in humans. TMEV infection of susceptible mice leads to a persistent virus infection of the central nervous system (CNS), which promotes the development of demyelinating disease associated with an inflammatory immune response in the CNS. TMEV infection of resistant C57BL6 mice results in viral clearance without development of demyelinating disease. Interestingly, TMEV infection of resistant mice deficient in IFNγ leads to a persistent virus infection in the CNS and development of demyelinating disease. We have previously shown that the innate immune response affects development of TMEV- induced demyelinating disease, thus we wanted to determine the role of IFNγ during the innate immune response. TMEV-infected IFNγ-deficient mice had an altered innate immune response, including reduced expression of innate immune cytokines, especially type I interferons. Administration of type I interferons, IFNα and IFNß, to TMEV-infected IFNγ-deficient mice during the innate immune response restored the expression of innate immune cytokines. Most importantly, administration of type I interferons to IFNγ-deficient mice during the innate immune response decreased the virus load in the CNS and decreased development of demyelinating disease. Microglia are the CNS resident immune cells that express innate immune receptors. In TMEV-infected IFNγ-deficient mice, microglia had reduced expression of innate immune cytokines, and administration of type I interferons to these mice restored the innate immune response by microglia. In the absence of IFNγ, microglia from TMEV-infected mice had reduced expression of some innate immune receptors and signaling molecules, especially IRF1. These results suggest that IFNγ plays an important role in the innate immune response to TMEV by enhancing the expression of innate immune cytokines

  11. Role and mechanism of the maturation cleavage of VP0 in poliovirus assembly: structure of the empty capsid assembly intermediate at 2.9 A resolution.

    Science.gov (United States)

    Basavappa, R.; Syed, R.; Flore, O.; Icenogle, J. P.; Filman, D. J.; Hogle, J. M.

    1994-01-01

    The crystal structure of the P1/Mahoney poliovirus empty capsid has been determined at 2.9 A resolution. The empty capsids differ from mature virions in that they lack the viral RNA and have yet to undergo a stabilizing maturation cleavage of VP0 to yield the mature capsid proteins VP4 and VP2. The outer surface and the bulk of the protein shell are very similar to those of the mature virion. The major differences between the 2 structures are focused in a network formed by the N-terminal extensions of the capsid proteins on the inner surface of the shell. In the empty capsids, the entire N-terminal extension of VP1, as well as portions corresponding to VP4 and the N-terminal extension of VP2, are disordered, and many stabilizing interactions that are present in the mature virion are missing. In the empty capsid, the VP0 scissile bond is located some 20 A away from the positions in the mature virion of the termini generated by VP0 cleavage. The scissile bond is located on the rim of a trefoil-shaped depression in the inner surface of the shell that is highly reminiscent of an RNA binding site in bean pod mottle virus. The structure suggests plausible (and ultimately testable) models for the initiation of encapsidation, for the RNA-dependent autocatalytic cleavage of VP0, and for the role of the cleavage in establishing the ordered N-terminal network and in generating stable virions. PMID:7849583

  12. Final Technical Report for the grant entitled "Genetic Factors Affecting Susceptibility to Low-Dose Radiation"

    Energy Technology Data Exchange (ETDEWEB)

    Morgan, William, F., Ph.D., D.Sc.

    2006-11-22

    The goal of this proposal was to test the hypothesis that mice heterozygous for the Nijmegen Breakage Syndrome (NBS1) gene are genetically susceptible to low doses of ionizing radiation. The rationale for this is that patients with NBS are radiation sensitive, because of defects in cellular responses to radiation induced genetic damage and haploinsufficiency at this genetic locus provides the potential for genetic susceptibility to low doses of ionizing radiation. Wild type and heterozygous NBS1 mice were irradiated and followed over their lifetime for radiation induced genomic instability, carcinogenesis and non-specific life shortening. No differences in cytogenetic damage, cancer induction or life span were observed between the hypomorphic mice indicating that genetic imbalance at the NBS1 loci does not modulate low dose radiation sensitivity.

  13. Genetic selection for coping style predicts stressor susceptibility.

    Science.gov (United States)

    Veenema, A H; Meijer, O C; de Kloet, E R; Koolhaas, J M

    2003-03-01

    Genetically selected aggressive (SAL) and nonaggressive (LAL) male wild house-mice which show distinctly different coping styles, also display a differential regulation of the hypothalamic-pituitary-adrenal axis after exposure to an acute stressor. To test the hypothesis that coping style predicts stressor susceptibility, the present study examined line differences in response to a chronic stressor. Chronic psychosocial stress was evoked using two paradigms. In the first paradigm, a SAL or LAL male was living in sensory contact (except tactile contact) with a dominant SAL male for 25 days (sensory contact stress). In the second paradigm, a SAL or LAL male was, in addition to the first paradigm, defeated by a SAL male for 21 consecutive days (defeat stress). The sensory contact stressor induced in LAL mice chronic body weight loss and increased plasma adrenocorticotropic hormone levels compared to SAL mice and increased corticosterone levels, thymus involution and lower hippocampal mineralocorticoid receptor (MR) : glucocorticoid receptor (GR) ratio compared to LAL controls. The defeat stressor increased corticosterone secretion and caused adrenal hypertrophy and thymus involution in both mouse lines. Defeated LAL mice showed long-lasting body weight loss and higher corticosterone concentrations than SAL mice and lower hippocampal MR : GR ratio and decreased immobility behaviour in the forced swimming test than LAL controls. Hypothalamic corticotropin-releasing hormone mRNA expression was higher in defeated SAL than in controls. The present data show that both stress paradigms induced line-dependent physiological and neuroendocrine changes, but that the sensory contact stressor produced chronic stress symptoms in LAL mice only. This latter stress paradigm therefore seems promising to analyse the role of genetic factors in the individual differences in stress-related psychopathology.

  14. Topological susceptibility from the overlap

    DEFF Research Database (Denmark)

    Del Debbio, Luigi; Pica, Claudio

    2003-01-01

    The chiral symmetry at finite lattice spacing of Ginsparg-Wilson fermionic actions constrains the renormalization of the lattice operators; in particular, the topological susceptibility does not require any renormalization, when using a fermionic estimator to define the topological charge. Theref...