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Sample records for antiviral antibody responses

  1. Antibody-independent control of gamma-herpesvirus latency via B cell induction of anti-viral T cell responses.

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    Kelly B McClellan

    2006-06-01

    Full Text Available B cells can use antibody-dependent mechanisms to control latent viral infections. It is unknown whether this represents the sole function of B cells during chronic viral infection. We report here that hen egg lysozyme (HEL-specific B cells can contribute to the control of murine gamma-herpesvirus 68 (gammaHV68 latency without producing anti-viral antibody. HEL-specific B cells normalized defects in T cell numbers and proliferation observed in B cell-/- mice during the early phase of gammaHV68 latency. HEL-specific B cells also reversed defects in CD8 and CD4 T cell cytokine production observed in B cell-/- mice, generating CD8 and CD4 T cells necessary for control of latency. Furthermore, HEL-specific B cells were able to present virally encoded antigen to CD8 T cells. Therefore, B cells have antibody independent functions, including antigen presentation, that are important for control of gamma-herpesvirus latency. Exploitation of this property of B cells may allow enhanced vaccine responses to chronic virus infection.

  2. Lack of antiviral antibody response in koalas infected with koala retroviruses (KoRV).

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    Fiebig, Uwe; Keller, Martina; Möller, Annekatrin; Timms, Peter; Denner, Joachim

    2015-02-16

    Many wild koalas are infected with the koala retrovirus, KoRV, some of which suffer from lymphoma and chlamydial disease. Three subgroups, KoRV-A, KoRV-B and KoRV-J, have so far been described. It is well known that other closely related gammaretroviruses can induce tumours and severe immunodeficiencies in their respective hosts and a possible role for KoRV infection in lymphoma and chlamydial disease in koalas has been suggested. In many wild koalas, KoRV-A has become endogenised, i.e., it is integrated in the germ-line and is passed on with normal cellular genes. In this study, sera from koalas in European zoos and from wild animals in Australia were screened for antibodies against KoRV-A. These naturally infected animals all carry endogenous KoRV-A and two zoo animals are also infected with KoRV-B. The antibody response is generally an important diagnostic tool for detecting retrovirus infections. However, when Western blot analyses were performed using purified virus or recombinant proteins corresponding to KoRV-A, none of the koalas tested positive for specific antibodies, suggesting a state of tolerance. These results have implications for koala vaccination, as they suggest that therapeutic immunisation of animals carrying and expressing endogenous KoRV-A will not be successful. However, it remains unclear whether these animals can be immunised against KoRV-B and immunisation of uninfected koalas could still be worthwhile. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Humanized Antibodies for Antiviral Therapy

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    Co, Man Sung; Deschamps, Marguerite; Whitley, Richard J.; Queen, Cary

    1991-04-01

    Antibody therapy holds great promise for the treatment of cancer, autoimmune disorders, and viral infections. Murine monoclonal antibodies are relatively easy to produce but are severely restricted for therapeutic use by their immunogenicity in humans. Production of human monoclonal antibodies has been problematic. Humanized antibodies can be generated by introducing the six hypervariable regions from the heavy and light chains of a murine antibody into a human framework sequence and combining it with human constant regions. We humanized, with the aid of computer modeling, two murine monoclonal antibodies against herpes simplex virus gB and gD glycoproteins. The binding, virus neutralization, and cell protection results all indicate that both humanized antibodies have retained the binding activities and the biological properties of the murine monoclonal antibodies.

  4. Recovery of an antiviral antibody response following attrition caused by unrelated infection.

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    Dorothy H L Ng

    2014-01-01

    Full Text Available The homeostatic mechanisms that regulate the maintenance of immunological memory to the multiple pathogen encounters over time are unknown. We found that a single malaria episode caused significant dysregulation of pre-established Influenza A virus-specific long-lived plasma cells (LLPCs resulting in the loss of Influenza A virus-specific Abs and increased susceptibility to Influenza A virus re-infection. This loss of LLPCs involved an FcγRIIB-dependent mechanism, leading to their apoptosis. However, given enough time following malaria, the LLPC pool and humoral immunity to Influenza A virus were eventually restored. Supporting a role for continuous conversion of Influenza A virus-specific B into LLPCs in the restoration of Influenza A virus immunity, B cell depletion experiments also demonstrated a similar requirement for the long-term maintenance of serum Influenza A virus-specific Abs in an intact LLPC compartment. These findings show that, in addition to their established role in the anamnestic response to reinfection, the B cell pool continues to be a major contributor to the maintenance of long-term humoral immunity following primary Influenza A virus infection, and to the recovery from attrition following heterologous infection. These data have implications for understanding the longevity of protective efficacy of vaccinations in countries where continuous infections are endemic.

  5. Subversion of early innate antiviral responses during antibody-dependent enhancement of Dengue virus infection induces severe disease in immunocompetent mice.

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    Costa, Vivian V; Fagundes, Caio T; Valadão, Deborah F; Ávila, Thiago V; Cisalpino, Daniel; Rocha, Rebeca F; Ribeiro, Lucas S; Ascenção, Fernando R; Kangussu, Lucas M; Celso, M Q; Astigarraga, Ruiz G; Gouveia, Frederico L; Silva, Tarcília A; Bonaventura, Daniela; Sampaio, Divaldo de Almeida; Leite, Ana Cristina L; Teixeira, Mauro M; Souza, Danielle G

    2014-08-01

    Dengue is a mosquito-borne disease caused by one of four serotypes of Dengue virus (DENV-1-4). Epidemiologic and observational studies demonstrate that the majority of severe dengue cases, dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS), occurs predominantly in either individuals with cross-reactive immunity following a secondary heterologous infection or in infants with primary DENV infections born from dengue-immune mothers, suggesting that B-cell-mediated and antibody responses impact on disease evolution. We demonstrate here that B cells play a pivotal role in host responses against primary DENV infection in mice. After infection, μMT(-/-) mice showed increased viral loads followed by severe disease manifestation characterized by intense thrombocytopenia, hemoconcentration, cytokine production and massive liver damage that culminated in death. In addition, we show that poly and monoclonal anti-DENV-specific antibodies can sufficiently increase viral replication through a suppression of early innate antiviral responses and enhance disease manifestation, so that a mostly non-lethal illness becomes a fatal disease resembling human DHF/DSS. Finally, treatment with intravenous immunoglobulin containing anti-DENV antibodies confirmed the potential enhancing capacity of subneutralizing antibodies to mediate virus infection and replication and induce severe disease manifestation of DENV-infected mice. Thus, our results show that humoral responses unleashed during DENV infections can exert protective or pathological outcomes and provide insight into the pathogenesis of this important human pathogen.

  6. Antibody-Dependent Enhancement of Dengue Virus Infection in Primary Human Macrophages; Balancing Higher Fusion against Antiviral Responses

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    Flipse, Jacky; Diosa-Toro, Mayra A.; Hoornweg, Tabitha E.; van de Pol, Denise P. I.; Urcuqui-Inchima, Silvio; Smit, Jolanda M.

    2016-01-01

    The dogma is that the human immune system protects us against pathogens. Yet, several viruses, like dengue virus, antagonize the hosts' antibodies to enhance their viral load and disease severity; a phenomenon called antibody-dependent enhancement of infection. This study offers novel insights in

  7. Optimization of Influenza Antiviral Response in Texas

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    2015-03-01

    originated 38 from Texas- Mexico border counties, TAVRS would average the 150 treatable curves that apply to that influenza scenario to be used in... INFLUENZA ANTIVIRAL RESPONSE IN TEXAS by Travis L. Chambers March 2015 Advisor: Nedialko B. Dimitrov Co-Advisor: Michael Atkinson Second...DATES COVERED March 2015 Master ’s Thesis 4. TITLE AND SUBTITLE OPTIMIZATION OF INFLUENZA ANTIVIRAL RESPONSE IN TEXAS 6. AUTHOR(S) Travis L. Chambers

  8. RNA Sensors Enable Human Mast Cell Anti-Viral Chemokine Production and IFN-Mediated Protection in Response to Antibody-Enhanced Dengue Virus Infection

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    Huang, Yan Y.; Haidl, Ian D.; Al-Afif, Ayham; Marshall, Jean S.; Anderson, Robert

    2012-01-01

    Dengue hemorrhagic fever and/or dengue shock syndrome represent the most serious pathophysiological manifestations of human dengue virus infection. Despite intensive research, the mechanisms and important cellular players that contribute to dengue disease are unclear. Mast cells are tissue-resident innate immune cells that play a sentinel cell role in host protection against infectious agents via pathogen-recognition receptors by producing potent mediators that modulate inflammation, cell recruitment and normal vascular homeostasis. Most importantly, mast cells are susceptible to antibody-enhanced dengue virus infection and respond with selective cytokine and chemokine responses. In order to obtain a global view of dengue virus-induced gene regulation in mast cells, primary human cord blood-derived mast cells (CBMCs) and the KU812 and HMC-1 mast cell lines were infected with dengue virus in the presence of dengue-immune sera and their responses were evaluated at the mRNA and protein levels. Mast cells responded to antibody-enhanced dengue virus infection or polyinosiniċpolycytidylic acid treatment with the production of type I interferons and the rapid and potent production of chemokines including CCL4, CCL5 and CXCL10. Multiple interferon-stimulated genes were also upregulated as well as mRNA and protein for the RNA sensors PKR, RIG-I and MDA5. Dengue virus-induced chemokine production by KU812 cells was significantly modulated by siRNA knockdown of RIG-I and PKR, in a negative and positive manner, respectively. Pretreatment of fresh KU812 cells with supernatants from dengue virus-infected mast cells provided protection from subsequent infection with dengue virus in a type I interferon-dependent manner. These findings support a role for tissue-resident mast cells in the early detection of antibody-enhanced dengue virus infection via RNA sensors, the protection of neighbouring cells through interferon production and the potential recruitment of leukocytes via

  9. RNA sensors enable human mast cell anti-viral chemokine production and IFN-mediated protection in response to antibody-enhanced dengue virus infection.

    Directory of Open Access Journals (Sweden)

    Michael G Brown

    Full Text Available Dengue hemorrhagic fever and/or dengue shock syndrome represent the most serious pathophysiological manifestations of human dengue virus infection. Despite intensive research, the mechanisms and important cellular players that contribute to dengue disease are unclear. Mast cells are tissue-resident innate immune cells that play a sentinel cell role in host protection against infectious agents via pathogen-recognition receptors by producing potent mediators that modulate inflammation, cell recruitment and normal vascular homeostasis. Most importantly, mast cells are susceptible to antibody-enhanced dengue virus infection and respond with selective cytokine and chemokine responses. In order to obtain a global view of dengue virus-induced gene regulation in mast cells, primary human cord blood-derived mast cells (CBMCs and the KU812 and HMC-1 mast cell lines were infected with dengue virus in the presence of dengue-immune sera and their responses were evaluated at the mRNA and protein levels. Mast cells responded to antibody-enhanced dengue virus infection or polyinosiniċpolycytidylic acid treatment with the production of type I interferons and the rapid and potent production of chemokines including CCL4, CCL5 and CXCL10. Multiple interferon-stimulated genes were also upregulated as well as mRNA and protein for the RNA sensors PKR, RIG-I and MDA5. Dengue virus-induced chemokine production by KU812 cells was significantly modulated by siRNA knockdown of RIG-I and PKR, in a negative and positive manner, respectively. Pretreatment of fresh KU812 cells with supernatants from dengue virus-infected mast cells provided protection from subsequent infection with dengue virus in a type I interferon-dependent manner. These findings support a role for tissue-resident mast cells in the early detection of antibody-enhanced dengue virus infection via RNA sensors, the protection of neighbouring cells through interferon production and the potential recruitment of

  10. Development of Tetravalent, Bispecific CCR5 Antibodies with Antiviral Activity against CCR5 Monoclonal Antibody-Resistant HIV-1 Strains▿

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    Schanzer, Jürgen; Jekle, Andreas; Nezu, Junichi; Lochner, Adriane; Croasdale, Rebecca; Dioszegi, Marianna; Zhang, Jun; Hoffmann, Eike; Dormeyer, Wilma; Stracke, Jan; Schäfer, Wolfgang; Ji, Changhua; Heilek, Gabrielle; Cammack, Nick; Brandt, Michael; Umana, Pablo; Brinkmann, Ulrich

    2011-01-01

    In this study, we describe novel tetravalent, bispecific antibody derivatives that bind two different epitopes on the HIV coreceptor CCR5. The basic protein formats that we applied were derived from Morrison-type bispecific antibodies: whole IgGs to which we connected single-chain antibodies (scFvs) via (Gly4Ser)n sequences at either the C or N terminus of the light chain or heavy chain. By design optimization, including disulfide stabilization of scFvs or introduction of 30-amino-acid linkers, stable molecules could be obtained in amounts that were within the same range as or no less than 4-fold lower than those observed with monoclonal antibodies in transient expression assays. In contrast to monospecific CCR5 antibodies, bispecific antibody derivatives block two alternative docking sites of CCR5-tropic HIV strains on the CCR5 coreceptor. Consequently, these molecules showed 18- to 57-fold increased antiviral activities compared to the parent antibodies. Most importantly, one prototypic tetravalent CCR5 antibody had antiviral activity against virus strains resistant to the single parental antibodies. In summary, physical linkage of two CCR5 antibodies targeting different epitopes on the HIV coreceptor CCR5 resulted in tetravalent, bispecific antibodies with enhanced antiviral potency against wild-type and CCR5 antibody-resistant HIV-1 strains. PMID:21300827

  11. Origin, diversity and maturation of human antiviral antibodies analyzed by high-throughput sequencing

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    Ponraj ePrabakaran

    2012-08-01

    Full Text Available Our understanding of how antibodies are generated and function could help develop effective vaccines and antibody-based therapeutics against viruses such as HIV-1, SARS Coronavirus (CoV, and Hendra and Nipah viruses (henipaviruses. Although broadly neutralizing antibodies (bnAbs against the HIV-1 were observed in patients, elicitation of such bnAbs remains a major challenge when compared to other viral targets. We previously hypothesized that HIV-1 could have evolved a strategy to evade the immune system due to absent or very weak binding of germline antibodies to the conserved epitopes that may not be sufficient to initiate and/or maintain an effective immune response. To further explore our hypothesis, we used the 454 sequence analysis of a large naïve library of human IgM antibodies which had been used for selecting antibodies against SARS Coronavirus (CoV receptor-binding domain (RBD, and soluble G proteins (sG of Hendra and Nipah viruses (henipaviruses. We found that the human IgM repertoires from the 454 sequencing have diverse germline usages, recombination patterns, junction diversity and a lower extent of somatic mutation. In this study, we identified germline intermediates of antibodies specific to HIV-1 and other viruses as observed in normal individuals, and compared their genetic diversity and somatic mutation level along with available structural and functional data. Further computational analysis will provide framework for understanding the underlying genetic and molecular determinants related to maturation pathways of antiviral bnAbs that could be useful for applying novel approaches to the design of effective vaccine immunogens and antibody-based therapeutics.

  12. Clinical features and effect of antiviral therapy on anti-liver/kidney microsomal antibody type 1 positive chronic hepatitis C.

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    Ferri, Silvia; Muratori, Luigi; Quarneti, Chiara; Muratori, Paolo; Menichella, Rita; Pappas, Georgios; Granito, Alessandro; Ballardini, Giorgio; Bianchi, Francesco B; Lenzi, Marco

    2009-06-01

    Anti-liver/kidney microsomal antibody type 1 (anti-LKM1), a serological marker of type 2 autoimmune hepatitis, is also detected in a small proportion of patients with hepatitis C. This study aimed to evaluate clinical features and effect of antiviral therapy in patients with hepatitis C who are anti-LKM1 positive. Sixty consecutive anti-LKM1 positive and 120 age and sex-matched anti-LKM1 negative chronic hepatitis C patients were assessed at diagnosis and during follow-up. Of these, 26 anti-LKM1 positive and 72 anti-LKM1 negative received antiviral therapy. Anti-LKM1 was detected by indirect immunofluorescence and immunoblot. Number of HCV-infected hepatocytes and intrahepatic CD8+ lymphocytes was determined by immunohistochemistry. At diagnosis anti-LKM1 positive patients had higher IgG levels and more intrahepatic CD8+ lymphocytes (p 0.022 and 0.046, respectively). Viral genotypes distribution and response to therapy were identical. Hepatic flares during antiviral treatment only occurred in a minority of patients in concomitance with anti-LKM1 positivity. Immune system activation is more pronounced in anti-LKM1 positive patients with hepatitis C, possibly representing the expression of autoimmune mechanisms of liver damage. Antiviral treatment is as beneficial in these patients as in anti-LKM1 negative patients, and the rare necroinflammatory flares are effectively controlled by corticosteroids, allowing subsequent resumption of antiviral therapy.

  13. Antiviral Therapy by HIV-1 Broadly Neutralizing and Inhibitory Antibodies

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    Zhiqing Zhang

    2016-11-01

    Full Text Available Human immunodeficiency virus type 1 (HIV-1 infection causes acquired immune deficiency syndrome (AIDS, a global epidemic for more than three decades. HIV-1 replication is primarily controlled through antiretroviral therapy (ART but this treatment does not cure HIV-1 infection. Furthermore, there is increasing viral resistance to ART, and side effects associated with long-term therapy. Consequently, there is a need of alternative candidates for HIV-1 prevention and therapy. Recent advances have discovered multiple broadly neutralizing antibodies against HIV-1. In this review, we describe the key epitopes on the HIV-1 Env protein and the reciprocal broadly neutralizing antibodies, and discuss the ongoing clinical trials of broadly neutralizing and inhibitory antibody therapy as well as antibody combinations, bispecific antibodies, and methods that improve therapeutic efficacy by combining broadly neutralizing antibodies (bNAbs with latency reversing agents. Compared with ART, HIV-1 therapeutics that incorporate these broadly neutralizing and inhibitory antibodies offer the advantage of decreasing virus load and clearing infected cells, which is a promising prospect in HIV-1 prevention and treatment.

  14. Characterization of immobilization methods of antiviral antibodies in serum for electrochemical biosensors

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    Huy, Tran Quang; Hanh, Nguyen Thi Hong; Van Chung, Pham; Anh, Dang Duc; Nga, Phan Thi; Tuan, Mai Anh

    2011-06-01

    In this paper, we describes different methods to immobilize Japanese encephalitis virus (JEV) antibodies in human serum onto the interdigitated surface of a microelectrode sensor for optimizing electrochemical detection: (1) direct covalent binding to the silanized surface, (2) binding to the silanized surface via a cross-linker of glutaraldehyde (GA), (3) binding to glutaraldehyde/silanized surface via goat anti-human IgG polyclonal antibody and (4) binding to glutaraldehyde/silanized surface via protein A (PrA). Field emission scanning electron microscopy, Fourier transform infrared spectrometry, and fluorescence microscopy are used to verify the characteristics of antibodies on the interdigitated surface after the serum antibodies immobilization. The analyzed results indicate that the use of protein A is an effective choice for immobilization and orientation of antibodies in serum for electrochemical biosensors. This study provides an advantageous immobilization method of serum containing antiviral antibodies to develop electrochemical biosensors for preliminary screening of viruses in clinical samples from outbreaks.

  15. HIV-1 vaccine-induced C1 and V2 Env-specific antibodies synergize for increased antiviral activities.

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    Pollara, Justin; Bonsignori, Mattia; Moody, M Anthony; Liu, Pinghuang; Alam, S Munir; Hwang, Kwan-Ki; Gurley, Thaddeus C; Kozink, Daniel M; Armand, Lawrence C; Marshall, Dawn J; Whitesides, John F; Kaewkungwal, Jaranit; Nitayaphan, Sorachai; Pitisuttithum, Punnee; Rerks-Ngarm, Supachai; Robb, Merlin L; O'Connell, Robert J; Kim, Jerome H; Michael, Nelson L; Montefiori, David C; Tomaras, Georgia D; Liao, Hua-Xin; Haynes, Barton F; Ferrari, Guido

    2014-07-01

    The RV144 ALVAC/AIDSVax HIV-1 vaccine clinical trial showed an estimated vaccine efficacy of 31.2%. Viral genetic analysis identified a vaccine-induced site of immune pressure in the HIV-1 envelope (Env) variable region 2 (V2) focused on residue 169, which is included in the epitope recognized by vaccinee-derived V2 monoclonal antibodies. The ALVAC/AIDSVax vaccine induced antibody-dependent cellular cytotoxicity (ADCC) against the Env V2 and constant 1 (C1) regions. In the presence of low IgA Env antibody levels, plasma levels of ADCC activity correlated with lower risk of infection. In this study, we demonstrate that C1 and V2 monoclonal antibodies isolated from RV144 vaccinees synergized for neutralization, infectious virus capture, and ADCC. Importantly, synergy increased the HIV-1 ADCC activity of V2 monoclonal antibody CH58 at concentrations similar to that observed in plasma of RV144 vaccinees. These findings raise the hypothesis that synergy among vaccine-induced antibodies with different epitope specificities contributes to HIV-1 antiviral antibody responses and is important to induce for reduction in the risk of HIV-1 transmission. Importance: The Thai RV144 ALVAC/AIDSVax prime-boost vaccine efficacy trial represents the only example of HIV-1 vaccine efficacy in humans to date. Studies aimed at identifying immune correlates involved in the modest vaccine-mediated protection identified HIV-1 envelope (Env) variable region 2-binding antibodies as inversely correlated with infection risk, and genetic analysis identified a site of immune pressure within the region recognized by these antibodies. Despite this evidence, the antiviral mechanisms by which variable region 2-specific antibodies may have contributed to lower rates of infection remain unclear. In this study, we demonstrate that vaccine-induced HIV-1 envelope variable region 2 and constant region 1 antibodies synergize for recognition of virus-infected cells, infectious virion capture, virus

  16. The Antiviral Mechanism of an Influenza A Virus Nucleoprotein-Specific Single-Domain Antibody Fragment

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    Hanke, Leo; Knockenhauer, Kevin E.; Brewer, R. Camille; van Diest, Eline; Schmidt, Florian I.; Schwartz, Thomas U.; Ploegh, Hidde L. (Whitehead); (MIT)

    2016-12-13

    Alpaca-derived single-domain antibody fragments (VHHs) that target the influenza A virus nucleoprotein (NP) can protect cells from infection when expressed in the cytosol. We found that one such VHH, αNP-VHH1, exhibits antiviral activity similar to that of Mx proteins by blocking nuclear import of incoming viral ribonucleoproteins (vRNPs) and viral transcription and replication in the nucleus. We determined a 3.2-Å crystal structure of αNP-VHH1 in complex with influenza A virus NP. The VHH binds to a nonconserved region on the body domain of NP, which has been associated with binding to host factors and serves as a determinant of host range. Several of the NP/VHH interface residues determine sensitivity of NP to antiviral Mx GTPases. The structure of the NP/αNP-VHH1 complex affords a plausible explanation for the inhibitory properties of the VHH and suggests a rationale for the antiviral properties of Mx proteins. Such knowledge can be leveraged for much-needed novel antiviral strategies.

    IMPORTANCEInfluenza virus strains can rapidly escape from protection afforded by seasonal vaccines or acquire resistance to available drugs. Additional ways to interfere with the virus life cycle are therefore urgently needed. The influenza virus nucleoprotein is one promising target for antiviral interventions. We have previously isolated alpaca-derived single-domain antibody fragments (VHHs) that protect cells from influenza virus infection if expressed intracellularly. We show here that one such VHH exhibits antiviral activities similar to those of proteins of the cellular antiviral defense (Mx proteins). We determined the three-dimensional structure of this VHH in complex with the influenza virus nucleoprotein and identified the interaction site, which overlaps regions that determine sensitivity of the virus to Mx proteins. Our data define a new vulnerability of influenza virus, help us to better understand the cellular antiviral mechanisms, and

  17. The Antiviral Mechanism of an Influenza A Virus Nucleoprotein-Specific Single-Domain Antibody Fragment.

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    Hanke, Leo; Knockenhauer, Kevin E; Brewer, R Camille; van Diest, Eline; Schmidt, Florian I; Schwartz, Thomas U; Ploegh, Hidde L

    2016-12-13

    Alpaca-derived single-domain antibody fragments (VHHs) that target the influenza A virus nucleoprotein (NP) can protect cells from infection when expressed in the cytosol. We found that one such VHH, αNP-VHH1, exhibits antiviral activity similar to that of Mx proteins by blocking nuclear import of incoming viral ribonucleoproteins (vRNPs) and viral transcription and replication in the nucleus. We determined a 3.2-Å crystal structure of αNP-VHH1 in complex with influenza A virus NP. The VHH binds to a nonconserved region on the body domain of NP, which has been associated with binding to host factors and serves as a determinant of host range. Several of the NP/VHH interface residues determine sensitivity of NP to antiviral Mx GTPases. The structure of the NP/αNP-VHH1 complex affords a plausible explanation for the inhibitory properties of the VHH and suggests a rationale for the antiviral properties of Mx proteins. Such knowledge can be leveraged for much-needed novel antiviral strategies. Influenza virus strains can rapidly escape from protection afforded by seasonal vaccines or acquire resistance to available drugs. Additional ways to interfere with the virus life cycle are therefore urgently needed. The influenza virus nucleoprotein is one promising target for antiviral interventions. We have previously isolated alpaca-derived single-domain antibody fragments (VHHs) that protect cells from influenza virus infection if expressed intracellularly. We show here that one such VHH exhibits antiviral activities similar to those of proteins of the cellular antiviral defense (Mx proteins). We determined the three-dimensional structure of this VHH in complex with the influenza virus nucleoprotein and identified the interaction site, which overlaps regions that determine sensitivity of the virus to Mx proteins. Our data define a new vulnerability of influenza virus, help us to better understand the cellular antiviral mechanisms, and provide a well-characterized tool to

  18. Antiviral responses of arthropod vectors: an update on recent advances.

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    Rückert, Claudia; Bell-Sakyi, Lesley; Fazakerley, John K; Fragkoudis, Rennos

    2014-01-01

    Arthropod vectors, such as mosquitoes, ticks, biting midges and sand flies, transmit many viruses that can cause outbreaks of disease in humans and animals around the world. Arthropod vector species are invading new areas due to globalisation and environmental changes, and contact between exotic animal species, humans and arthropod vectors is increasing, bringing with it the regular emergence of new arboviruses. For future strategies to control arbovirus transmission, it is important to improve our understanding of virus-vector interactions. In the last decade knowledge of arthropod antiviral immunity has increased rapidly. RNAi has been proposed as the most important antiviral response in mosquitoes and it is likely to be the most important antiviral response in all arthropods. However, other newly-discovered antiviral strategies such as melanisation and the link between RNAi and the JAK/STAT pathway via the cytokine Vago have been characterised in the last few years. This review aims to summarise the most important and most recent advances made in arthropod antiviral immunity.

  19. Innate immunity to dengue virus infection and subversion of antiviral responses

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    Green, Angela M.; Beatty, P. Robert; Hadjilaou, Alexandros; Harris, Eva

    2014-01-01

    Dengue is a major public health issue in tropical and subtropical regions worldwide. The four serotypes of dengue virus (DENV1-4) are spread primarily by Aedes aegypti and Ae. albopictus mosquitoes, whose geographic range continues to expand. Humans are the only host for epidemic strains of DENV, and the virus has developed sophisticated mechanisms to evade human innate immune responses. The host cell's first line of defense begins with an intracellular signaling cascade resulting in production of interferon (IFN)-α/β, which promotes intracellular antiviral responses and helps initiates the adaptive response during the course of DENV infection. In response, DENV has developed numerous ways to subvert these intracellular antiviral responses and directly inhibit cellular signaling cascades. Specifically, DENV manipulates the unfolded protein response and autophagy to counter cellular stress and delay apoptosis. The DENV non-structural protein NS4B and subgenomic sfRNA interfere with the RNAi pathway by inhibiting the RNAse Dicer. During heterotypic secondary DENV infection, subneutralizing antibodies can enable viral uptake through Fcγ receptors and down-regulate signaling cascades initiated via the pattern recognition receptors TLR3 and MDA5/RIG-I, thus reducing the antiviral state of the cell. The DENV NS2B/3 protein cleaves human STING/MITA, interfering with induction of IFN-α/β. Finally, DENV NS2A, NS4A, and NS4B complex together to block STAT1 phosphorylation, while NS5 binds and promotes degradation of human STAT2, thus preventing formation of the STAT1/STAT2 heterodimer and its transcriptional induction of ISGs. Here we discuss the host innate immune response to DENV and the mechanisms of immune evasion DENV has developed to manipulate cellular antiviral responses. PMID:24316047

  20. Innate immunity to dengue virus infection and subversion of antiviral responses.

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    Green, Angela M; Beatty, P Robert; Hadjilaou, Alexandros; Harris, Eva

    2014-03-20

    Dengue is a major public health issue in tropical and subtropical regions worldwide. The four serotypes of dengue virus (DENV1-DENV4) are spread primarily by Aedes aegypti and Aedes albopictus mosquitoes, whose geographic range continues to expand. Humans are the only host for epidemic strains of DENV, and the virus has developed sophisticated mechanisms to evade human innate immune responses. The host cell's first line of defense begins with an intracellular signaling cascade resulting in production of interferon α/β (IFN-α/β), which promotes intracellular antiviral responses and helps initiates the adaptive response during the course of DENV infection. In response, DENV has developed numerous ways to subvert these intracellular antiviral responses and directly inhibit cellular signaling cascades. Specifically, DENV manipulates the unfolded protein response and autophagy to counter cellular stress and delay apoptosis. The DENV non-structural protein NS4B and subgenomic flavivirus RNA interfere with the RNA interference pathway by inhibiting the RNase Dicer. During heterotypic secondary DENV infection, subneutralizing antibodies can enable viral uptake through Fcγ receptors and down-regulate signaling cascades initiated via the pattern recognition receptors TLR-3 and MDA5/RIG-I, thus reducing the antiviral state of the cell. The DENV NS2B/3 protein cleaves human STING/MITA, interfering with induction of IFN-α/β. Finally, DENV NS2A, NS4A, and NS4B complex together to block STAT1 phosphorylation, while NS5 binds and promotes degradation of human STAT2, thus preventing formation of the STAT1/STAT2 heterodimer and its transcriptional induction of interferon stimulating genes. Here, we discuss the host innate immune response to DENV and the mechanisms of immune evasion that DENV has developed to manipulate cellular antiviral responses. Copyright © 2013 Elsevier Ltd. All rights reserved.

  1. Senataxin suppresses the antiviral transcriptional response and controls viral biogenesis.

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    Miller, Matthew S; Rialdi, Alexander; Ho, Jessica Sook Yuin; Tilove, Micah; Martinez-Gil, Luis; Moshkina, Natasha P; Peralta, Zuleyma; Noel, Justine; Melegari, Camilla; Maestre, Ana M; Mitsopoulos, Panagiotis; Madrenas, Joaquín; Heinz, Sven; Benner, Chris; Young, John A T; Feagins, Alicia R; Basler, Christopher F; Fernandez-Sesma, Ana; Becherel, Olivier J; Lavin, Martin F; van Bakel, Harm; Marazzi, Ivan

    2015-05-01

    The human helicase senataxin (SETX) has been linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS4) and ataxia with oculomotor apraxia (AOA2). Here we identified a role for SETX in controlling the antiviral response. Cells that had undergone depletion of SETX and SETX-deficient cells derived from patients with AOA2 had higher expression of antiviral mediators in response to infection than did wild-type cells. Mechanistically, we propose a model whereby SETX attenuates the activity of RNA polymerase II (RNAPII) at genes stimulated after a virus is sensed and thus controls the magnitude of the host response to pathogens and the biogenesis of various RNA viruses (e.g., influenza A virus and West Nile virus). Our data indicate a potentially causal link among inborn errors in SETX, susceptibility to infection and the development of neurologic disorders.

  2. Direct versus sequential immunoglobulin switch in allergy and antiviral responses.

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    Svirshchevskaya, E; Fattakhova, G; Khlgatian, S; Chudakov, D; Kashirina, E; Ryazantsev, D; Kotsareva, O; Zavriev, S

    2016-09-01

    Allergy is characterized by IgE production to innocuous antigens. The question whether the switch to IgE synthesis occurs via direct or sequential pathways is still unresolved. The aim of this work was to analyze the distribution of immunoglobulins (Ig) to house dust mite D. farinae and A. alternata fungus in allergic children with primarily established diagnosis and compare it to Epstein-Barr antiviral (EBV) response in the same patients. In allergy patients the only significant difference was found in allergen specific IgE, likely mediated by a direct isotype switch, while antiviral response was dominated by EBV specific IgG and low level of concordant IgA and IgG4 production consistent with a minor sequential Ig switches. Taken collectively, we concluded that sequential isotype switch is likely to be a much rarer event than a direct one. Copyright © 2016. Published by Elsevier Inc.

  3. The interferon response circuit in antiviral host defense.

    Science.gov (United States)

    Haller, O; Weber, F

    2009-01-01

    Viruses have learned to multiply in the face of a powerful innate and adaptive immune response of the host. They have evolved multiple strategies to evade the interferon (IFN) system which would otherwise limit virus growth at an early stage of infection. IFNs induce the synthesis of a range of antiviral proteins which serve as cell-autonomous intrinsic restriction factors. For example, the dynamin-like MxA GTPase inhibits the multiplication of influenza and bunyaviruses (such as La Crosse virus, Hantaan virus, Rift Valley Fever virus, and Crimean-Congo hemorrhagic fever virus) by binding and sequestering the nucleocapsid protein into large perinuclear complexes. To overcome such intracellular restrictions, virulent viruses either inhibit IFN synthesis, bind and inactivate secreted IFN molecules, block IFN-activated signaling, or disturb the action of IFN-induced antiviral proteins. Many viruses produce specialized proteins to disarm the danger signal or express virulence genes that target members of the IFN regulatory factor family (IRFs) or components of the JAK-STAT signaling pathway. An alternative evasion strategy is based on extreme viral replication speed which out-competes the IFN response. The identification of viral proteins with IFN antagonistic functions has great implications for disease prevention and therapy. Virus mutants lacking IFN antagonistic properties represent safe yet highly immunogenic candidate vaccines. Furthermore, novel drugs intercepting viral IFN-antagonists could be used to disarm the viral intruders.

  4. Antiviral antibodies stimulate production of reactive oxygen species in cultured canine brain cells infected with canine distemper virus.

    Science.gov (United States)

    Bürge, T; Griot, C; Vandevelde, M; Peterhans, E

    1989-06-01

    Canine distemper is characterized mainly by respiratory, enteric, and nervous symptoms. Infection of the central nervous system results in demyelination, to which inflammation has been shown to contribute significantly. It has been proposed that macrophages play a major role as effector cells in this process. We report that cultured dog brain cells contain a population of macrophages capable of producing reactive oxygen species as measured by luminol-dependent chemiluminescence. In cultures infected with canine distemper virus, a burst of reactive oxygen is triggered by antiviral antibody. This response depends on the presence of viral antigens on the surfaces of infected cells and is mediated by the interaction of antigen-bound antibody with Fc receptors on the macrophages. Since there is no evidence in vitro or in vivo that oligodendrocytes, the cells forming myelin, are infected, our observation supports the hypothesis that "innocent bystander killing" is important in demyelination caused by canine distemper virus. Reactive oxygen species released from macrophages may contribute to destruction of myelin.

  5. Evasion of the Interferon-Mediated Antiviral Response by Filoviruses

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    Washington B. Cárdenas

    2010-01-01

    Full Text Available The members of the filoviruses are recognized as some of the most lethal viruses affecting human and non-human primates. The only two genera of the Filoviridae family, Marburg virus (MARV and Ebola virus (EBOV, comprise the main etiologic agents of severe hemorrhagic fever outbreaks in central Africa, with case fatality rates ranging from 25 to 90%. Fatal outcomes have been associated with a late and dysregulated immune response to infection, very likely due to the virus targeting key host immune cells, such as macrophages and dendritic cells (DCs that are necessary to mediate effective innate and adaptive immune responses. Despite major progress in the development of vaccine candidates for filovirus infections, a licensed vaccine or therapy for human use is still not available. During the last ten years, important progress has been made in understanding the molecular mechanisms of filovirus pathogenesis. Several lines of evidence implicate the impairment of the host interferon (IFN antiviral innate immune response by MARV or EBOV as an important determinant of virulence. In vitro and in vivo experimental infections with recombinant Zaire Ebola virus (ZEBOV, the best characterized filovirus, demonstrated that the viral protein VP35 plays a key role in inhibiting the production of IFN-α/β. Further, the action of VP35 is synergized by the inhibition of cellular responses to IFN-α/β by the minor matrix viral protein VP24. The dual action of these viral proteins may contribute to an efficient initial virus replication and dissemination in the host. Noticeably, the analogous function of these viral proteins in MARV has not been reported. Because the IFN response is a major component of the innate immune response to virus infection, this chapter reviews recent findings on the molecular mechanisms of IFN-mediated antiviral evasion by filovirus infection.

  6. Evasion of Early Antiviral Responses by Herpes Simplex Viruses

    Directory of Open Access Journals (Sweden)

    Paula A. Suazo

    2015-01-01

    Full Text Available Besides overcoming physical constraints, such as extreme temperatures, reduced humidity, elevated pressure, and natural predators, human pathogens further need to overcome an arsenal of antimicrobial components evolved by the host to limit infection, replication and optimally, reinfection. Herpes simplex virus-1 (HSV-1 and herpes simplex virus-2 (HSV-2 infect humans at a high frequency and persist within the host for life by establishing latency in neurons. To gain access to these cells, herpes simplex viruses (HSVs must replicate and block immediate host antiviral responses elicited by epithelial cells and innate immune components early after infection. During these processes, infected and noninfected neighboring cells, as well as tissue-resident and patrolling immune cells, will sense viral components and cell-associated danger signals and secrete soluble mediators. While type-I interferons aim at limiting virus spread, cytokines and chemokines will modulate resident and incoming immune cells. In this paper, we discuss recent findings relative to the early steps taking place during HSV infection and replication. Further, we discuss how HSVs evade detection by host cells and the molecular mechanisms evolved by these viruses to circumvent early antiviral mechanisms, ultimately leading to neuron infection and the establishment of latency.

  7. Evasion of early antiviral responses by herpes simplex viruses.

    Science.gov (United States)

    Suazo, Paula A; Ibañez, Francisco J; Retamal-Díaz, Angello R; Paz-Fiblas, Marysol V; Bueno, Susan M; Kalergis, Alexis M; González, Pablo A

    2015-01-01

    Besides overcoming physical constraints, such as extreme temperatures, reduced humidity, elevated pressure, and natural predators, human pathogens further need to overcome an arsenal of antimicrobial components evolved by the host to limit infection, replication and optimally, reinfection. Herpes simplex virus-1 (HSV-1) and herpes simplex virus-2 (HSV-2) infect humans at a high frequency and persist within the host for life by establishing latency in neurons. To gain access to these cells, herpes simplex viruses (HSVs) must replicate and block immediate host antiviral responses elicited by epithelial cells and innate immune components early after infection. During these processes, infected and noninfected neighboring cells, as well as tissue-resident and patrolling immune cells, will sense viral components and cell-associated danger signals and secrete soluble mediators. While type-I interferons aim at limiting virus spread, cytokines and chemokines will modulate resident and incoming immune cells. In this paper, we discuss recent findings relative to the early steps taking place during HSV infection and replication. Further, we discuss how HSVs evade detection by host cells and the molecular mechanisms evolved by these viruses to circumvent early antiviral mechanisms, ultimately leading to neuron infection and the establishment of latency.

  8. Complement inhibition enables tumor delivery of LCMV glycoprotein pseudotyped viruses in the presence of antiviral antibodies

    Directory of Open Access Journals (Sweden)

    Laura Evgin

    2016-01-01

    Full Text Available The systemic delivery of therapeutic viruses, such as oncolytic viruses or vaccines, is limited by the generation of neutralizing antibodies. While pseudotyping of rhabdoviruses with the lymphocytic choriomeningitis virus glycoprotein has previously allowed for multiple rounds of delivery in mice, this strategy has not translated to other animal models. For the first time, we provide experimental evidence that antibodies generated against the lymphocytic choriomeningitis virus glycoprotein mediate robust complement-dependent viral neutralization via activation of the classical pathway. We show that this phenotype can be capitalized upon to deliver maraba virus pseudotyped with the lymphocytic choriomeningitis virus glycoprotein in a Fischer rat model in the face of neutralizing antibody through the use of complement modulators. This finding changes the understanding of the humoral immune response to arenaviruses, and also describes methodology to deliver viral vectors to their therapeutic sites of action without the interference of neutralizing antibody.

  9. DMPD: An arms race: innate antiviral responses and counteracting viral strategies. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18031256 An arms race: innate antiviral responses and counteracting viral strategie...s. Schroder M, Bowie AG. Biochem Soc Trans. 2007 Dec;35(Pt 6):1512-4. (.png) (.svg) (.html) (.csml) Show An arm...s race: innate antiviral responses and counteracting viral strategies. PubmedID 18031256 Title An arms ra

  10. Crystal Structure of HIV-1 Primary Receptor CD4 i Complex with a Potent Antiviral Antibody

    Energy Technology Data Exchange (ETDEWEB)

    Freeman, M.M.; Hong, X.; Seaman, M.S.; Rits-Vollock, S.p Kao, C.Y.; Ho, D.D.; Chen, B.

    2010-06-18

    Ibalizumab is a humanized, anti-CD4 monoclonal antibody. It potently blocks HIV-1 infection and targets an epitope in the second domain of CD4 without interfering with immune functions mediated by interaction of CD4 with major histocompatibility complex (MHC) class II molecules. We report here the crystal structure of ibalizumab Fab fragment in complex with the first two domains (D1-D2) of CD4 at 2.2 {angstrom} resolution. Ibalizumab grips CD4 primarily by the BC-loop (residues 121125) of D2, sitting on the opposite side of gp120 and MHC-II binding sites. No major conformational change in CD4 accompanies binding to ibalizumab. Both monovalent and bivalent forms of ibalizumab effectively block viral infection, suggesting that it does not need to crosslink CD4 to exert antiviral activity. While gp120-induced structural rearrangements in CD4 are probably minimal, CD4 structural rigidity is dispensable for ibalizumab inhibition. These results could guide CD4-based immunogen design and lead to a better understanding of HIV-1 entry.

  11. Antibody complementarity-determining regions (CDRs can display differential antimicrobial, antiviral and antitumor activities.

    Directory of Open Access Journals (Sweden)

    Luciano Polonelli

    Full Text Available BACKGROUND: Complementarity-determining regions (CDRs are immunoglobulin (Ig hypervariable domains that determine specific antibody (Ab binding. We have shown that synthetic CDR-related peptides and many decapeptides spanning the variable region of a recombinant yeast killer toxin-like antiidiotypic Ab are candidacidal in vitro. An alanine-substituted decapeptide from the variable region of this Ab displayed increased cytotoxicity in vitro and/or therapeutic effects in vivo against various bacteria, fungi, protozoa and viruses. The possibility that isolated CDRs, represented by short synthetic peptides, may display antimicrobial, antiviral and antitumor activities irrespective of Ab specificity for a given antigen is addressed here. METHODOLOGY/PRINCIPAL FINDINGS: CDR-based synthetic peptides of murine and human monoclonal Abs directed to: a a protein epitope of Candida albicans cell wall stress mannoprotein; b a synthetic peptide containing well-characterized B-cell and T-cell epitopes; c a carbohydrate blood group A substance, showed differential inhibitory activities in vitro, ex vivo and/or in vivo against C. albicans, HIV-1 and B16F10-Nex2 melanoma cells, conceivably involving different mechanisms of action. Antitumor activities involved peptide-induced caspase-dependent apoptosis. Engineered peptides, obtained by alanine substitution of Ig CDR sequences, and used as surrogates of natural point mutations, showed further differential increased/unaltered/decreased antimicrobial, antiviral and/or antitumor activities. The inhibitory effects observed were largely independent of the specificity of the native Ab and involved chiefly germline encoded CDR1 and CDR2 of light and heavy chains. CONCLUSIONS/SIGNIFICANCE: The high frequency of bioactive peptides based on CDRs suggests that Ig molecules are sources of an unlimited number of sequences potentially active against infectious agents and tumor cells. The easy production and low cost of small

  12. Coxsackievirus cloverleaf RNA containing a 5' triphosphate triggers an antiviral response via RIG-I activation

    NARCIS (Netherlands)

    Feng, Qian; Langereis, Martijn A; Olagnier, David; Chiang, Cindy; van de Winkel, Roel; van Essen, Peter; Zoll, Jan; Hiscott, John; van Kuppeveld, Frank J M

    2014-01-01

    Upon viral infections, pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs) and stimulate an antiviral state associated with the production of type I interferons (IFNs) and inflammatory markers. Type I IFNs play crucial roles in innate antiviral responses by

  13. Modelling viral infections using zebrafish: Innate immune response and antiviral research.

    Science.gov (United States)

    Varela, Mónica; Figueras, Antonio; Novoa, Beatriz

    2017-03-01

    Zebrafish possess a highly developed immune system that is remarkably similar to the human one. Therefore, it is expected that the majority of the signalling pathways and molecules involved in the immune response of mammals exist and behave similarly in fish. The innate antiviral response depends on the recognition of viral components by host cells. Pattern recognition receptors initiate antimicrobial defence mechanisms via several well-conserved signalling pathways. In this paper, we review current knowledge of the antiviral innate immune response in zebrafish by considering the main molecules that have been characterized and the infection models used for the in vivo study of the antiviral innate immune response. We next summarize published studies in which larval and adult zebrafish were used to study viral diseases of fish, then provide a similar review of studies of human viral diseases in zebrafish and experience with antiviral drug screening in this model organism. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Clinical impact of non-organ-specific autoantibodies on the response to combined antiviral treatment in patients with hepatitis C.

    Science.gov (United States)

    Muratori, Paolo; Muratori, Luigi; Guidi, Marcello; Granito, Alessandro; Susca, Micaela; Lenzi, Marco; Bianchi, Francesco B

    2005-02-15

    Hepatitis C virus (HCV)-related chronic hepatitis is frequently associated with non-organ-specific autoantibodies (NOSAs), but available data about the relationship between NOSA positivity and the effect of antiviral therapy in persons with hepatitis C are few and controversial. Our aim was to evaluate the impact of NOSA positivity on the outcome of combined antiviral therapy in HCV-positive patients. A total of 143 consecutive adult patients with hepatitis C were studied. Antinuclear antibody (ANA), anti-smooth muscle antibody (SMA), and anti-liver/kidney microsomal antibody type 1 (LKM1) were detected by indirect immunofluorescence. All patients were treatment naive and received combined antiviral therapy (interferon [IFN]-ribavirin) after enrollment in the study. Patients were classified as nonresponders if HCV RNA was detectable after 6 months of therapy, as relapsers if abnormal transaminase levels and reactivation of HCV replication were observed after the end of treatment, and as long-term responders if transaminase levels were persistently normal and HCV RNA was undetectable 6 months after the end of treatment. Thirty-seven patients (25%) were NOSA positive (SMA was detected in 19 patients, ANA in 10, ANA and SMA in 4, LKM1 in 3, and SMA and LKM1 in 1). The prevalence of long-term response was similar between NOSA-positive patients and NOSA-negative patients (48.6% vs. 56.6%; P=not significant). Compared with HCV genotype 1 (HCV-1), HCV genotypes other than 1 were more often associated with long-term response among NOSA-positive patients (93.3% vs. 30%; P=.0017). The overall rate of long-term response, irrespective of NOSA status, was 54.5%. Detection of HCV-1 and elevated gamma-glutamyl transpeptidase serum levels were independent negative prognostic factors of treatment response (P=.007 and P=.026, respectively). Combined antiviral treatment (IFN-ribavirin) is safe and effective in NOSA-positive patients with hepatitis C, even if long-term response is

  15. Unidentified angular recurrent ulceration responsive to antiviral therapy

    Directory of Open Access Journals (Sweden)

    Rahmi Amtha

    2013-03-01

    Full Text Available Background: Recurrent ulcer on angular area is usually called stomatitis angularis. It is caused by many factors such as vertical dimension reduce, vitamin B12, and immune system deficiency, C. albicans and staphylococcus involvement. Clinically is characterized by painful fissure with erythematous base without fever. Purpose: to describe an unidentified angular ulcer proceeded by recurrent ulcers with no response of topical therapy. Case: An 18-years old male came to Oral Medicine clinic in RSCM who complained of angular recurrent ulcers since 3 years ago which developed on skin and bleed easily on mouth opening. Patient had fever before the onset of ulcers. Large, painful, irregular ulcers covered by red crustae on angular area bilaterally. Patient has been treated with various drugs without improvement and lead to mouth opening limitation. Intra oral shows herpetiformtype of ulcer and swollen of gingival. Case management: Provisional diagnosis was established as viral infection thus acyclovir 200 mg five times daily for two weeks and topical anti inflammation gel were administered. Blood test for IgG/IgM of HSV1 and HSV2 were non reactive, however ulceration showed a remarkable improvement. The ulcers healed completely after next 2 weeks with acyclovir. Conclusion: The angular ulceration on above patient failed to fulfill the criteria of stomatitis angularis or herpes labialis lesion. However it showed a good response to antiviral. Therefore, unidentified angular ulceration was appointed, as the lesion might be triggered by other type of human herpes virus or types of virus that response to acyclovir.Latar belakang: ulser rekuren pada sudut mulut biasanya disebut stomatitis angularis. Kelainan ini disebabkan oleh banyak faktor seperti berkurangnya dimensi vertikal, defisiensi vitamin B12 dan sistem kekebalan tubuh, infeksi C. albicans serta staphylococcus. Secara klinis kelainan ini ditandai dengan fisur sakit pada sudut mulut dengan dasar

  16. Dengue virus cell entry : Unraveling the role of antibodies, maturation status, and antiviral drugs

    NARCIS (Netherlands)

    Ayala Nunez, Vanesa

    2014-01-01

    Antibody-dependent enhancement (ADE) is thought to play a critical role in the exacerbation of dengue virus-induced disease during a heterologous re-infection. Pre-existing cross-reactive anti-dengue antibodies are generally believed to bind to the newly infecting DENV and target the antibody-virus

  17. The challenge of treating hepatitis C virus-associated cryoglobulinemic vasculitis in the era of anti-CD20 monoclonal antibodies and direct antiviral agents.

    Science.gov (United States)

    Roccatello, Dario; Sciascia, Savino; Rossi, Daniela; Solfietti, Laura; Fenoglio, Roberta; Menegatti, Elisa; Baldovino, Simone

    2017-06-20

    Mixed cryoglobulinemia syndrome (MC) is a systemic vasculitis involving kidneys, joints, skin, and peripheral nerves. While many autoimmune, lymphoproliferative, and neoplastic disorders have been associated with this disorder, hepatitis C virus (HCV) is known to be the etiologic agent in the majority of patients. Therefore, clinical research has focused on anti-viral drugs and, more recently, on the new, highly potent Direct-acting Antiviral Agents (DAAs). These drugs assure sustained virologic response (SVR) rates >90%. Nevertheless, data on their efficacy in patients with HCV-associated cryoglobulinemic vasculitis are disappointing, possibly due to the inability of the drugs to suppress the immune-mediated process once it has been triggered.Despite the potential risk of exacerbation of the infection, immunosuppression has traditionally been regarded as the first-line intervention in cryoglobulinemic vasculitis, especially if renal involvement is severe. Biologic agents have raised hopes for more manageable therapeutic approaches, and Rituximab (RTX), an anti CD20 monoclonal antibody, is the most widely used biologic drug. It has proved to be safer than conventional immunosuppressants, thus substantially changing the natural history of HCV-associated cryoglobulinemic vasculitis by providing long-term remission, especially with intensive regimens.The present review focuses on the new therapeutic opportunities offered by the combination of biological drugs, mainly Rituximab, with DAAs.

  18. Does Vitamin D Level Affect the Response to Antiviral Treatment in Egyptian Patients with Chronic Hepatitis C?

    Directory of Open Access Journals (Sweden)

    Hoda Abdelbadie HUSSEIN

    2017-12-01

    Full Text Available Objective: Vitamin D deficiency is common in patients with chronic liver disease. Several studies demonstrated that its levels are inversely related to the disease severity and documented improvement of the disease following supplementation especially regarding to hepatitis C virus (HCV infection. To study level of vitamin D in Egyptian patients with chronic HCV infection and to investigate its correlation with activity and fibrosis scores of their liver biopsies, as well as the relationship of vitamin D levels with patients’ response to antiviral therapy. Materials and Methods: The study included 60 Egyptian patients with chronic HCV infection who were scheduled for antiviral medications (pegylated-interferon and ribavirin for 48 weeks and 50 healthy age- and sex-matched individuals non-reactive for HCV antibodies as a control group. Serum 25-hydroxyvitamin D was measured in all patients and controls and compared with patients’ liver biopsy results and their virological response (after 48 weeks treatment assessed by polymerase chain reaction for HCV. Results: Serum vitamin D levels were inversely correlated with activity and fibrosis scores in liver biopsy. On the other hand, 63.3% of cases had good response to interferon treatment and 36.7% of them had no response without significant difference in serum vitamin D levels between responders and non-responders (39.2±23.6 and 37.1±13.2 ng/mL, respectively. Conclusion: Vitamin D levels could affect liver necro-inflammatory process in Egyptian patients with chronic hepatitis C infection, but did not show significant effect on response to antiviral therapy.

  19. Development of Tetravalent, Bispecific CCR5 Antibodies with Antiviral Activity against CCR5 Monoclonal Antibody-Resistant HIV-1 Strains▿

    OpenAIRE

    Schanzer, Jürgen; Jekle, Andreas; Nezu, Junichi; Lochner, Adriane; Croasdale, Rebecca; Dioszegi, Marianna; Zhang, Jun; Hoffmann, Eike; Dormeyer, Wilma; Stracke, Jan; Schäfer, Wolfgang; Ji, Changhua; Heilek, Gabrielle; Cammack, Nick; Brandt, Michael

    2011-01-01

    In this study, we describe novel tetravalent, bispecific antibody derivatives that bind two different epitopes on the HIV coreceptor CCR5. The basic protein formats that we applied were derived from Morrison-type bispecific antibodies: whole IgGs to which we connected single-chain antibodies (scFvs) via (Gly4Ser)n sequences at either the C or N terminus of the light chain or heavy chain. By design optimization, including disulfide stabilization of scFvs or introduction of 30-amino-acid linker...

  20. Viral evasion mechanisms of early antiviral responses involving regulation of ubiquitin pathways.

    Science.gov (United States)

    Rajsbaum, Ricardo; García-Sastre, Adolfo

    2013-08-01

    Early innate and cell-intrinsic responses are essential to protect host cells against pathogens. In turn, viruses have developed sophisticated mechanisms to establish productive infections by counteracting host innate immune responses. Increasing evidence indicates that these antiviral factors may have a dual role by directly inhibiting viral replication as well as by sensing and transmitting signals to induce antiviral cytokines. Recent studies have pointed at new, unappreciated mechanisms of viral evasion of host innate protective responses including manipulating the host ubiquitin (Ub) system. Virus-mediated inhibition of antiviral factors by Ub-dependent degradation is emerging as a crucial mechanism for evading the antiviral response. In addition, recent studies have uncovered new mechanisms by which virus-encoded proteins inhibit Ub and Ub-like (Ubl) modification of host proteins involved in innate immune signaling pathways. Here we discuss recent findings and novel strategies that viruses have developed to counteract these early innate antiviral defenses. Copyright © 2013 Elsevier Ltd. All rights reserved.

  1. Antibody proteases: induction of catalytic response.

    Science.gov (United States)

    Gabibov, A G; Friboulet, A; Thomas, D; Demin, A V; Ponomarenko, N A; Vorobiev, I I; Pillet, D; Paon, M; Alexandrova, E S; Telegin, G B; Reshetnyak, A V; Grigorieva, O V; Gnuchev, N V; Malishkin, K A; Genkin, D D

    2002-10-01

    Most of the data accumulated throughout the years on investigation of catalytic antibodies indicate that their production increases on the background of autoimmune abnormalities. The different approaches to induction of catalytic response toward recombinant gp120 HIV-1 surface protein in mice with various autoimmune pathologies are described. The peptidylphosphonate conjugate containing structural part of gp120 molecule is used for reactive immunization of NZB/NZW F1, MRL, and SJL mice. The specific modification of heavy and light chains of mouse autoantibodies with Val-Ala-Glu-Glu-Glu-Val-PO(OPh)2 reactive peptide was demonstrated. Increased proteolytic activity of polyclonal antibodies in SJL mice encouraged us to investigate the production of antigen-specific catalytic antibodies on the background of induced experimental autoimmune encephalomyelitis (EAE). The immunization of autoimmune-prone mice with the engineered fusions containing the fragments of gp120 and encephalitogenic epitope of myelin basic protein (MBP(89-104)) was made. The proteolytic activity of polyclonal antibodies isolated from the sera of autoimmune mice immunized by the described antigen was shown. Specific immune response of SJL mice to these antigens was characterized. Polyclonal antibodies purified from sera of the immunized animals revealed proteolytic activity. The antiidiotypic approach to raise the specific proteolytic antibody as an "internal image" of protease is described. The "second order" monoclonal antibodies toward subtilisin Carlsberg revealed pronounced proteolytic activity.

  2. Viral Response to Specifically Targeted Antiviral Therapy for Hepatitis C and the Implications for Treatment Success

    Directory of Open Access Journals (Sweden)

    Curtis L Cooper

    2010-01-01

    Full Text Available Currently, hepatitis C virus (HCV antiviral therapy is characterized by long duration, a multitude of side effects, difficult administration and suboptimal success; clearly, alternatives are needed. Collectively, specifically targeted antiviral therapy for HCV (STAT-C molecules achieve rapid viral suppression and very high rapid virological response rates, and improve sustained virological response rates. The attrition rate of agents within this class has been high due to various toxicities. Regardless, several STAT-C molecules are poised to become the standard of care for HCV treatment in the foreseeable future. Optimism must be tempered with concerns related to the rapid development of drug resistance with resulting HCV rebound. Strategies including induction dosing with interferon and ribavirin, use of combination high-potency STAT-C molecules and an intensive emphasis on adherence to HCV antiviral therapy will be critical to the success of this promising advance in HCV therapy.

  3. Molecular Mechanisms of Foot-and-Mouth Disease Virus Targeting the Host Antiviral Response

    Directory of Open Access Journals (Sweden)

    Miguel Rodríguez Pulido

    2017-06-01

    Full Text Available Foot-and-mouth disease virus (FMDV is the causative agent of an acute vesicular disease affecting pigs, cattle and other domestic, and wild animals worldwide. The aim of the host interferon (IFN response is to limit viral replication and spread. Detection of the viral genome and products by specialized cellular sensors initiates a signaling cascade that leads to a rapid antiviral response involving the secretion of type I- and type III-IFNs and other antiviral cytokines with antiproliferative and immunomodulatory functions. During co-evolution with their hosts, viruses have acquired strategies to actively counteract host antiviral responses and the balance between innate response and viral antagonism may determine the outcome of disease and pathogenesis. FMDV proteases Lpro and 3C have been found to antagonize the host IFN response by a repertoire of mechanisms. Moreover, the putative role of other viral proteins in IFN antagonism is being recently unveiled, uncovering sophisticated immune evasion strategies different to those reported to date for other members of the Picornaviridae family. Here, we review the interplay between antiviral responses induced by FMDV infection and viral countermeasures to block them. Research on strategies used by viruses to modulate immunity will provide insights into the function of host pathways involved in defense against pathogens and will also lead to development of new therapeutic strategies to fight virus infections.

  4. Sustained virological response to antiviral therapy reduces mortality in HCV reinfection after liver transplantation.

    Science.gov (United States)

    Picciotto, Francesco Paolo; Tritto, Giovanni; Lanza, Alfonso Galeota; Addario, Luigi; De Luca, Massimo; Di Costanzo, Giovan Giuseppe; Lampasi, Filippo; Tartaglione, Maria Teresa; Marsilia, Giuseppina Marino; Calise, Fulvio; Cuomo, Oreste; Ascione, Antonio

    2007-03-01

    HCV infection recurs almost in all HCV-positive patients receiving liver transplantation and carries a poor prognosis. Aim of this study was to analyze efficacy and effect on survival of antiviral therapy in this clinical setting. Pegylated-interferon alpha-2b and ribavirin were administered at a dose of 1 microg/kg of bwt weekly and 600-800 mg/day. Planned duration of treatment was 24 or 48 weeks according to HCV genotype. Patients who failed to respond at week 24 were considered as non-responders. 61 patients were enrolled. According to intention-to-treat analysis, 44 (72%) patients were considered as treatment failure (31 non-responders, 4 relapsers, 9 dropout). Sustained virological response was achieved in 17 cases (28%). Genotype 2, higher doses of antivirals and absence of histological cirrhosis were predictors of sustained virological response. In the follow up, patients with sustained virological response had a significantly lower mortality compared to patients with treatment failure (chi2=6.9; P<0.01). Response rate to antiviral therapy in HCV reinfection after liver transplantation is higher if a full dose of antiviral drugs is administered and if treatment starts before histological cirrhosis has developed. Sustained virological response improves patient survival.

  5. Coxsackievirus cloverleaf RNA containing a 5' triphosphate triggers an antiviral response via RIG-I activation.

    Directory of Open Access Journals (Sweden)

    Qian Feng

    Full Text Available Upon viral infections, pattern recognition receptors (PRRs recognize pathogen-associated molecular patterns (PAMPs and stimulate an antiviral state associated with the production of type I interferons (IFNs and inflammatory markers. Type I IFNs play crucial roles in innate antiviral responses by inducing expression of interferon-stimulated genes and by activating components of the adaptive immune system. Although pegylated IFNs have been used to treat hepatitis B and C virus infections for decades, they exert substantial side effects that limit their use. Current efforts are directed toward the use of PRR agonists as an alternative approach to elicit host antiviral responses in a manner similar to that achieved in a natural infection. RIG-I is a cytosolic PRR that recognizes 5' triphosphate (5'ppp-containing RNA ligands. Due to its ubiquitous expression profile, induction of the RIG-I pathway provides a promising platform for the development of novel antiviral agents and vaccine adjuvants. In this study, we investigated whether structured RNA elements in the genome of coxsackievirus B3 (CVB3, a picornavirus that is recognized by MDA5 during infection, could activate RIG-I when supplied with 5'ppp. We show here that a 5'ppp-containing cloverleaf (CL RNA structure is a potent RIG-I inducer that elicits an extensive antiviral response that includes induction of classical interferon-stimulated genes, as well as type III IFNs and proinflammatory cytokines and chemokines. In addition, we show that prophylactic treatment with CVB3 CL provides protection against various viral infections including dengue virus, vesicular stomatitis virus and enterovirus 71, demonstrating the antiviral efficacy of this RNA ligand.

  6. Integrative Genomics-Based Discovery of Novel Regulators of the Innate Antiviral Response

    NARCIS (Netherlands)

    Lee, R. van der; Feng, Q.; Langereis, M.A.; Horst, R. ter; Szklarczyk, R.J.; Netea, M.G.; Andeweg, A.C.; Kuppeveld, F.J.M. van; Huynen, M.A.

    2015-01-01

    The RIG-I-like receptor (RLR) pathway is essential for detecting cytosolic viral RNA to trigger the production of type I interferons (IFNalpha/beta) that initiate an innate antiviral response. Through systematic assessment of a wide variety of genomics data, we discovered 10 molecular signatures of

  7. Integrative Genomics-Based Discovery of Novel Regulators of the Innate Antiviral Response

    NARCIS (Netherlands)

    van der Lee, Robin; Feng, Qian; Langereis, Martijn A; Ter Horst, Rob; Szklarczyk, Radek; Netea, Mihai G; Andeweg, Arno C; van Kuppeveld, Frank J M; Huynen, Martijn A

    2015-01-01

    The RIG-I-like receptor (RLR) pathway is essential for detecting cytosolic viral RNA to trigger the production of type I interferons (IFNα/β) that initiate an innate antiviral response. Through systematic assessment of a wide variety of genomics data, we discovered 10 molecular signatures of known

  8. Integrative Genomics-Based Discovery of Novel Regulators of the Innate Antiviral Response

    NARCIS (Netherlands)

    R. van der Lee (Robin); Q. Feng (Qian); M.A. Langereis (Martijn A.); R. ter Horst (Rob); R. Szklarczyk (Radek); M.G. Netea (Mihai); A.C. Andeweg (Arno); F.J.M. van Kuppeveld (Frank ); M. Huynen (Martijn)

    2015-01-01

    textabstractThe RIG-I-like receptor (RLR) pathway is essential for detecting cytosolic viral RNA to trigger the production of type I interferons (IFNα/β) that initiate an innate antiviral response. Through systematic assessment of a wide variety of genomics data, we discovered 10 molecular

  9. Viral Proteins That Bind Double-Stranded RNA: Countermeasures Against Host Antiviral Responses

    OpenAIRE

    Krug, Robert M.

    2014-01-01

    Several animal viruses encode proteins that bind double-stranded RNA (dsRNA) to counteract host dsRNA-dependent antiviral responses. This article discusses the structure and function of the dsRNA-binding proteins of influenza A virus and Ebola viruses (EBOVs).

  10. Passive transfer of antiviral antibodies restricts replication of Aleutian mink disease parvovirus in vivo

    DEFF Research Database (Denmark)

    Alexandersen, Søren; Larsen, S; Cohn, A.

    1989-01-01

    When mink kits were infected neonatally with a highly virulent strain of Aleutian disease virus (ADV), 100% of both Aleutian and non-Aleutian genotype mink died of interstitial pneumonia characterized by permissive ADV infection of alveolar type II cells. Treatment of infected kits with either mink...... found that the number of ADV-infected type II cells was the same in both untreated and antibody-treated kits. However, in the treated kits, viral replication and transcription were restricted at the cellular level. These data suggested that antibodies prevented acute viral pneumonia by restricting...

  11. T lymphocytes promote the antiviral and inflammatory responses of airway epithelial cells.

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    Lan Jornot

    Full Text Available HYPOTHESIS: T cells modulate the antiviral and inflammatory responses of airway epithelial cells to human rhinoviruses (HRV. METHODS: Differentiated primary human nasal epithelial cells (HNEC grown on collagen-coated filters were exposed apically to HRV14 for 6 h, washed thoroughly and co-cultured with anti-CD3/CD28 activated T cells added in the basolateral compartment for 40 h. RESULTS: HRV14 did not induce IFNγ, NOS2, CXCL8 and IL-6 in HNEC, but enhanced expression of the T cell attractant CXCL10. On the other hand, HNEC co-cultured with activated T cells produced CXCL10 at a level several orders of magnitude higher than that induced by HRV14. Albeit to a much lower degree, activated T cells also induced CXCL8, IL-6 and NOS2. Anti-IFNγ antibodies and TNF soluble receptor completely blocked CXCL10 upregulation. Furthermore, a significant correlation was observed between epithelial CXCL10 mRNA expression and the amounts of IFNγ and TNF secreted by T cells. Likewise, increasing numbers of T cells to a constant number of HNEC in co-cultures resulted in increasing epithelial CXCL10 production, attaining a plateau at high IFNγ and TNF levels. Hence, HNEC activation by T cells is induced mainly by IFNγ and/or TNF. Activated T cells also markedly inhibited viral replication in HNEC, partially through activation of the nitric oxide pathway. CONCLUSION: Cross-talk between T cells and HNEC results in activation of the latter and increases their contribution to airway inflammation and virus clearance.

  12. Arenavirus Evasion of Host Anti-Viral Responses

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    Melissa Hayes

    2012-10-01

    Full Text Available The innate response to infection by an Old World arenavirus is initiated and mediated by extracellular and intracellular receptors, and effector molecules. In response, the invading virus has evolved to inhibit these responses and create the best environment possible for replication and spread. Here, we will discuss both the host’s response to infection with data from human infection and lessons learned from animal models, as well as the multitude of ways the virus combats the resulting immune response. Finally, we will highlight recent work identifying TLR2 as an innate sensor for arenaviruses and how the TLR2-dependent response differs depending on the pathogenicity of the strain.

  13. Arenavirus evasion of host anti-viral responses.

    Science.gov (United States)

    Hayes, Melissa; Salvato, Maria

    2012-10-17

    The innate response to infection by an Old World arenavirus is initiated and mediated by extracellular and intracellular receptors, and effector molecules. In response, the invading virus has evolved to inhibit these responses and create the best environment possible for replication and spread. Here, we will discuss both the host's response to infection with data from human infection and lessons learned from animal models, as well as the multitude of ways the virus combats the resulting immune response. Finally, we will highlight recent work identifying TLR2 as an innate sensor for arenaviruses and how the TLR2-dependent response differs depending on the pathogenicity of the strain.

  14. Anopheles gambiae antiviral immune response to systemic O'nyong-nyong infection.

    Directory of Open Access Journals (Sweden)

    Joanna Waldock

    Full Text Available Mosquito-borne viral diseases cause significant burden in much of the developing world. Although host-virus interactions have been studied extensively in the vertebrate host, little is known about mosquito responses to viral infection. In contrast to mosquitoes of the Aedes and Culex genera, Anopheles gambiae, the principal vector of human malaria, naturally transmits very few arboviruses, the most important of which is O'nyong-nyong virus (ONNV. Here we have investigated the A. gambiae immune response to systemic ONNV infection using forward and reverse genetic approaches.We have used DNA microarrays to profile the transcriptional response of A. gambiae inoculated with ONNV and investigate the antiviral function of candidate genes through RNAi gene silencing assays. Our results demonstrate that A. gambiae responses to systemic viral infection involve genes covering all aspects of innate immunity including pathogen recognition, modulation of immune signalling, complement-mediated lysis/opsonisation and other immune effector mechanisms. Patterns of transcriptional regulation and co-infections of A. gambiae with ONNV and the rodent malaria parasite Plasmodium berghei suggest that hemolymph immune responses to viral infection are diverted away from melanisation. We show that four viral responsive genes encoding two putative recognition receptors, a galectin and an MD2-like receptor, and two effector lysozymes, function in limiting viral load.This study is the first step in elucidating the antiviral mechanisms of A. gambiae mosquitoes, and has revealed interesting differences between A. gambiae and other invertebrates. Our data suggest that mechanisms employed by A. gambiae are distinct from described invertebrate antiviral immunity to date, and involve the complement-like branch of the humoral immune response, supressing the melanisation response that is prominent in anti-parasitic immunity. The antiviral immune response in A. gambiae is thus

  15. The Complexity of a Dengue Vaccine: A Review of the Human Antibody Response.

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    Jacky Flipse

    Full Text Available Dengue is the most prevalent mosquito-borne viral disease worldwide. Yet, there are no vaccines or specific antivirals available to prevent or treat the disease. Several dengue vaccines are currently in clinical or preclinical stages. The most advanced vaccine is the chimeric tetravalent CYD-TDV vaccine of Sanofi Pasteur. This vaccine has recently cleared Phase III, and efficacy results have been published. Excellent tetravalent seroconversion was seen, yet the protective efficacy against infection was surprisingly low. Here, we will describe the complicating factors involved in the generation of a safe and efficacious dengue vaccine. Furthermore, we will discuss the human antibody responses during infection, including the epitopes targeted in humans. Also, we will discuss the current understanding of the assays used to evaluate antibody response. We hope this review will aid future dengue vaccine development as well as fundamental research related to the phenomenon of antibody-dependent enhancement of dengue virus infection.

  16. The Complexity of a Dengue Vaccine: A Review of the Human Antibody Response

    Science.gov (United States)

    Flipse, Jacky; Smit, Jolanda M.

    2015-01-01

    Dengue is the most prevalent mosquito-borne viral disease worldwide. Yet, there are no vaccines or specific antivirals available to prevent or treat the disease. Several dengue vaccines are currently in clinical or preclinical stages. The most advanced vaccine is the chimeric tetravalent CYD-TDV vaccine of Sanofi Pasteur. This vaccine has recently cleared Phase III, and efficacy results have been published. Excellent tetravalent seroconversion was seen, yet the protective efficacy against infection was surprisingly low. Here, we will describe the complicating factors involved in the generation of a safe and efficacious dengue vaccine. Furthermore, we will discuss the human antibody responses during infection, including the epitopes targeted in humans. Also, we will discuss the current understanding of the assays used to evaluate antibody response. We hope this review will aid future dengue vaccine development as well as fundamental research related to the phenomenon of antibody-dependent enhancement of dengue virus infection. PMID:26065421

  17. DMPD: The interferon-alpha/beta system in antiviral responses: a multimodal machineryof gene regulation by the IRF family of transcription factors. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 11790540 The interferon-alpha/beta system in antiviral responses: a multimodal mach...l. 2002 Feb;14(1):111-6. (.png) (.svg) (.html) (.csml) Show The interferon-alpha/beta system in antiviral responses: a multimoda...ion factors. PubmedID 11790540 Title The interferon-alpha/beta system in antiviral responses: a multimodal m

  18. The helicase senataxin suppresses the antiviral transcriptional response and controls viral biogenesis

    Science.gov (United States)

    Miller, Matthew S.; Rialdi, Alexander; Ho, Jessica Sook Yuin; Tilove, Micah; Martinez-Gil, Luis; Moshkina, Natasha P.; Peralta, Zuleyma; Noel, Justine; Melegari, Camilla; Maestre, Ana; Mitsopoulos, Panagiotis; Madrenas, Joaquín; Heinz, Sven; Benner, Chris; Young, John A. T.; Feagins, Alicia R.; Basler, Christopher; Fernandez-Sesma, Ana; Becherel, Olivier J.; Lavin, Martin F.; van Bakel, Harm; Marazzi, Ivan

    2015-01-01

    The human helicase senataxin (SETX) is implicated in the neurodegenerative diseases amyotrophic lateral sclerosis (ALS4) and ataxia with oculomotor apraxia (AOA2). Here, we reveal a role for SETX in controlling the antiviral response. Cells depleted for SETX and AOA2 patient-derived SETX-deficient cells exhibit increased expression of antiviral mediators in response to infection. Mechanistically, we propose a model whereby SETX attenuates RNA polymerase II (RNAPII) activity at genes stimulated upon viral sensing, thus controlling the magnitude of the host response to pathogens and the biogenesis of numerous RNA viruses (e. g. Influenza A virus and West Nile virus). Our data indicate a potentially causal link between SETX inborn errors, susceptibility to infection and development of neurologic disorders. PMID:25822250

  19. Integrative Genomics-Based Discovery of Novel Regulators of the Innate Antiviral Response.

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    Robin van der Lee

    2015-10-01

    Full Text Available The RIG-I-like receptor (RLR pathway is essential for detecting cytosolic viral RNA to trigger the production of type I interferons (IFNα/β that initiate an innate antiviral response. Through systematic assessment of a wide variety of genomics data, we discovered 10 molecular signatures of known RLR pathway components that collectively predict novel members. We demonstrate that RLR pathway genes, among others, tend to evolve rapidly, interact with viral proteins, contain a limited set of protein domains, are regulated by specific transcription factors, and form a tightly connected interaction network. Using a Bayesian approach to integrate these signatures, we propose likely novel RLR regulators. RNAi knockdown experiments revealed a high prediction accuracy, identifying 94 genes among 187 candidates tested (~50% that affected viral RNA-induced production of IFNβ. The discovered antiviral regulators may participate in a wide range of processes that highlight the complexity of antiviral defense (e.g. MAP3K11, CDK11B, PSMA3, TRIM14, HSPA9B, CDC37, NUP98, G3BP1, and include uncharacterized factors (DDX17, C6orf58, C16orf57, PKN2, SNW1. Our validated RLR pathway list (http://rlr.cmbi.umcn.nl/, obtained using a combination of integrative genomics and experiments, is a new resource for innate antiviral immunity research.

  20. Intracellular reprogramming of expression, glycosylation, and function of a plant-derived antiviral therapeutic monoclonal antibody.

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    Jeong-Hwan Lee

    Full Text Available Plant genetic engineering, which has led to the production of plant-derived monoclonal antibodies (mAb(Ps, provides a safe and economically effective alternative to conventional antibody expression methods. In this study, the expression levels and biological properties of the anti-rabies virus mAb(P SO57 with or without an endoplasmic reticulum (ER-retention peptide signal (Lys-Asp-Glu-Leu; KDEL in transgenic tobacco plants (Nicotiana tabacum were analyzed. The expression levels of mAb(P SO57 with KDEL (mAb(PK were significantly higher than those of mAb(P SO57 without KDEL (mAb(P regardless of the transcription level. The Fc domains of both purified mAb(P and mAb(PK and hybridoma-derived mAb (mAb(H had similar levels of binding activity to the FcγRI receptor (CD64. The mAb(PK had glycan profiles of both oligomannose (OM type (91.7% and Golgi type (8.3%, whereas the mAb(P had mainly Golgi type glycans (96.8% similar to those seen with mAb(H. Confocal analysis showed that the mAb(PK was co-localized to ER-tracker signal and cellular areas surrounding the nucleus indicating accumulation of the mAb(P with KDEL in the ER. Both mAb(P and mAb(PK disappeared with similar trends to mAb(H in BALB/c mice. In addition, mAb(PK was as effective as mAb(H at neutralizing the activity of the rabies virus CVS-11. These results suggest that the ER localization of the recombinant mAb(P by KDEL reprograms OM glycosylation and enhances the production of the functional antivirus therapeutic antibody in the plant.

  1. Llama-derived single domain antibodies to build multivalent, superpotent and broadened neutralizing anti-viral molecules.

    Directory of Open Access Journals (Sweden)

    Anna Hultberg

    2011-04-01

    Full Text Available For efficient prevention of viral infections and cross protection, simultaneous targeting of multiple viral epitopes is a powerful strategy. Llama heavy chain antibody fragments (VHH against the trimeric envelope proteins of Respiratory Syncytial Virus (Fusion protein, Rabies virus (Glycoprotein and H5N1 Influenza (Hemagglutinin 5 were selected from llama derived immune libraries by phage display. Neutralizing VHH recognizing different epitopes in the receptor binding sites on the spikes with affinities in the low nanomolar range were identified for all the three viruses by viral neutralization assays. By fusion of VHH with variable linker lengths, multimeric constructs were made that improved neutralization potencies up to 4,000-fold for RSV, 1,500-fold for Rabies virus and 75-fold for Influenza H5N1. The potencies of the VHH constructs were similar or better than best performing monoclonal antibodies. The cross protection capacity against different viral strains was also improved for all three viruses, both by multivalent (two or three identical VHH and biparatopic (two different VHH constructs. By combining a VHH neutralizing RSV subtype A, but not subtype B with a poorly neutralizing VHH with high affinity for subtype B, a biparatopic construct was made with low nanomolar neutralizing potency against both subtypes. Trivalent anti-H5N1 VHH neutralized both Influenza H5N1 clade1 and 2 in a pseudotype assay and was very potent in neutralizing the NIBRG-14 Influenza H5N1 strain with IC(50 of 9 picomolar. Bivalent and biparatopic constructs against Rabies virus cross neutralized both 10 different Genotype 1 strains and Genotype 5.The results show that multimerization of VHH fragments targeting multiple epitopes on a viral trimeric spike protein is a powerful tool for anti-viral therapy to achieve "best-in-class" and broader neutralization capacity.

  2. Histone Deacetylase 2 Is a Component of Influenza A Virus-Induced Host Antiviral Response.

    Science.gov (United States)

    Nagesh, Prashanth T; Hussain, Mazhar; Galvin, Henry D; Husain, Matloob

    2017-01-01

    Host cells produce variety of antiviral factors that create an antiviral state and target various stages of influenza A virus (IAV) life cycle to inhibit infection. However, IAV has evolved various strategies to antagonize those antiviral factors. Recently, we reported that a member of class I host histone deacetylases (HDACs), HDAC1 possesses an anti-IAV function. Herein, we provide evidence that HDAC2, another class I member and closely related to HDAC1 in structure and function, also possesses anti-IAV properties. In turn, IAV, like HDAC1, dysregulates HDAC2, mainly at the polypeptide level through proteasomal degradation to potentially minimize its antiviral effect. We found that IAV downregulated the HDAC2 polypeptide level in A549 cells in an H1N1 strain-independent manner by up to 47%, which was recovered to almost 100% level in the presence of proteasome-inhibitor MG132. A further knockdown in HDAC2 expression by up to 90% via RNA interference augmented the growth kinetics of IAV in A549 cells by more than four-fold after 24 h of infection. Furthermore, the knockdown of HDAC2 expression decreased the IAV-induced phosphorylation of the transcription factor, Signal Transducer and Activator of Transcription I (STAT1) and the expression of interferon-stimulated gene, viperin in infected cells by 41 and 53%, respectively. The role of HDAC2 in viperin expression was analogous to that of HDAC1, but it was not in the phosphorylation of STAT1. This indicated that, like HDAC1, HDAC2 is a component of IAV-induced host innate antiviral response and performs both redundant and non-redundant functions vis-a-vis HDAC1; however, IAV dysregulates them both in a redundant manner.

  3. Histone Deacetylase 2 Is a Component of Influenza A Virus-Induced Host Antiviral Response

    Directory of Open Access Journals (Sweden)

    Prashanth T. Nagesh

    2017-07-01

    Full Text Available Host cells produce variety of antiviral factors that create an antiviral state and target various stages of influenza A virus (IAV life cycle to inhibit infection. However, IAV has evolved various strategies to antagonize those antiviral factors. Recently, we reported that a member of class I host histone deacetylases (HDACs, HDAC1 possesses an anti-IAV function. Herein, we provide evidence that HDAC2, another class I member and closely related to HDAC1 in structure and function, also possesses anti-IAV properties. In turn, IAV, like HDAC1, dysregulates HDAC2, mainly at the polypeptide level through proteasomal degradation to potentially minimize its antiviral effect. We found that IAV downregulated the HDAC2 polypeptide level in A549 cells in an H1N1 strain-independent manner by up to 47%, which was recovered to almost 100% level in the presence of proteasome-inhibitor MG132. A further knockdown in HDAC2 expression by up to 90% via RNA interference augmented the growth kinetics of IAV in A549 cells by more than four-fold after 24 h of infection. Furthermore, the knockdown of HDAC2 expression decreased the IAV-induced phosphorylation of the transcription factor, Signal Transducer and Activator of Transcription I (STAT1 and the expression of interferon-stimulated gene, viperin in infected cells by 41 and 53%, respectively. The role of HDAC2 in viperin expression was analogous to that of HDAC1, but it was not in the phosphorylation of STAT1. This indicated that, like HDAC1, HDAC2 is a component of IAV-induced host innate antiviral response and performs both redundant and non-redundant functions vis-a-vis HDAC1; however, IAV dysregulates them both in a redundant manner.

  4. RO 90-7501 enhances TLR3 and RLR agonist induced antiviral response.

    Directory of Open Access Journals (Sweden)

    Fang Guo

    Full Text Available Recognition of virus infection by innate pattern recognition receptors (PRRs, including membrane-associated toll-like receptors (TLR and cytoplasmic RIG-I-like receptors (RLR, activates cascades of signal transduction pathways leading to production of type I interferons (IFN and proinflammatory cytokines that orchestrate the elimination of the viruses. Although it has been demonstrated that PRR-mediated innate immunity plays an essential role in defending virus from infection, it also occasionally results in overwhelming production of proinflammatory cytokines that cause severe inflammation, blood vessel leakage and tissue damage. In our efforts to identify small molecules that selectively enhance PRR-mediated antiviral, but not the detrimental inflammatory response, we discovered a compound, RO 90-7501 ('2'-(4-Aminophenyl-[2,5'-bi-1H-benzimidazol]-5-amine, that significantly promoted both TLR3 and RLR ligand-induced IFN-β gene expression and antiviral response, most likely via selective activation of p38 mitogen-activated protein kinase (MAPK pathway. Our results thus imply that pharmacological modulation of PRR signal transduction pathways in favor of the induction of a beneficial antiviral response can be a novel therapeutic strategy.

  5. A heritable antiviral RNAi response limits Orsay virus infection in Caenorhabditis elegans N2.

    Directory of Open Access Journals (Sweden)

    Mark G Sterken

    Full Text Available Orsay virus (OrV is the first virus known to be able to complete a full infection cycle in the model nematode species Caenorhabditis elegans. OrV is transmitted horizontally and its infection is limited by antiviral RNA interference (RNAi. However, we have no insight into the kinetics of OrV replication in C. elegans. We developed an assay that infects worms in liquid, allowing precise monitoring of the infection. The assay revealed a dual role for the RNAi response in limiting Orsay virus infection in C. elegans. Firstly, it limits the progression of the initial infection at the step of recognition of dsRNA. Secondly, it provides an inherited protection against infection in the offspring. This establishes the heritable RNAi response as anti-viral mechanism during OrV infections in C. elegans. Our results further illustrate that the inheritance of the anti-viral response is important in controlling the infection in the canonical wild type Bristol N2. The OrV replication kinetics were established throughout the worm life-cycle, setting a standard for further quantitative assays with the OrV-C. elegans infection model.

  6. Systems-Biology Approaches to Discover Anti-Viral Effectors of the Human Innate Immune Response

    Directory of Open Access Journals (Sweden)

    Andreas F.R. Sommer

    2011-07-01

    Full Text Available Virus infections elicit an immediate innate response involving antiviral factors. The activities of some of these factors are, in turn, blocked by viral countermeasures. The ensuing battle between the host and the viruses is crucial for determining whether the virus establishes a foothold and/or induces adaptive immune responses. A comprehensive systems-level understanding of the repertoire of anti-viral effectors in the context of these immediate virus-host responses would provide significant advantages in devising novel strategies to interfere with the initial establishment of infections. Recent efforts to identify cellular factors in a comprehensive and unbiased manner, using genome-wide siRNA screens and other systems biology “omics” methodologies, have revealed several potential anti-viral effectors for viruses like Human immunodeficiency virus type 1 (HIV-1, Hepatitis C virus (HCV, West Nile virus (WNV, and influenza virus. This review describes the discovery of novel viral restriction factors and discusses how the integration of different methods in systems biology can be used to more comprehensively identify the intimate interactions of viruses and the cellular innate resistance.

  7. Non-specific dsRNA-mediated antiviral response in the honey bee.

    Directory of Open Access Journals (Sweden)

    Michelle L Flenniken

    Full Text Available Honey bees are essential pollinators of numerous agricultural crops. Since 2006, honey bee populations have suffered considerable annual losses that are partially attributed to Colony Collapse Disorder (CCD. CCD is an unexplained phenomenon that correlates with elevated incidence of pathogens, including RNA viruses. Honey bees are eusocial insects that live in colonies of genetically related individuals that work in concert to gather and store nutrients. Their social organization provides numerous benefits, but also facilitates pathogen transmission between individuals. To investigate honey bee antiviral defense mechanisms, we developed an RNA virus infection model and discovered that administration of dsRNA, regardless of sequence, reduced virus infection. Our results suggest that dsRNA, a viral pathogen associated molecular pattern (PAMP, triggers an antiviral response that controls virus infection in honey bees.

  8. Non-Specific dsRNA-Mediated Antiviral Response in the Honey Bee

    Science.gov (United States)

    Flenniken, Michelle L.; Andino, Raul

    2013-01-01

    Honey bees are essential pollinators of numerous agricultural crops. Since 2006, honey bee populations have suffered considerable annual losses that are partially attributed to Colony Collapse Disorder (CCD). CCD is an unexplained phenomenon that correlates with elevated incidence of pathogens, including RNA viruses. Honey bees are eusocial insects that live in colonies of genetically related individuals that work in concert to gather and store nutrients. Their social organization provides numerous benefits, but also facilitates pathogen transmission between individuals. To investigate honey bee antiviral defense mechanisms, we developed an RNA virus infection model and discovered that administration of dsRNA, regardless of sequence, reduced virus infection. Our results suggest that dsRNA, a viral pathogen associated molecular pattern (PAMP), triggers an antiviral response that controls virus infection in honey bees. PMID:24130869

  9. Solute Carrier NTCP Regulates Innate Antiviral Immune Responses Targeting Hepatitis C Virus Infection of Hepatocytes

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    Eloi R. Verrier

    2016-10-01

    Full Text Available Chronic hepatitis B, C, and D virus (HBV, HCV, and HDV infections are the leading causes of liver disease and cancer worldwide. Recently, the solute carrier and sodium taurocholate co-transporter NTCP has been identified as a receptor for HBV and HDV. Here, we uncover NTCP as a host factor regulating HCV infection. Using gain- and loss-of-function studies, we show that NTCP mediates HCV infection of hepatocytes and is relevant for cell-to-cell transmission. NTCP regulates HCV infection by augmenting the bile-acid-mediated repression of interferon-stimulated genes (ISGs, including IFITM3. In conclusion, our results uncover NTCP as a mediator of innate antiviral immune responses in the liver, and they establish a role for NTCP in the infection process of multiple viruses via distinct mechanisms. Collectively, our findings suggest a role for solute carriers in the regulation of innate antiviral responses, and they have potential implications for virus-host interactions and antiviral therapies.

  10. Radiosensitivity of antibody responses and radioresistant secondary tetanus antitoxin responses

    International Nuclear Information System (INIS)

    Stoner, R.; Terres, G.; Cottier, H.; Hess, M.

    1976-01-01

    Primary tetanus antitoxin responses were increasingly repressed in mice when gamma radiation doses of 100 to 400 rads were delivered by whole-body exposure prior to immunization with fluid tetanus toxoid (FTT). Nearly normal secondary antitoxin responses were obtained in mice exposed to 600 rads of gamma radiation 4 days after secondary antigenic stimulation with FTT. A rapid transition from radiosensitivity of the antibody-forming system on days 1 to 3 was followed by relative radioresistance on day 4 after the booster injection of toxoid. Studies on lymphoid cellular kinetics in popliteal lymph nodes after injection of 3 H--thymidine ( 3 H--TdR) and incorporation of 3 H--L-histidine into circulating antitoxin were carried out. Analysis of tritium radioactivity in antigen--antibody precipitates of serums 2 hr after injection of the labeled amino acid revealed maximum incorporation into antibody around day 7 after the booster in nonirradiated controls and about day 12, i.e., 8 days after irradiation, in experimental mice. The shift from radiosensitivity to relative radioresistance was attributed to a marked peak of plasma-cell proliferation in the medulla of lymph nodes on day 3. Many medullary plasma cells survived and continued to proliferate after exposure to radiation. Germinal centers were destroyed by radiation within 1 day. Since antibody formation continued after exposure to radiation and after the loss of germinal centers, this supports the view that germinal-center cells were involved more in the generation of memory cells than in antibody synthesis

  11. West Nile virus noncoding subgenomic RNA contributes to viral evasion of the type I interferon-mediated antiviral response.

    Science.gov (United States)

    Schuessler, Andrea; Funk, Anneke; Lazear, Helen M; Cooper, Daphne A; Torres, Shessy; Daffis, Stephane; Jha, Babal Kant; Kumagai, Yutaro; Takeuchi, Osamu; Hertzog, Paul; Silverman, Robert; Akira, Shizuo; Barton, David J; Diamond, Michael S; Khromykh, Alexander A

    2012-05-01

    We previously showed that a noncoding subgenomic flavivirus RNA (sfRNA) is required for viral pathogenicity, as a mutant West Nile virus (WNV) deficient in sfRNA production replicated poorly in wild-type mice. To investigate the possible immunomodulatory or immune evasive functions of sfRNA, we utilized mice and cells deficient in elements of the type I interferon (IFN) response. Replication of the sfRNA mutant WNV was rescued in mice and cells lacking interferon regulatory factor 3 (IRF-3) and IRF-7 and in mice lacking the type I alpha/beta interferon receptor (IFNAR), suggesting a contribution for sfRNA in overcoming the antiviral response mediated by type I IFN. This was confirmed by demonstrating rescue of mutant virus replication in the presence of IFNAR neutralizing antibodies, greater sensitivity of mutant virus replication to IFN-α pretreatment, partial rescue of its infectivity in cells deficient in RNase L, and direct effects of transfected sfRNA on rescuing replication of unrelated Semliki Forest virus in cells pretreated with IFN-α. The results define a novel function of sfRNA in flavivirus pathogenesis via its contribution to viral evasion of the type I interferon response.

  12. SAMD9 is an innate antiviral host factor with stress response properties that can be antagonized by poxviruses.

    Science.gov (United States)

    Liu, Jia; McFadden, Grant

    2015-02-01

    We show that SAMD9 is an innate host antiviral stress response element that participates in the formation of antiviral granules. Poxviruses, myxoma virus and vaccinia virus specifically, utilize a virus-encoded host range factor(s), such as a member of the C7L superfamily, to antagonize SAMD9 to prevent granule formation in a eukaryotic initiation factor 2α (eIF2α)-independent manner. When SAMD9 is stimulated due to failure of the viral antagonism during infection, the resulting antiviral granules exhibit properties different from those of the canonical stress granules. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  13. Enterovirus 71 protease 2Apro targets MAVS to inhibit anti-viral type I interferon responses.

    Directory of Open Access Journals (Sweden)

    Bei Wang

    2013-03-01

    Full Text Available Enterovirus 71 (EV71 is the major causative pathogen of hand, foot, and mouth disease (HFMD. Its pathogenicity is not fully understood, but innate immune evasion is likely a key factor. Strategies to circumvent the initiation and effector phases of anti-viral innate immunity are well known; less well known is whether EV71 evades the signal transduction phase regulated by a sophisticated interplay of cellular and viral proteins. Here, we show that EV71 inhibits anti-viral type I interferon (IFN responses by targeting the mitochondrial anti-viral signaling (MAVS protein--a unique adaptor molecule activated upon retinoic acid induced gene-I (RIG-I and melanoma differentiation associated gene (MDA-5 viral recognition receptor signaling--upstream of type I interferon production. MAVS was cleaved and released from mitochondria during EV71 infection. An in vitro cleavage assay demonstrated that the viral 2A protease (2A(pro, but not the mutant 2A(pro (2A(pro-110 containing an inactivated catalytic site, cleaved MAVS. The Protease-Glo assay revealed that MAVS was cleaved at 3 residues between the proline-rich and transmembrane domains, and the resulting fragmentation effectively inactivated downstream signaling. In addition to MAVS cleavage, we found that EV71 infection also induced morphologic and functional changes to the mitochondria. The EV71 structural protein VP1 was detected on purified mitochondria, suggesting not only a novel role for mitochondria in the EV71 replication cycle but also an explanation of how EV71-derived 2A(pro could approach MAVS. Taken together, our findings reveal a novel strategy employed by EV71 to escape host anti-viral innate immunity that complements the known EV71-mediated immune-evasion mechanisms.

  14. Regulation and evasion of antiviral immune responses by porcine reproductive and respiratory syndrome virus.

    Science.gov (United States)

    Huang, Chen; Zhang, Qiong; Feng, Wen-hai

    2015-04-16

    Virus infection of mammalian cells triggers host innate immune responses to restrict viral replication and induces adaptive immunity for viral elimination. In order to survive and propagate, viruses have evolved sophisticated mechanisms to subvert host defense system by encoding proteins that target key components of the immune signaling pathways. Porcine reproductive and respiratory syndrome virus (PRRSV), a RNA virus, impairs several processes of host immune responses including interfering with interferon production and signaling, modulating cytokine expression, manipulating apoptotic responses and regulating adaptive immunity. In this review, we highlight the molecular mechanisms of how PRRSV interferes with the different steps of initial antiviral host responses to establish persistent infection in pigs. Dissection of the PRRSV-host interaction is the key in understanding PRRSV pathogenesis and will provide a basis for the rational design of vaccines. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Broad RNA interference-mediated antiviral immunity and virus-specific inducible responses in Drosophila.

    Science.gov (United States)

    Kemp, Cordula; Mueller, Stefanie; Goto, Akira; Barbier, Vincent; Paro, Simona; Bonnay, François; Dostert, Catherine; Troxler, Laurent; Hetru, Charles; Meignin, Carine; Pfeffer, Sébastien; Hoffmann, Jules A; Imler, Jean-Luc

    2013-01-15

    The fruit fly Drosophila melanogaster is a good model to unravel the molecular mechanisms of innate immunity and has led to some important discoveries about the sensing and signaling of microbial infections. The response of Drosophila to virus infections remains poorly characterized and appears to involve two facets. On the one hand, RNA interference involves the recognition and processing of dsRNA into small interfering RNAs by the host RNase Dicer-2 (Dcr-2), whereas, on the other hand, an inducible response controlled by the evolutionarily conserved JAK-STAT pathway contributes to the antiviral host defense. To clarify the contribution of the small interfering RNA and JAK-STAT pathways to the control of viral infections, we have compared the resistance of flies wild-type and mutant for Dcr-2 or the JAK kinase Hopscotch to infections by seven RNA or DNA viruses belonging to different families. Our results reveal a unique susceptibility of hop mutant flies to infection by Drosophila C virus and cricket paralysis virus, two members of the Dicistroviridae family, which contrasts with the susceptibility of Dcr-2 mutant flies to many viruses, including the DNA virus invertebrate iridescent virus 6. Genome-wide microarray analysis confirmed that different sets of genes were induced following infection by Drosophila C virus or by two unrelated RNA viruses, Flock House virus and Sindbis virus. Overall, our data reveal that RNA interference is an efficient antiviral mechanism, operating against a large range of viruses, including a DNA virus. By contrast, the antiviral contribution of the JAK-STAT pathway appears to be virus specific.

  16. Interferon gamma modulation of disease manifestation and the local antibody response to alphavirus encephalomyelitis.

    Science.gov (United States)

    Baxter, Victoria K; Griffin, Diane E

    2016-11-01

    Infection of mice with Sindbis virus (SINV) produces encephalomyelitis and provides a model for examination of the central nervous system (CNS) immune response to alphavirus infection. Clearance of infectious virus is accomplished through a cooperative effort between SINV-specific antibody and IFN-γ, but the regulatory interactions are poorly understood. To determine the effects of IFN-γ on clinical disease and the antiviral immune response, C57BL/6 mice lacking IFN-γ (Ifng-/-) or IFN-γ receptor (Ifngr1-/-) were studied in comparison to WT mice. Maximum production of Ifng mRNA and IFN-γ protein in the CNS of WT and Ifngr1-/- mice occurred 5-7 days after infection, with higher levels of IFN-γ in Ifngr1-/- mice. Onset of clinical disease was earlier in mice with impaired IFN-γ signalling, although Ifngr1-/- mice recovered more rapidly. Ifng-/- and Ifngr1-/- mice maintained body weight better than WT mice, associated with better food intake and lower brain levels of inflammatory cytokines. Clearance of infectious virus from the spinal cords was slower, and CNS, but not serum, levels of SINV-specific IgM, IgG2a and IgG2b were lower in Ifngr1-/- and Ifng-/- mice compared to WT mice. Decreased CNS antiviral antibody was associated with lower expression of mRNAs for B-cell attracting chemokines CXCL9, CXCL10 and CXCL13 and fewer B cells in the CNS. Therefore, IFN-γ signalling increases levels of CNS pro-inflammatory cytokines, leading to clinical disease, but synergistically clears virus with SINV-specific antibody at least in part by increasing chemokine production important for infiltration of antibody-secreting B cells into the CNS.

  17. Influenza A Virus Protein PA-X Contributes to Viral Growth and Suppression of the Host Antiviral and Immune Responses.

    Science.gov (United States)

    Hayashi, Tsuyoshi; MacDonald, Leslie A; Takimoto, Toru

    2015-06-01

    Influenza virus infection causes global inhibition of host protein synthesis in infected cells. This host shutoff is thought to allow viruses to escape from the host antiviral response, which restricts virus replication and spread. Although the mechanism of host shutoff is unclear, a novel viral protein expressed by ribosomal frameshifting, PA-X, was found to play a major role in influenza virus-induced host shutoff. However, little is known about the impact of PA-X expression on currently circulating influenza A virus pathogenicity and the host antiviral response. In this study, we rescued a recombinant influenza A virus, A/California/04/09 (H1N1, Cal), containing mutations at the frameshift motif in the polymerase PA gene (Cal PA-XFS). Cal PA-XFS expressed significantly less PA-X than Cal wild type (WT). Cal WT, but not Cal PA-XFS, induced degradation of host β-actin mRNA and suppressed host protein synthesis, supporting the idea that PA-X induces host shutoff via mRNA decay. Moreover, Cal WT inhibited beta interferon (IFN-β) expression and replicated more rapidly than Cal PA-XFS in human respiratory cells. Mice infected with Cal PA-XFS had significantly lower levels of viral growth and greater expression of IFN-β mRNA in their lungs than mice infected with Cal WT. Importantly, more antihemagglutinin and neutralizing antibodies were produced in Cal PA-XFS-infected mice than in Cal WT-infected mice, despite the lower level of virus replication in the lungs. Our data indicate that PA-X of the pandemic H1N1 virus has a strong impact on viral growth and the host innate and acquired immune responses to influenza virus. Virus-induced host protein shutoff is considered to be a major factor allowing viruses to evade innate and acquired immune recognition. We provide evidence that the 2009 H1N1 influenza A virus protein PA-X plays a role in virus replication and inhibition of host antiviral response by means of its host protein synthesis shutoff activity both in vitro

  18. The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA.

    Science.gov (United States)

    Zhong, Bo; Zhang, Lu; Lei, Caoqi; Li, Ying; Mao, Ai-Ping; Yang, Yan; Wang, Yan-Yi; Zhang, Xiao-Lian; Shu, Hong-Bing

    2009-03-20

    Viral infection activates transcription factors NF-kappaB and IRF3, which collaborate to induce type I interferons (IFNs) and elicit innate antiviral response. MITA (also known as STING) has recently been identified as an adaptor that links virus-sensing receptors to IRF3 activation. Here, we showed that the E3 ubiquitin ligase RNF5 interacted with MITA in a viral-infection-dependent manner. Overexpression of RNF5 inhibited virus-triggered IRF3 activation, IFNB1 expression, and cellular antiviral response, whereas knockdown of RNF5 had opposite effects. RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection. Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER) and viral infection caused their redistribution to the ER and mitochondria, respectively. We further found that virus-induced ubiquitination and degradation of MITA by RNF5 occurred at the mitochondria. These findings suggest that RNF5 negatively regulates virus-triggered signaling by targeting MITA for ubiquitination and degradation at the mitochondria.

  19. The Imd pathway is involved in antiviral immune responses in Drosophila.

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    Alexandre Costa

    2009-10-01

    Full Text Available Cricket Paralysis virus (CrPV is a member of the Dicistroviridae family of RNA viruses, which infect a broad range of insect hosts, including the fruit fly Drosophila melanogaster. Drosophila has emerged as an effective system for studying innate immunity because of its powerful genetic techniques and the high degree of gene and pathway conservation. Intra-abdominal injection of CrPV into adult flies causes a lethal infection that provides a robust assay for the identification of mutants with altered sensitivity to viral infection. To gain insight into the interactions between viruses and the innate immune system, we injected wild type flies with CrPV and observed that antimicrobial peptides (AMPs were not induced and hemocytes were depleted in the course of infection. To investigate the contribution of conserved immune signaling pathways to antiviral innate immune responses, CrPV was injected into isogenic mutants of the Immune Deficiency (Imd pathway, which resembles the mammalian Tumor Necrosis Factor Receptor (TNFR pathway. Loss-of-function mutations in several Imd pathway genes displayed increased sensitivity to CrPV infection and higher CrPV loads. Our data show that antiviral innate immune responses in flies infected with CrPV depend upon hemocytes and signaling through the Imd pathway.

  20. TRBP and eIF6 homologue in Marsupenaeus japonicus play crucial roles in antiviral response.

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    Shuai Wang

    Full Text Available Plants and invertebrates can suppress viral infection through RNA silencing, mediated by RNA-induced silencing complex (RISC. Trans-activation response RNA-binding protein (TRBP, consisting of three double-stranded RNA-binding domains, is a component of the RISC. In our previous paper, a TRBP homologue in Fenneropenaeus chinensis (Fc-TRBP was reported to directly bind to eukaryotic initiation factor 6 (Fc-eIF6. In this study, we further characterized the function of TRBP and the involvement of TRBP and eIF6 in antiviral RNA interference (RNAi pathway of shrimp. The double-stranded RNA binding domains (dsRBDs B and C of the TRBP from Marsupenaeus japonicus (Mj-TRBP were found to mediate the interaction of TRBP and eIF6. Gel-shift assays revealed that the N-terminal of Mj-TRBP dsRBD strongly binds to double-stranded RNA (dsRNA and that the homodimer of the TRBP mediated by the C-terminal dsRBD increases the affinity to dsRNA. RNAi against either Mj-TRBP or Mj-eIF6 impairs the dsRNA-induced sequence-specific RNAi pathway and facilitates the proliferation of white spot syndrome virus (WSSV. These results further proved the important roles of TRBP and eIF6 in the antiviral response of shrimp.

  1. Is sustained virological response a marker of treatment efficacy in patients with chronic hepatitis C viral infection with no response or relapse to previous antiviral intervention?

    DEFF Research Database (Denmark)

    Gurusamy, Kurinchi S; Wilson, Edward; Koretz, Ronald L

    2013-01-01

    Randomised clinical trials (RCTs) of antiviral interventions in patients with chronic hepatitis C virus (HCV) infection use sustained virological response (SVR) as the main outcome. There is sparse information on long-term mortality from RCTs....

  2. Structural Basis for Suppression of a Host Antiviral Response by Influenza A Virus

    Energy Technology Data Exchange (ETDEWEB)

    Das,K.; Ma, L.; Xiao, R.; Radvansky, B.; Aramini, J.; Zhao, L.; Marklund, J.; Kuo, R.; Twu, K.; Arnold, E.

    2008-01-01

    Influenza A viruses are responsible for seasonal epidemics and high mortality pandemics. A major function of the viral NS1A protein, a virulence factor, is the inhibition of the production of IFN-{beta}{beta} mRNA and other antiviral mRNAs. The NS1A protein of the human influenza A/Udorn/72 (Ud) virus inhibits the production of these antiviral mRNAs by binding the cellular 30-kDa subunit of the cleavage and polyadenylation specificity factor (CPSF30), which is required for the 3' end processing of all cellular pre-mRNAs. Here we report the 1.95- Angstroms resolution X-ray crystal structure of the complex formed between the second and third zinc finger domain (F2F3) of CPSF30 and the C-terminal domain of the Ud NS1A protein. The complex is a tetramer, in which each of two F2F3 molecules wraps around two NS1A effector domains that interact with each other head-to-head. This structure identifies a CPSF30 binding pocket on NS1A comprised of amino acid residues that are highly conserved among human influenza A viruses. Single amino acid changes within this binding pocket eliminate CPSF30 binding, and a recombinant Ud virus expressing an NS1A protein with such a substitution is attenuated and does not inhibit IFN-{beta} pre-mRNA processing. This binding pocket is a potential target for antiviral drug development. The crystal structure also reveals that two amino acids outside of this pocket, F103 and M106, which are highly conserved (>99%) among influenza A viruses isolated from humans, participate in key hydrophobic interactions with F2F3 that stabilize the complex.

  3. Genotype 1 hepatitis C virus envelope features that determine antiviral response assessed through optimal covariance networks.

    Directory of Open Access Journals (Sweden)

    John M Murray

    Full Text Available The poor response to the combined antiviral therapy of pegylated alfa-interferon and ribavarin for hepatitis C virus (HCV infection may be linked to mutations in the viral envelope gene E1E2 (env, which can result in escape from the immune response and higher efficacy of viral entry. Mutations that result in failure of therapy most likely require compensatory mutations to achieve sufficient change in envelope structure and function. Compensatory mutations were investigated by determining positions in the E1E2 gene where amino acids (aa covaried across groups of individuals. We assessed networks of covarying positions in E1E2 sequences that differentiated sustained virological response (SVR from non-response (NR in 43 genotype 1a (17 SVR, and 49 genotype 1b (25 SVR chronically HCV-infected individuals. Binary integer programming over covariance networks was used to extract aa combinations that differed between response groups. Genotype 1a E1E2 sequences exhibited higher degrees of covariance and clustered into 3 main groups while 1b sequences exhibited no clustering. Between 5 and 9 aa pairs were required to separate SVR from NR in each genotype. aa in hypervariable region 1 were 6 times more likely than chance to occur in the optimal networks. The pair 531-626 (EI appeared frequently in the optimal networks and was present in 6 of 9 NR in one of the 1a clusters. The most frequent pairs representing SVR were 431-481 (EE, 500-522 (QA in 1a, and 407-434 (AQ in 1b. Optimal networks based on covarying aa pairs in HCV envelope can indicate features that are associated with failure or success to antiviral therapy.

  4. Effect of the temperature during antiviral immune response ontogeny in teleosts.

    Science.gov (United States)

    Dios, Sonia; Romero, Alejandro; Chamorro, Rubén; Figueras, Antonio; Novoa, Beatriz

    2010-12-01

    Zebrafish were used to investigate the expression levels of several antiviral and inflammatory genes (IL-1β, iNOS, TNF-α, TLR3, IFN-I, IFNγ, IRF3, MDA-5, Mx) constitutively and after viral stimulation during early development. We also determined how their expression was affected by changes in the temperature. The antiviral genes were almost completely inhibited at 15°C with the exception of TLR3. In contrast, IL-1β, iNOS and TNF-α expression was not obviously different between the two temperatures. At 15°C, most of the genes examined did not differ following stimulation with poly I:C or viral hemorrhagic septicemia virus (VHSV). However, at 28°C, all of the genes showed significant differences in at least some of the sampling points after poly I:C treatment with the largest differences observed for Mx. Mx expression in adult zebrafish was not significantly altered by temperature and poly I:C treatment led to a smaller increase in gene expression when compared to larval Mx levels. Thus, Mx seems to play an important role in viral immunity in larvae, when the adaptive immune response is not fully functional. Copyright © 2010 Elsevier Ltd. All rights reserved.

  5. Vaccine-induced antibody responses in relation to season

    NARCIS (Netherlands)

    Termorshuizen F; Sleijffers A; Hof S van den; Melker H de; Garssen J; Boland GJ; Hattum J van; Gruijl FR de; Loveren H van; LPI

    2001-01-01

    The effect of season on the antibody response after Hepatitis B (HB), Measles and Rubella vaccination in humans was investigated. In view of the immunosuppressive effects of ultraviolet radiation (UVR), especially the B-waveband (UVB), it was hypothesised that a lower antibody response after

  6. Inhibition of dengue and chikungunya virus infections by RIG-I-mediated type I interferon-independent stimulation of the innate antiviral response.

    Science.gov (United States)

    Olagnier, David; Scholte, Florine E M; Chiang, Cindy; Albulescu, Irina C; Nichols, Carmen; He, Zhong; Lin, Rongtuan; Snijder, Eric J; van Hemert, Martijn J; Hiscott, John

    2014-04-01

    RIG-I is a cytosolic sensor critically involved in the activation of the innate immune response to RNA virus infection. In the present study, we evaluated the inhibitory effect of a RIG-I agonist on the replication of two emerging arthropod-borne viral pathogens, dengue virus (DENV) and chikungunya virus (CHIKV), for which no therapeutic options currently exist. We demonstrate that when a low, noncytotoxic dose of an optimized 5'triphosphorylated RNA (5'pppRNA) molecule was administered, RIG-I stimulation generated a robust antiviral response against these two viruses. Strikingly, 5'pppRNA treatment before or after challenge with DENV or CHIKV provided protection against infection. In primary human monocytes and monocyte-derived dendritic cells, the RIG-I agonist blocked both primary infection and antibody-dependent enhancement of DENV infection. The protective response against DENV and CHIKV induced by 5'pppRNA was dependent on an intact RIG-I/MAVS/TBK1/IRF3 axis and was largely independent of the type I IFN response. Altogether, this in vitro analysis of the antiviral efficacy of 5'pppRNA highlights the therapeutic potential of RIG-I agonists against emerging viruses such as DENV and CHIKV. DENV and CHIKV are two reemerging mosquito-borne viruses for which no therapeutic options currently exist. Both viruses overlap geographically in tropical regions of the world, produce similar fever-like symptoms, and are difficult to diagnose. This study investigated the inhibitory effect of a RIG-I agonist on the replication of these two viruses. RIG-I stimulation using 5'pppRNA before or after DENV or CHIKV infection generated a protective antiviral response against both pathogens in immune and nonimmune cells; interestingly, the protective response against the viruses was largely independent of the classical type I interferon response. The antiviral efficacy of 5'pppRNA highlights the therapeutic potential of RIG-I agonists against emerging viruses such as DENV and CHIKV.

  7. HBV Bypasses the Innate Immune Response and Does Not Protect HCV From Antiviral Activity of Interferon.

    Science.gov (United States)

    Mutz, Pascal; Metz, Philippe; Lempp, Florian A; Bender, Silke; Qu, Bingqian; Schöneweis, Katrin; Seitz, Stefan; Tu, Thomas; Restuccia, Agnese; Frankish, Jamie; Dächert, Christopher; Schusser, Benjamin; Koschny, Ronald; Polychronidis, Georgios; Schemmer, Peter; Hoffmann, Katrin; Baumert, Thomas F; Binder, Marco; Urban, Stephan; Bartenschlager, Ralf

    2018-05-01

    Hepatitis C virus (HCV) infection is sensitive to interferon (IFN)-based therapy, whereas hepatitis B virus (HBV) infection is not. It is unclear whether HBV escapes detection by the IFN-mediated immune response or actively suppresses it. Moreover, little is known on how HBV and HCV influence each other in coinfected cells. We investigated interactions between HBV and the IFN-mediated immune response using HepaRG cells and primary human hepatocytes (PHHs). We analyzed the effects of HBV on HCV replication, and vice versa, at the single-cell level. PHHs were isolated from liver resection tissues from HBV-, HCV-, and human immunodeficiency virus-negative patients. Differentiated HepaRG cells overexpressing the HBV receptor sodium taurocholate cotransporting polypeptide (dHepaRGNTCP) and PHHs were infected with HBV. Huh7.5 cells were transfected with circular HBV DNA genomes resembling viral covalently closed circular DNA (cccDNA), and subsequently infected with HCV; this served as a model of HBV and HCV coinfection. Cells were incubated with IFN inducers, or IFNs, and antiviral response and viral replication were analyzed by immune fluorescence, reverse-transcription quantitative polymerase chain reaction, enzyme-linked immunosorbent assays, and flow cytometry. HBV infection of dHepaRGNTCP cells and PHHs neither activated nor inhibited signaling via pattern recognition receptors. Incubation of dHepaRGNTCP cells and PHHs with IFN had little effect on HBV replication or levels of cccDNA. HBV infection of these cells did not inhibit JAK-STAT signaling or up-regulation of IFN-stimulated genes. In coinfected cells, HBV did not prevent IFN-induced suppression of HCV replication. In dHepaRGNTCP cells and PHHs, HBV evades the induction of IFN and IFN-induced antiviral effects. HBV infection does not rescue HCV from the IFN-mediated response. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

  8. Activation of innate antiviral immune response via double-stranded RNA-dependent RLR receptor-mediated necroptosis.

    Science.gov (United States)

    Wang, Wei; Wang, Wei-Hua; Azadzoi, Kazem M; Su, Ning; Dai, Peng; Sun, Jianbin; Wang, Qin; Liang, Ping; Zhang, Wentao; Lei, Xiaoying; Yan, Zhen; Yang, Jing-Hua

    2016-03-03

    Viruses induce double-stranded RNA (dsRNA) in the host cells. The mammalian system has developed dsRNA-dependent recognition receptors such as RLRs that recognize the long stretches of dsRNA as PAMPs to activate interferon-mediated antiviral pathways and apoptosis in severe infection. Here we report an efficient antiviral immune response through dsRNA-dependent RLR receptor-mediated necroptosis against infections from different classes of viruses. We demonstrated that virus-infected A549 cells were efficiently killed in the presence of a chimeric RLR receptor, dsCARE. It measurably suppressed the interferon antiviral pathway but promoted IL-1β production. Canonical cell death analysis by morphologic assessment, phosphatidylserine exposure, caspase cleavage and chemical inhibition excluded the involvement of apoptosis and consistently suggested RLR receptor-mediated necroptosis as the underlying mechanism of infected cell death. The necroptotic pathway was augmented by the formation of RIP1-RIP3 necrosome, recruitment of MLKL protein and the activation of cathepsin D. Contributing roles of RIP1 and RIP3 were confirmed by gene knockdown. Furthermore, the necroptosis inhibitor necrostatin-1 but not the pan-caspase inhibitor zVAD impeded dsCARE-dependent infected cell death. Our data provides compelling evidence that the chimeric RLR receptor shifts the common interferon antiviral responses of infected cells to necroptosis and leads to rapid death of the virus-infected cells. This mechanism could be targeted as an efficient antiviral strategy.

  9. Interactions of macrophages with probiotic bacteria lead to increased antiviral response against vesicular stomatitis virus

    DEFF Research Database (Denmark)

    Ivec, Martin; Botic, Tanja; Koren, Srecko

    2007-01-01

    and by producing chemokines and immunoregulatory cytokines that enable the adaptive immune response to recognize infected cells and perform antiviral effector functions. Probiotics, as a part of the normal gut intestinal flora, are important in supporting a functional yet balanced immune system. Improving our...... understanding of their role in the activation of macrophages and their stimulation of proinflammatory cytokine production in early viral infection was the main goal of this study. Our in vitro model study showed that probiotic bacteria, either from the species Lactobacillus or Bifidobacteria have the ability...... dehydrogenases activity could be implied as the first indicator of potential inhibitory effects of the probiotics on virus replication. The interactions between probiotic bacteria, macrophages and vesicular stomatitis virus (VSV), markedly depended on the bacterial strain studied....

  10. SPOC1-mediated antiviral host cell response is antagonized early in human adenovirus type 5 infection

    DEFF Research Database (Denmark)

    Schreiner, Sabrina; Kinkley, Sarah; Bürck, Carolin

    2013-01-01

    Little is known about immediate phases after viral infection and how an incoming viral genome complex counteracts host cell defenses, before the start of viral gene expression. Adenovirus (Ad) serves as an ideal model, since entry and onset of gene expression are rapid and highly efficient......, and mechanisms used 24-48 hours post infection to counteract host antiviral and DNA repair factors (e.g. p53, Mre11, Daxx) are well studied. Here, we identify an even earlier host cell target for Ad, the chromatin-associated factor and epigenetic reader, SPOC1, recently found recruited to double strand breaks......, and playing a role in DNA damage response. SPOC1 co-localized with viral replication centers in the host cell nucleus, interacted with Ad DNA, and repressed viral gene expression at the transcriptional level. We discovered that this SPOC1-mediated restriction imposed upon Ad growth is relieved by its...

  11. Antiviral activity of a small molecule deubiquitinase inhibitor occurs via induction of the unfolded protein response.

    Directory of Open Access Journals (Sweden)

    Jeffrey W Perry

    Full Text Available Ubiquitin (Ub is a vital regulatory component in various cellular processes, including cellular responses to viral infection. As obligate intracellular pathogens, viruses have the capacity to manipulate the ubiquitin (Ub cycle to their advantage by encoding Ub-modifying proteins including deubiquitinases (DUBs. However, how cellular DUBs modulate specific viral infections, such as norovirus, is poorly understood. To examine the role of DUBs during norovirus infection, we used WP1130, a small molecule inhibitor of a subset of cellular DUBs. Replication of murine norovirus in murine macrophages and the human norovirus Norwalk virus in a replicon system were significantly inhibited by WP1130. Chemical proteomics identified the cellular DUB USP14 as a target of WP1130 in murine macrophages, and pharmacologic inhibition or siRNA-mediated knockdown of USP14 inhibited murine norovirus infection. USP14 is a proteasome-associated DUB that also binds to inositol-requiring enzyme 1 (IRE1, a critical mediator of the unfolded protein response (UPR. WP1130 treatment of murine macrophages did not alter proteasome activity but activated the X-box binding protein-1 (XBP-1 through an IRE1-dependent mechanism. In addition, WP1130 treatment or induction of the UPR also reduced infection of other RNA viruses including encephalomyocarditis virus, Sindbis virus, and La Crosse virus but not vesicular stomatitis virus. Pharmacologic inhibition of the IRE1 endonuclease activity partially rescued the antiviral effect of WP1130. Taken together, our studies support a model whereby induction of the UPR through cellular DUB inhibition blocks specific viral infections, and suggest that cellular DUBs and the UPR represent novel targets for future development of broad spectrum antiviral therapies.

  12. Nonpathogenic Lactobacillus rhamnosus activates the inflammasome and antiviral responses in human macrophages

    Science.gov (United States)

    Miettinen, Minja; Pietilä, Taija E.; Kekkonen, Riina A.; Kankainen, Matti; Latvala, Sinikka; Pirhonen, Jaana; Österlund, Pamela; Korpela, Riitta; Julkunen, Ilkka

    2012-01-01

    In this study, we have utilized global gene expression profiling to compare the responses of human primary macrophages to two closely related, well-characterized Lactobacillus rhamnosus strains GG and LC705, since our understanding of the responses elicited by nonpathogenic bacteria in human innate immune system is limited. Macrophages are phagocytic cells of the innate immune system that perform sentinel functions to initiate appropriate responses to surrounding stimuli. Macrophages that reside on gut mucosa encounter ingested and intestinal bacteria. Bacteria of Lactobacillus genus are nonpathogenic and used in food and as supplements with health-promoting probiotic potential. Our results demonstrate that live GG and LC705 induced quantitatively different gene expression profiles in macrophages. A gene ontology analysis revealed functional similarities and differences in responses to GG and LC705 that were reflected in host defense responses. Both GG and LC705 induced interleukin-1β production in macrophages that required caspase-1 activity. LC705, but not GG, induced type I interferon -dependent gene activation that correlated with its ability to prevent influenza A virus replication and production of viral proteins in macrophages. Our results indicate that nonpathogenic bacteria are able to activate the inflammasome. In addition, our results suggest that L. rhamnosus may prime the antiviral potential of human macrophages. PMID:22895087

  13. The Human Antibody Response to Dengue Virus Infection

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    Aravinda M. de Silva

    2011-11-01

    Full Text Available Dengue viruses (DENV are the causative agents of dengue fever (DF and dengue hemorrhagic fever (DHF. Here we review the current state of knowledge about the human antibody response to dengue and identify important knowledge gaps. A large body of work has demonstrated that antibodies can neutralize or enhance DENV infection. Investigators have mainly used mouse monoclonal antibodies (MAbs to study interactions between DENV and antibodies. These studies indicate that antibody neutralization of DENVs is a “multi-hit” phenomenon that requires the binding of multiple antibodies to neutralize a virion. The most potently neutralizing mouse MAbs bind to surface exposed epitopes on domain III of the dengue envelope (E protein. One challenge facing the dengue field now is to extend these studies with mouse MAbs to better understand the human antibody response. The human antibody response is complex as it involves a polyclonal response to primary and secondary infections with 4 different DENV serotypes. Here we review studies conducted with immune sera and MAbs isolated from people exposed to dengue infections. Most dengue-specific antibodies in human immune sera are weakly neutralizing and bind to multiple DENV serotypes. The human antibodies that potently and type specifically neutralize DENV represent a small fraction of the total DENV-specific antibody response. Moreover, these neutralizing antibodies appear to bind to novel epitopes including complex, quaternary epitopes that are only preserved on the intact virion. These studies establish that human and mouse antibodies recognize distinct epitopes on the dengue virion. The leading theory proposed to explain the increased risk of severe disease in secondary cases is antibody dependent enhancement (ADE, which postulates that weakly neutralizing antibodies from the first infection bind to the second serotype and enhance infection of FcγR bearing myeloid cells such as monocytes and macrophages. Here

  14. A synthetic peptide derived from the animo acid sequence of canine parvovirus structural proteins which defines a B cell epitope and elicits antiviral antibody in BALB c mice.

    NARCIS (Netherlands)

    G.F. Rimmelzwaan (Guus); J. Carlson; F.G.C.M. Uytdehaag (Fons); A.D.M.E. Osterhaus (Albert)

    1990-01-01

    textabstractSynthetic peptides, recombinant fusion proteins and mouse monoclonal antibodies were used to delineate a B cell epitope of the VP'2 structural protein of canine parvovirus (CPV). Although this epitope is not preferentially recognized in the normal antibody response to CPV, virus-specific

  15. Low-level HCV viraemia after initial response during antiviral therapy: transcription-mediated amplification predicts treatment failure

    NARCIS (Netherlands)

    Gelderblom, Huub C.; Reesink, Henk W.; Beld, Marcel G. H. M.; Weegink, Christine J.; Jansen, Peter L. M.; Dijkgraaf, Marcel G. W.; Zaaijer, Hans L.

    2007-01-01

    BACKGROUND: In chronic hepatitis C patients with an initial virological response (IVR) during antiviral therapy (that is, HCV RNA becomes negative before week 16 of treatment) the significance of reappearing viraemia below the detection limit of PCR is not known. We studied this phenomenon in

  16. Spectroscopic investigation of herpes simplex viruses infected cells and their response to antiviral therapy

    Science.gov (United States)

    Erukhimovitch, Vitaly; Talyshinsky, Marina; Souprun, Yelena; Huleihel, Mahmoud

    2006-07-01

    In the present study, we used microscopic Fourier transform infrared spectroscopy (FTIR) to evaluate the antiviral activity of known antiviral agents against herpes viruses. The antiviral activity of Caffeic acid phenethyl ester (CAPE) (which is an active compound of propolis) against herpes simplex type 1 and 2 was examined in cell culture. The advantage of microscopic FTIR spectroscopy over conventional FTIR spectroscopy is that it facilitates inspection of restricted regions of cell culture or tissue. Our results showed significant spectral differences at early stages of infection between infected and non-infected cells, and between infected cells treated with the used antiviral agent and those not treated. In infected cells, there was a considerable increase in phosphate levels. Our results show that treatment with used antiviral agent considerably abolish the spectral changes induced by the viral infection. In addition, it is possible to track by FTIR microscopy method the deferential effect of various doses of the drug.

  17. Henipaviruses Employ a Multifaceted Approach to Evade the Antiviral Interferon Response

    Directory of Open Access Journals (Sweden)

    Megan L. Shaw

    2009-12-01

    Full Text Available Hendra and Nipah virus, which constitute the genus Henipavirus, are zoonotic paramyxoviruses that have been associated with sporadic outbreaks of severe disease and mortality in humans since their emergence in the late 1990s. Similar to other paramyxoviruses, their ability to evade the host interferon (IFN response is conferred by the P gene. The henipavirus P gene encodes four proteins; the P, V, W and C proteins, which have all been described to inhibit the antiviral response. Further studies have revealed that these proteins have overlapping but unique properties which enable the virus to block multiple signaling pathways in the IFN response. The best characterized of these is the JAK-STAT signaling pathway which is targeted by the P, V and W proteins via an interaction with the transcription factor STAT1. In addition the V and W proteins can both limit virus-induced induction of IFN but they appear to do this via distinct mechanisms that rely on unique sequences in their C-terminal domains. The ability to generate recombinant Nipah viruses now gives us the opportunity to determine the precise role for each of these proteins and address their contribution to pathogenicity. Additionally, the question of whether these multiple anti-IFN strategies are all active in the different mammalian hosts for henipaviruses, particularly the fruit bat reservoir, warrants further exploration.

  18. Expression of IL-18 by SIV does not modify the outcome of the antiviral immune response.

    Science.gov (United States)

    Giavedoni, Luis D; Velasquillo, M Cristina; Parodi, Laura M; Hubbard, Gene B; Hodara, Vida L

    2002-11-25

    Interleukin 18 (IL-18) is a proinflammatory cytokine expressed by several cell types, including activated dendritic cells and macrophages, that acts in synergy with IL-12 as an important amplifying factor for IFN-gamma production and Th1 development. To study the immunological and virological effects of IL-18 expression in the context of a lentiviral infection, we inoculated rhesus macaques with a high dose of replication-competent simian immunodeficiency virus (SIV) vectors carrying the rhesus IL-18 gene in the sense (SIV(IL-18)) or antisense (SIV(FIGI)) orientation. Both vectors behaved as attenuated viruses, resulting in low viral loads, induction of low and transient levels of inflammatory cytokines, no CD4(+) T cell depletion, and mild activation of T lymphocytes. Although IL-18-expressing virus could be isolated from some SIV(IL18)-infected macaques for 12 weeks postinfection, the anti-SIV humoral and cellular immune responses of macaques inoculated with SIV(IL18) and SIV(FIGI) were similar to each other, with the exception of an early IFN-gamma response in animals infected with SIV(IL18). In summary, expression of IL-18 during the acute phase of SIV infection does not increase viral replication or influence the outcome of the antiviral immune response.

  19. Broadly protective influenza vaccines: Redirecting the antibody response through adjuvation

    NARCIS (Netherlands)

    Cox, F.

    2016-01-01

    Influenza virus infections are responsible for significant morbidity worldwide and current vaccines have limited coverage, therefore it remains a high priority to develop broadly protective vaccines. With the discovery of broadly neutralizing antibodies (bnAbs) against influenza these vaccines

  20. Identification of Secreted Proteins Involved in Nonspecific dsRNA-Mediated Lutzomyia longipalpis LL5 Cell Antiviral Response

    Directory of Open Access Journals (Sweden)

    Andrea Martins-da-Silva

    2018-01-01

    Full Text Available Hematophagous insects transmit infectious diseases. Sand flies are vectors of leishmaniasis, but can also transmit viruses. We have been studying immune responses of Lutzomyia longipalpis, the main vector of visceral leishmaniasis in the Americas. We identified a non-specific antiviral response in L. longipalpis LL5 embryonic cells when treated with non-specific double-stranded RNAs (dsRNAs. This response is reminiscent of interferon response in mammals. We are investigating putative effectors for this antiviral response. Secreted molecules have been implicated in immune responses, including interferon-related responses. We conducted a mass spectrometry analysis of conditioned medium from LL5 cells 24 and 48 h after dsRNA or mock treatment. We identified 304 proteins. At 24 h, 19 proteins had an abundance equal or greater than 2-fold change, while the levels of 17 proteins were reduced when compared to control cells. At the 48 h time point, these numbers were 33 and 71, respectively. The two most abundant secreted peptides at 24 h in the dsRNA-transfected group were phospholipid scramblase, an interferon-inducible protein that mediates antiviral activity, and forskolin-binding protein (FKBP, a member of the immunophilin family, which mediates the effect of immunosuppressive drugs. The transcription profile of most candidates did not follow the pattern of secreted protein abundance.

  1. Plasmablast-derived polyclonal antibody response after influenza vaccination.

    Science.gov (United States)

    He, Xiao-Song; Sasaki, Sanae; Narvaez, Carlos F; Zhang, Caiqiu; Liu, Hui; Woo, Jennifer C; Kemble, George W; Dekker, Cornelia L; Davis, Mark M; Greenberg, Harry B

    2011-02-28

    Conventional measurement of antibody responses to vaccines largely relies on serum antibodies, which are primarily produced by bone marrow plasma cells and may not represent the entire vaccine-induced B cell repertoire, including important functional components such as those targeted to mucosal sites. After immunization or infection, activated B cells differentiate into plasmablasts in local lymphoid organs, then traffic through circulation to the target sites where they further develop into plasma cells. On day 7 after influenza vaccination, a burst of plasmablasts, highly enriched for vaccine-specific antibody secreting cells, appears in the peripheral blood. This provides a unique window to the overall B cell response to the vaccine, without interference of pre-existing cross-reactive serum antibody. In this study we isolated B cells from volunteers on day 7 after immunization with the inactivated influenza vaccine and cultured them ex vivo to collect plasmablast-derived polyclonal antibodies (PPAb). The PPAb contained secreted IgG and IgA, which was approximately 0.2ng per antibody secreting cell. Influenza-specific IgG and IgA binding activity was detected in PPAb at dilutions up to 10(5) by ELISA. The ratio of the titers of influenza-specific IgA to IgG by ELISA was 4-fold higher in PPAb than in day 28 post-vaccination sera, suggesting that vaccine-induced IgA is enriched in PPAb compared to sera. Functional activity was also detected in PPAb as determined by microneutralization and hemagglutination inhibition assays. In addition to bulk B cell cultures, we also cultured plasmablast subsets sorted by cell surface markers to generate PPAb. These results suggest that PPAb better reflects the mucosal IgA response than serum samples. Since PPAb are exclusively produced by recently activated B cells, it allows assessing vaccine-induced antibody response without interference from pre-existing cross-reactive serum antibodies and permits an assessment of antibody

  2. Sequence-Specific Modifications Enhance the Broad-Spectrum Antiviral Response Activated by RIG-I Agonists

    Science.gov (United States)

    Chiang, Cindy; Beljanski, Vladimir; Yin, Kevin; Olagnier, David; Ben Yebdri, Fethia; Steel, Courtney; Goulet, Marie-Line; DeFilippis, Victor R.; Streblow, Daniel N.; Haddad, Elias K.; Trautmann, Lydie; Ross, Ted; Lin, Rongtuan

    2015-01-01

    ABSTRACT The cytosolic RIG-I (retinoic acid-inducible gene I) receptor plays a pivotal role in the initiation of the immune response against RNA virus infection by recognizing short 5′-triphosphate (5′ppp)-containing viral RNA and activating the host antiviral innate response. In the present study, we generated novel 5′ppp RIG-I agonists of varieous lengths, structures, and sequences and evaluated the generation of the antiviral and inflammatory responses in human epithelial A549 cells, human innate immune primary cells, and murine models of influenza and chikungunya viral pathogenesis. A 99-nucleotide, uridine-rich hairpin 5′pppRNA termed M8 stimulated an extensive and robust interferon response compared to other modified 5′pppRNA structures, RIG-I aptamers, or poly(I·C). Interestingly, manipulation of the primary RNA sequence alone was sufficient to modulate antiviral activity and inflammatory response, in a manner dependent exclusively on RIG-I and independent of MDA5 and TLR3. Both prophylactic and therapeutic administration of M8 effectively inhibited influenza virus and dengue virus replication in vitro. Furthermore, multiple strains of influenza virus that were resistant to oseltamivir, an FDA-approved therapeutic treatment for influenza, were highly sensitive to inhibition by M8. Finally, prophylactic M8 treatment in vivo prolonged survival and reduced lung viral titers of mice challenged with influenza virus, as well as reducing chikungunya virus-associated foot swelling and viral load. Altogether, these results demonstrate that 5′pppRNA can be rationally designed to achieve a maximal RIG-I-mediated protective antiviral response against human-pathogenic RNA viruses. IMPORTANCE The development of novel therapeutics to treat human-pathogenic RNA viral infections is an important goal to reduce spread of infection and to improve human health and safety. This study investigated the design of an RNA agonist with enhanced antiviral and inflammatory

  3. LSm14A Plays a Critical Role in Antiviral Immune Responses by Regulating MITA Level in a Cell-Specific Manner.

    Science.gov (United States)

    Liu, Tian-Tian; Yang, Qing; Li, Mi; Zhong, Bo; Ran, Yong; Liu, Li-Li; Yang, Yan; Wang, Yan-Yi; Shu, Hong-Bing

    2016-06-15

    Viral infection triggers induction of antiviral cytokines and effectors, which are critical mediators of innate antiviral immune response. It has been shown that the processing body-associated protein LSm14A is involved in the induction of antiviral cytokines in cell lines but in vivo evidence is lacking. By generating LSm14A-deficient mice, in this study, we show that LSm14A plays a critical and specific role in the induction of antiviral cytokines in dendritic cells (DCs) but not in macrophages and fibroblasts. Induction of antiviral cytokines triggered by the DNA viruses HSV-1 and murid herpesvirus 68 and the RNA virus vesicular stomatitis virus but not Sendai virus was impaired in Lsm14a(-/-) DCs, which is correlated to the functions of the adaptor protein MITA/STING in the antiviral signaling pathways. LSm14A deficiency specifically downregulated MITA/STING level in DCs by impairing its nuclear mRNA precursor processing and subsequently impaired antiviral innate and adaptive immune responses. Our findings reveal a nuclear mRNA precursor processing and cell-specific regulatory mechanism of antiviral immune responses. Copyright © 2016 by The American Association of Immunologists, Inc.

  4. Primary Liver Diffuse Large B-Cell Lymphoma following Complete Response for Hepatitis C Infection after Direct Antiviral Therapy.

    Science.gov (United States)

    Andrade, Xavier A; Paz, Luis H; Nassar, Mo''ath; Oramas, Diana M; Fuentes, Harry E; Kovarik, Paula; Mishra, Satya; Singh, Anshu

    2018-01-01

    Hepatitis C infection is highly prevalent worldwide and has a well-known association with B-cell lymphoid malignancies. Antiviral therapy has successfully decreased the rate of liver cirrhosis and improved the outcome in patients with hepatitis C-associated lymphomas. However, although there are a few case reports of aggressive lymphomas after successful hepatitis C therapy, the mechanism behind this association remains unclear. We present the case of a 55-year-old man with chronic hepatitis C infection and liver cirrhosis who received antiviral therapy with sofosbuvir and ribavirin and achieved a sustained complete virological response. One year after successful therapy, there was an unexplained decline of his liver function and atypical liver nodularity, which led to the diagnosis of a primary liver diffuse large B-cell lymphoma. We review the evidence supporting possible mechanisms of lymphomagenesis after successful hepatitis C therapy, particularly involving late "second-hit" mutations after viral-induced DNA damage and antiviral therapy facilitating the emergence of latent malignant B-cell clones by decreasing local inflammation and immune surveillance. More reports may help elucidate any association between hepatitis C antiviral therapy and late lymphoid malignancies. © 2018 S. Karger AG, Basel.

  5. Antibody and B cell responses to Plasmodium sporozoites

    Directory of Open Access Journals (Sweden)

    Johanna N Dups

    2014-11-01

    Full Text Available Antibodies are capable of blocking infection of the liver by Plasmodium sporozoites. Accordingly the induction of anti-sporozoite antibodies is a major aim of various vaccine approaches to malaria. In recent years our knowledge of the specificity and quantities of antibodies required for protection has been greatly expanded by clinical trials of various whole sporozoite and subunit vaccines. Moreover, the development of humanized mouse models and transgenic parasites have also aided our ability to assess the specificity of antibodies and their ability to block infection. Nonetheless, considerable gaps remain in our knowledge - in particular in understanding what antigens are recognized by infection blocking antibodies and in knowing how we can induce robust, long-lived antibody responses. Maintaining high levels of circulating antibodies is likely to be of primary importance, as antibodies must block infection in the short time it takes for sporozoites to reach the liver from the skin. It is clear that a better understanding of the development of protective B cell-mediated immunity will aid the development and refinement of malaria vaccines.

  6. Neonatal plasmacytoid dendritic cells (pDCs display subset variation but can elicit potent anti-viral innate responses.

    Directory of Open Access Journals (Sweden)

    Xiaoming Zhang

    Full Text Available Neonates are highly susceptible to infectious diseases and defective antiviral pDC immune responses have been proposed to contribute to this phenomenon. Isolated cord blood pDCs innately responded to a variety of TLR7 and TLR9 dependent viruses, including influenza A virus (IAV, human immunodeficiency virus (HIV or herpes-simplex virus (HSV by efficiently producing IFN-α, TNF-α as well as chemokines. Interestingly, following activation by CpGA, but not viruses, cord pDCs tend to survive less efficiently. We found that a hallmark of pDCs in neonates is an extended CD2+pDCs compartment compared to adult pDCs without affecting the antiviral IFN-α response. Within CD2+pDCs, we identified a subpopulation expressing CD5 and responsible for IL-12p40 production, however this population is significantly decreased in cord blood compared to adult blood. Therefore, neonatal pDCs clearly display variation in phenotype and subset composition, but without major consequences for their antiviral responses.

  7. Detection of Aleutian mink disease virus DNA and antiviral antibodies in American mink (Neovison vison) 10 days postinoculation.

    Science.gov (United States)

    Farid, A Hossain; Hussain, Irshad; Arju, Irin

    2015-05-01

    Early detection of infection by the Aleutian mink disease virus (AMDV; Carnivore amdoparvovirus 1) by polymerase chain reaction (PCR) or counterimmunoelectrophoresis (CIEP) has important ramifications in virus eradication programs. A spleen homogenate containing a local isolate of AMDV was injected intraperitoneally into black (n = 44) and sapphire (n = 12) American mink (Neovison vison). Animals were euthanized 10 days postinoculation and anti-AMDV antibodies and AMDV DNA were tested in plasma and 7 organs by CIEP and PCR, respectively. Viral DNA was detected in the plasma, spleen, lymph nodes, bone marrow, and lung samples of all inoculated mink, but was not detected in some small intestine, kidney, and liver samples. In contrast, antibodies were detected in the plasma of 3 sapphire (25.0%) and 19 black (43.2%) mink but not in any of the organs. The sensitivity of the CIEP test on plasma samples was 39.3%, implying that low levels of antibodies during the early stages of virus exposure resulted in failure to detect infection by the CIEP test. We concluded that CIEP is not a reliable test for early detection of AMDV infection in mink and that there were considerable differences among mink of each color type for production of detectable levels of antibodies. PCR tests on samples of saliva, rectal swabs, and feces did not produce consistent and reliable results. © 2015 The Author(s).

  8. Chicken MDA5 senses short double-stranded RNA with implications for antiviral response against avian influenza viruses in chicken.

    Science.gov (United States)

    Hayashi, Tsuyoshi; Watanabe, Chiaki; Suzuki, Yasushi; Tanikawa, Taichiro; Uchida, Yuko; Saito, Takehiko

    2014-01-01

    Mammalian melanoma differentiation-associated gene-5 (MDA5) and retinoic acid-inducible gene-I (RIG-I) selectively sense double-stranded RNA (dsRNA) according to length, as well as various RNA viruses to induce an antiviral response. RIG-I, which plays a predominant role in the induction of antiviral responses against influenza virus infection, has been considered to be lacking in chicken, putting the function of chicken MDA5 (chMDA5) under the spotlight. Here, we show that chMDA5, unlike mammalian MDA5, preferentially senses shorter dsRNA synthetic analogues, poly(I:C), in chicken DF-1 fibroblasts. A requirement for caspase activation and recruitment domains for chMDA5-mediated chicken interferon beta (chIFNβ) induction and its interaction with mitochondrial antiviral signaling proteins were demonstrated. We also found that chMDA5 is involved in chIFNβ induction against avian influenza virus infection. Our findings imply that chMDA5 compensates in part the function of RIG-I in chicken, and highlights the importance of chMDA5 in the innate immune response in chicken. © 2013 S. Karger AG, Basel.

  9. Antiviral Efficacy and Host Immune Response Induction during Sequential Treatment with SB 9200 Followed by Entecavir in Woodchucks.

    Directory of Open Access Journals (Sweden)

    Manasa Suresh

    Full Text Available SB 9200, an orally bioavailable dinucleotide, activates the viral sensor proteins, retinoic acid-inducible gene 1 (RIG-I and nucleotide-binding oligomerization domain-containing protein 2 (NOD2 causing the induction of the interferon (IFN signaling cascade for antiviral defense. The present study evaluated the overall antiviral response in woodchucks upon induction of immune response, first with SB 9200 followed by Entecavir (ETV versus reduction of viral burden with ETV followed by SB 9200 immunomodulation. Woodchucks chronically infected with woodchuck hepatitis virus (WHV were treated orally with SB 9200 (30 mg/kg/day and ETV (0.5 mg/kg/day. Group 1 received ETV for 4 weeks followed by SB 9200 for 12 weeks. Group 2 received SB 9200 for 12 weeks followed by ETV for 4 weeks. At the end of treatment in Group 2, average reductions of 6.4 log10 in serum WHV DNA and 3.3 log10 in WHV surface antigen were observed whereas in Group 1, average reductions of 4.2 log10 and 1.1 log10 in viremia and antigenemia were noted. Both groups demonstrated marked reductions in hepatic WHV nucleic acid levels which were more pronounced in Group 2. Following treatment cessation and the 8-week follow-up, recrudescence of viral replication was observed in Group 1 while viral relapse in Group 2 was significantly delayed. The antiviral effects observed in both groups were associated with temporally different induction of IFN-α, IFN-β, and IFN-stimulated genes in blood and liver. These results suggest that the induction of host immune responses by pretreatment with SB 9200 followed by ETV resulted in antiviral efficacy that was superior to that obtained using the strategy of viral reduction with ETV followed by immunomodulation.

  10. Contrasting antibody responses to intrasubtype superinfection with CRF02_AG.

    Directory of Open Access Journals (Sweden)

    Colleen R Courtney

    Full Text Available HIV superinfection describes the sequential infection of an individual with two or more unrelated HIV strains. Intersubtype superinfection has been shown to cause a broader and more potent heterologous neutralizing antibody response when compared to singly infected controls, yet the effects of intrasubtype superinfection remain controversial. Longitudinal samples were analyzed phylogenetically for pol and env regions using Next-Generation Sequencing and envelope cloning. The impact of CRF02_AG intrasubtype superinfection was assessed for heterologous neutralization and antibody binding responses. We compared two cases of CRF02_AG intrasubtype superinfection that revealed complete replacement of the initial virus by superinfecting CRF02_AG variants with signs of recombination. NYU6564, who became superinfected at an early time point, exhibited greater changes in antibody binding profiles and generated a more potent neutralizing antibody response post-superinfection compared to NYU6501. In contrast, superinfection occurred at a later time point in NYU6501 with strains harboring significantly longer V1V2 regions with no observable changes in neutralization patterns. Here we show that CRF02_AG intrasubtype superinfection can induce a cross-subtype neutralizing antibody response, and our data suggest timing and/or superinfecting viral envelope characteristics as contributing factors. These results highlight differential outcomes in intrasubtype superinfection and provide the first insight into cases with CRF02_AG, the fourth most prevalent HIV-1 strain worldwide.

  11. Focusing antibody responses against distraction and loss in diversity

    Science.gov (United States)

    Wang, Shenshen; Kardar, Mehran; Chakraborty, Arup

    Pathogens are complex and evolving fast. They have developed full ranges of disguises to divert immune responses and often manage to escape recognition and thereby outpace natural immunity. A prominent example is the scarce and staggered development of broadly neutralizing antibodies against highly mutable viruses. It remains unclear under what evolutionary conditions these exceptional antibodies could emerge and dominate the response. To address this challenge, we construct an individual-based stochastic model of the Darwinian evolution of antibody-producing immune cells. We consider complexity of viral epitopes, vary seeding diversity of the immune cell population, and allow a time varying population size and extinction - new aspects essential for designing a realistic vaccine. We show that various temporal statistics of antigenic environments would select distinct evolutionary paths that lead to predominantly non-neutralizing, strain-specific or broadly neutralizing antibody responses. We suggest strategies to focus antibody responses on the targeted vulnerability of the virus and confer selective advantage to cross-reactive lineages. This implies a new step toward an effective vaccine against rapidly mutating complex pathogens. This work is supported by NIH.

  12. Boosting antibody responses by targeting antigens to dendritic cells.

    Science.gov (United States)

    Caminschi, Irina; Shortman, Ken

    2012-02-01

    Delivering antigens directly to dendritic cells (DCs) in situ, by injecting antigens coupled to antibodies specific for DC surface molecules, is a promising strategy for enhancing vaccine efficacy. Enhanced cytotoxic T cell responses are obtained if an adjuvant is co-administered to activate the DC. Such DC targeting is also effective at enhancing humoral immunity, via the generation of T follicular helper cells. Depending on the DC surface molecule targeted, antibody production can be enhanced even in the absence of adjuvants. In the case of Clec9A as the DC surface target, enhanced antibody production is a consequence of the DC-restricted expression of the target molecule. Few other cells absorb the antigen-antibody construct, therefore, it persists in the bloodstream, allowing sustained antigen presentation, even by non-activated DCs. Copyright © 2011 Elsevier Ltd. All rights reserved.

  13. Severe antiphospholipid antibody syndrome - response to plasmapheresis and rituximab.

    Science.gov (United States)

    Gkogkolou, Paraskevi; Ehrchen, Jan; Goerge, Tobias

    2017-09-01

    Antiphospholipid antibody syndrome (APS) is a systemic autoimmune disease characterized by arterial and/or venous thrombosis, recurrent abortions and detection of antiphospholipid antibodies. In fulminant cases, involvement of multiple organs can lead to significant morbidity and even fatal outcomes, so that a rapid, interdisciplinary treatment is needed. Here, we describe the case of a 39-year-old woman with a severe hard-to-treat APS with arterial occlusion and progressive skin necrosis, who was successfully treated with a combination therapy with plasmapheresis and rituximab. The treatment led to complete remission of the skin lesions for over a year. Clinical response correlated with a long-lasting reduction of antiphospholipid antibodies and B-cell depletion. This case demonstrates the use of antiphospholipid antibodies for monitoring APS-activity and shows that this severe vascular disease requires rigorous therapeutic approaches.

  14. Accessory factors of cytoplasmic viral RNA sensors required for antiviral innate immune response

    Directory of Open Access Journals (Sweden)

    Hiroyuki eOshiumi

    2016-05-01

    Full Text Available Type I interferon (IFN induces many antiviral factors in host cells. RIG-I-like receptors (RLRs are cytoplasmic viral RNA sensors that trigger the signal to induce the innate immune response that includes type I IFN production. RIG-I and MDA5 are RLRs that form nucleoprotein filaments along viral double-stranded RNA, resulting in the activation of MAVS adaptor molecule. The MAVS protein forms a prion-like aggregation structure, leading to type I IFN production. RIG-I and MDA5 undergo post-translational modification. TRIM25 and Riplet ubiquitin ligases deliver a K63-linked polyubiquitin moiety to the RIG-I N-terminal caspase activation and recruitment domains (CARDs and C-terminal region; the polyubiquitin chain then stabilizes the two-CARD tetramer structure required for MAVS assembly. MDA5 activation is regulated by phosphorylation. RIOK3 is a protein kinase that phosphorylates the MDA5 protein in a steady state, and PP1α/γ dephosphorylate this protein, resulting in its activation. RIG-I and MDA5 require cytoplasmic RNA helicases for their efficient activation. LGP2, another RLR, is an RNA helicase involved in RLR signaling. This protein does not possess N-terminal CARDs and thus cannot trigger downstream signaling by itself. Recent studies have revealed that this protein modulates MDA5 filament formation, resulting in enhanced type I IFN production. Several other cytoplasmic RNA helicases are involved in RLR signaling. DDX3, DHX29, DHX36, and DDX60 RNA helicases have been reported to be involved in RLR-mediated type I IFN production after viral infection. However, the underlying mechanism is largely unknown. Future studies are required to reveal the role of RNA helicases in the RLR signaling pathway.

  15. Ranitidine improves postoperative suppression of antibody response to preoperative vaccination

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen; Hammer, J H; Moesgaard, F

    1992-01-01

    The effect of the histamine-2 receptor antagonist ranitidine (100 mg intravenously every 12 hours for 72 hours) on postoperative serum antibody responses to preoperative immunization with six limit of flocculation tetanus toxoid and six limit of flocculation diphtheria toxoid was assessed...... and antidiphtheria toxoid were drawn before skin incision and on postoperative days 1, 3, 5, 7, 10, 14, 21, and 28. Ranitidine significantly increased the postoperative antibody response to tetanus toxoid, (p less than 0.01) and insignificantly increased that to diphtheria toxoid vaccination (p less than 0...

  16. Human antibody and antigen response to IncA antibody of Chlamydia trachomatis.

    Science.gov (United States)

    Tsai, P Y; Hsu, M C; Huang, C T; Li, S Y

    2007-01-01

    The high prevalence of C. trachomatis worldwide has underscored the importance of identifying specific immunogenic antigens in facilitating diagnosis as well as vaccine development. The aim of this study is to evaluate IncA antibody and antigen production in natural human infections. Our temporal expression study showed that IncA transcription and protein expression could be detected as early as 4 hours after the start of infection. Antibody responses could be detected in urine and genital swab samples from C. trachomatis-positive patients. It is especially interesting to note that the IncA antigen could be detected in urine. In conclusion, we have identified IncA as an important antigen in human. The potential applicability of the IncA antibody or antigen in the diagnosis as well as to vaccine development for C. trachomatis is also discussed.

  17. Provider-patient in-office discussions of response to hepatitis C antiviral therapy and impact on patient comprehension.

    Science.gov (United States)

    Hamilton, Heidi E; Nelson, Meaghan; Martin, Paul; Cotler, Scott J

    2006-04-01

    Providers need to communicate projected response rates effectively to enable patients with hepatitis C virus to make informed decisions about therapy. This study used interactional sociolinguistics (1) to evaluate how gastroenterologists and allied health professionals communicate information regarding response rates to antiviral therapy, (2) to determine how these discussions relate to where the patient is in the continuum of evaluation and treatment, (3) to assess whether patients were aligned with providers in their perceptions of response rates after office visits, and (4) to identify factors that improve provider-patient alignment. Gastroenterologists, allied health professionals, and patients with hepatitis C virus were videotaped and audiotaped during regularly scheduled visits. Postvisit interviews were conducted separately with patients and providers. Visits and postvisits were transcribed and analyzed using validated sociolinguistic techniques. The phase of hepatitis C virus treatment shaped the benchmarks of response talk, although across the treatment continuum providers overwhelmingly made strategic use of positive statistics, providing motivation. In postvisit interviews, 55% of providers and patients were aligned on response rates. Patients with a favorable outcome and patients who asked response-related questions in the visit were more likely to be aligned with providers. Areas identified for improvement included the tendency to discuss response rates before an individualized assessment could be made, balancing motivation and accuracy, and assessing the patient's perspective before delivering any bad news, if necessary. Sociolinguistic analysis provides a powerful tool to evaluate provider-patient interactions and to identify ways to improve in-office communication regarding antiviral therapy.

  18. Maternal and infant antibody response to meningococcal vaccination in pregnancy.

    Science.gov (United States)

    de Andrade Carvalho, A; Giampaglia, C M; Kimura, H; de Pereira, O A; Farhat, C K; Neves, J C; Prandini, R; da Silva Carvalho, E; Zarvos, A M

    1977-10-15

    The antigenic capacity of a mixed vaccine prepared with polysaccharides of meningococcus groups A and C, the placental transfer of antibodies, and the persistence of positive titres in the infant were evaluated in 21 pregnant women and their offspring during an epidemic of meningitis in São Paulo, Brazil; and antibody response was assessed in 29 infants vaccinated at less than 6 months of age. Antibodies were detected by passive haemagglutination; the high titres found and the high frequency of positive results are thought to be due to the use of a more sensitive technique. Increased antibody titres were found in most women, and there was evidence for passive transfer to the newborn, especially with regard to antibody type C. However, passive transfer was irregular, and the presence of antibodies in the mother did not guarantee their presence in the child. Passive transfer lasted for only 2-5 months. Vaccination in children under 6 months of age had poor results; only 1 child seroconverted.

  19. Development of Broadly Neutralizing Antibody Mimitopes for Characterization of CRF01_AE HIV-1 Antibody Responses

    Directory of Open Access Journals (Sweden)

    Jesse V. Schoen

    2017-10-01

    Full Text Available Mapping humoral immune responses to HIV-1 over the course of natural infection is important in understanding epitope exposure in relation to elicitation of broadly neutralizing antibodies (bNAbs, which is considered imperative for effective vaccine design. When analyzing HIV-specific immune responses, the antibody binding profiles may be a correlate for functional antibody activity. In this study, we utilized phage display technology to identify novel mimitopes that may represent Env epitope structures bound by bNAbs directed at V1V2 and V3 domains, CD4 binding site (CD4bs and the membrane proximal external region (MPER of Env. Mimitope sequence motifs were determined for each bNAb epitope. Given the ongoing vaccine development efforts in Thailand, these mimitopes that represent CD4bs and MPER epitopes were used to map immune responses of HIV-1 CRF01_AE-infected individuals with known neutralizing responses from two distinct time periods, 1996-98 and 2012-15. The more contemporary cohort showed an increase in binding breadth with binding observed for all MPER and CD4bs mimitopes, while the older cohort showed only 75% recognition of the CD4bs mimitopes and no MPER mimotope binding. Furthermore, mimitope binding profiles correlated significantly with magnitude (p=0.0036 and breadth (p=0.0358 of neutralization of a multi-subtype Tier 1 panel of pseudoviruses. These results highlight the utility of this mimitope mapping approach for detecting human plasma IgG-specificities that target known neutralizing antibody epitopes, and may also provide an indication of the plasticity of antibody binding within HIV-1 Env neutralization determinants.

  20. A single social defeat transiently suppresses the anti-viral immune response in mice

    NARCIS (Netherlands)

    de Groot, Johanna; Milligen, Florine J. van; Moonen-Leusen, Bernie W.M.; Thomas, Gethin; Koolhaas, Jaap M.

    1999-01-01

    Most of the studies dealing with effects of stress on anti-viral immunity have been carried out with stressors that are of long duration and that bear little relationship to the nature of the species. In this paper, we investigated the effect of a stressor mimicking real-life situations more

  1. Cross-Linking of a CD4-Mimetic Miniprotein with HIV-1 Env gp140 Alters Kinetics and Specificities of Antibody Responses against HIV-1 Env in Macaques.

    Science.gov (United States)

    Shen, Xiaoying; Bogers, Willy M; Yates, Nicole L; Ferrari, Guido; Dey, Antu K; Williams, William T; Jaeger, Frederick H; Wiehe, Kevin; Sawant, Sheetal; Alam, S Munir; LaBranche, Celia C; Montefiori, David C; Martin, Loic; Srivastava, Indresh; Heeney, Jonathan; Barnett, Susan W; Tomaras, Georgia D

    2017-10-01

    Evaluation of the epitope specificities, locations (systemic or mucosal), and effector functions of antibodies elicited by novel HIV-1 immunogens engineered to improve exposure of specific epitopes is critical for HIV-1 vaccine development. Utilizing an array of humoral assays, we evaluated the magnitudes, epitope specificities, avidities, and functions of systemic and mucosal immune responses elicited by a vaccine regimen containing Env cross-linked to a CD4-mimetic miniprotein (gp140-M64U1) in rhesus macaques. Cross-linking of gp140 Env to M64U1 resulted in earlier increases of both the magnitude and avidity of the IgG binding response than those with Env protein alone. Notably, IgG binding responses at an early time point correlated with antibody-dependent cellular cytotoxicity (ADCC) function at the peak immunity time point, which was higher for the cross-linked Env group than for the Env group. In addition, the cross-linked Env group developed higher IgG responses against a linear epitope in the gp120 C1 region of the HIV-1 envelope glycoprotein. These data demonstrate that structural modification of the HIV-1 envelope immunogen by cross-linking of gp140 with the CD4-mimetic M64U1 elicited an earlier increase of binding antibody responses and altered the specificity of the IgG responses, correlating with the rise of subsequent antibody-mediated antiviral functions. IMPORTANCE The development of an efficacious HIV-1 vaccine remains a global priority to prevent new cases of HIV-1 infection. Of the six HIV-1 efficacy trials to date, only one has demonstrated partial efficacy, and immune correlate analysis of that trial revealed a role for binding antibodies and antibody Fc-mediated effector functions. New HIV-1 envelope immunogens are being engineered to selectively expose the most vulnerable and conserved sites on the HIV-1 envelope, with the goal of eliciting antiviral antibodies. Evaluation of the humoral responses elicited by these novel immunogen designs in

  2. Evaluation of antibody response in mice against avian influenza A

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Biosciences; Volume 39; Issue 3. Evaluation of antibody response in mice against avian influenza A (H5N1) strain neuraminidase expressed in yeast Pichia pastoris. Murugan Subathra Ponsekaran Santhakumar Mangamoori Lakshmi Narasu Syed Sultan Beevi Sunil K Lal. Articles Volume 39 ...

  3. Antibody response to routine measles vaccination among a ...

    African Journals Online (AJOL)

    Background: Despite a global decline in mortality and morbidity from measles in the last decade, outbreaks continue to occur in some parts of the world including Nigeria. Objective: To determine antibody response to routine measles vaccination in Nigerian children and evaluate vaccine potency. Methods: A prospective ...

  4. Antibody response to routine measles vaccination among a ...

    African Journals Online (AJOL)

    owner

    2013-02-08

    Feb 8, 2013 ... Abstract Background: Despite a global decline in mortality and morbidity from measles in the last decade, outbreaks continue to occur in some parts of the world including Nigeria. Objective: To determine antibody response to routine measles vacci- nation in Nigerian children and evaluate vaccine potency.

  5. Peripheral dendritic cells are essential for both the innate and adaptive antiviral immune responses in the central nervous system

    International Nuclear Information System (INIS)

    Steel, Christina D.; Hahto, Suzanne M.; Ciavarra, Richard P.

    2009-01-01

    Intranasal application of vesicular stomatitis virus (VSV) causes acute infection of the central nervous system (CNS). However, VSV encephalitis is not invariably fatal, suggesting that the CNS may contain a professional antigen-presenting cell (APC) capable of inducing or propagating a protective antiviral immune response. To examine this possibility, we first characterized the cellular elements that infiltrate the brain as well as the activation status of resident microglia in the brains of normal and transgenic mice acutely ablated of peripheral dendritic cells (DCs) in vivo. VSV encephalitis was characterized by a pronounced infiltrate of myeloid cells (CD45 high CD11b + ) and CD8 + T cells containing a subset that was specific for the immunodominant VSV nuclear protein epitope. This T cell response correlated temporally with a rapid and sustained upregulation of MHC class I expression on microglia, whereas class II expression was markedly delayed. Ablation of peripheral DCs profoundly inhibited the inflammatory response as well as infiltration of virus-specific CD8 + T cells. Unexpectedly, the VSV-induced interferon-gamma (IFN-γ) response in the CNS remained intact in DC-deficient mice. Thus, both the inflammatory and certain components of the adaptive primary antiviral immune response in the CNS are dependent on peripheral DCs in vivo.

  6. Duration of antibody response following vaccination against feline immunodeficiency virus.

    Science.gov (United States)

    Westman, Mark E; Malik, Richard; Hall, Evelyn; Harris, Matthew; Hosie, Margaret J; Norris, Jacqueline M

    2017-10-01

    Objectives Recently, two point-of-care (PoC) feline immunodeficiency virus (FIV) antibody test kits (Witness and Anigen Rapid) were reported as being able to differentiate FIV-vaccinated from FIV-infected cats at a single time point, irrespective of the gap between testing and last vaccination (0-7 years). The aim of the current study was to investigate systematically anti-FIV antibody production over time in response to the recommended primary FIV vaccination series. Methods First, residual plasma from the original study was tested using a laboratory-based ELISA to determine whether negative results with PoC testing were due to reduced as opposed to absent antibodies to gp40. Second, a prospective study was performed using immunologically naive client-owned kittens and cats given a primary FIV vaccination series using a commercially available inactivated whole cell/inactivated whole virus vaccine (Fel-O-Vax FIV, three subcutaneous injections at 4 week intervals) and tested systematically (up to 11 times) over 6 months, using four commercially available PoC FIV antibody kits (SNAP FIV/FeLV Combo [detects antibodies to p15/p24], Witness FeLV/FIV [gp40], Anigen Rapid FIV/FeLV [p24/gp40] and VetScan FeLV/FIV Rapid [p24]). Results The laboratory-based ELISA showed cats from the original study vaccinated within the previous 0-15 months had detectable levels of antibodies to gp40, despite testing negative with two kits that use gp40 as a capture antigen (Witness and Anigen Rapid kits). The prospective study showed that antibody testing with SNAP Combo and VetScan Rapid was positive in all cats 2 weeks after the second primary FIV vaccination, and remained positive for the duration of the study (12/12 and 10/12 cats positive, respectively). Antibody testing with Witness and Anigen Rapid was also positive in a high proportion of cats 2 weeks after the second primary FIV vaccination (8/12 and 7/12, respectively), but antibody levels declined below the level of detection in

  7. Comparisons of the effect of naturally acquired maternal pertussis antibodies and antenatal vaccination induced maternal tetanus antibodies on infant's antibody secreting lymphocyte responses and circulating plasma antibody

    Science.gov (United States)

    The goal of this study was to explore the effects of trans-placental tetanus toxoid (TT) and pertussis (PT) antibodies on an infant's response to vaccination in the context of antenatal immunization with tetanus but not with pertussis. 38 mothers received a single dose of TT vaccine during pregnancy...

  8. Antiviral immunity in marine molluscs.

    Science.gov (United States)

    Green, Timothy J; Raftos, David; Speck, Peter; Montagnani, Caroline

    2015-09-01

    Marine molluscs, like all living organisms, are constantly exposed to viruses and have evolved efficient antiviral defences. We review here recent developments in molluscan antiviral immunity against viruses belonging to the order Herpesvirales. Emerging results suggest an interferon-like response and autophagy are involved in the antiviral defence of bivalves to viral infection. Multi-functional plasma proteins from gastropods and bivalves have been identified to have broad-spectrum antiviral activity against mammalian viruses. The antiviral defences present in molluscs can be enhanced by genetic selection, as shown by the presence of oyster strains specifically resistant to ostreid herpesvirus type 1. Whether varying amounts or different isoforms of these antiviral plasma proteins contributes to genetic resistance is worthy of further research. Other evolutionarily conserved antiviral mechanisms, such as RNA interference and apoptosis, still need further characterization.

  9. Enhancement of anamnestic immunospecific antibody response in orally immunized chickens

    DEFF Research Database (Denmark)

    Mayo, Susan; Carlsson, Hans-Erik; Zagon, Andrea

    2008-01-01

    Production of immunospecific egg yolk antibodies (IgY antibodies) in egg laying hens through oral immunization is an attractive alternative to conventional antibody production in mammals for economic reasons as well as for animal welfare reasons. Oral immunization results in a systemic humoral...... response, but oral booster immunizations lack efficiency. The aim of the present study was to develop immunization schemes in which the concentration of immunospecific IgY would increase following oral booster immunizations. Two groups of egg laying hens (5 in each group) were immunized orally (each...... and one oral dose with BSA+RV. The eggs of the chickens in this group had a significantly higher immunospecific anti BSA IgY-concentration than did any of the eggs from the orally immunized chickens. One of the immunization regimes (immunizations in weeks 1, 7 and 18) clearly included a booster effect...

  10. CD49b, a major marker of regulatory T-cells type 1, predicts the response to antiviral therapy of recurrent hepatitis C after liver transplantation.

    Science.gov (United States)

    Fabien, Stenard; Olivier, Morales; Khaldoun, Ghazal; Vivian, Viallon; Lynda, Aoudjehane; Laurissa, Ouaguia; Gautier, Goormachtigh; Yvon, Calmus; Nadira, Delhem; Filomena, Conti

    2014-01-01

    The TRANSPEG study was a prospective study to assess the efficacy of antiviral therapy in patients with a recurrent hepatitis C virus (HCV) after liver transplantation. The influence of regulatory T-cells (Tregs) on the response to antiviral therapy was analyzed. Patients were considered as a function of their sustained virological response (SVR) at 18 months after treatment initiation. A transcriptomic analysis was performed to assess Treg markers (Tr1 and FoxP3(+)) in serum, PBMC, and liver biopsies. 100 patients had been included in the TRANSPEG study. Data from 27 of these patients were available. The results showed that the expression of CD49b (a predominant marker of Tr1) before the introduction of antiviral therapy was significantly associated with SVR. Responders displayed lower serum levels of CD49b than nonresponders (P antiviral therapy. This data suggests that CD49b may be a marker of the failure of the immune response and antiviral therapy during HCV recurrence. The assessment of CD49b could help to select patients who require earlier and more intensive antiviral therapy.

  11. A dual vaccine against influenza & Alzheimer's disease failed to enhance anti-β-amyloid antibody responses in mice with pre-existing virus specific memory.

    Science.gov (United States)

    Davtyan, Hayk; Ghochikyan, Anahit; Hovakimyan, Armine; Davtyan, Arpine; Cadagan, Richard; Marleau, Annette M; Albrecht, Randy A; García-Sastre, Adolfo; Agadjanyan, Michael G

    2014-12-15

    Novel dual vaccine, WSN-Aβ(1-10), based on the recombinant influenza virus, expressing immunodominant B-cell epitope of β-amyloid, simultaneously induced therapeutically potent anti-Aβ and anti-influenza antibodies. In this study we showed that boosting of WSN-WT primed mice with WSN-Aβ(1-10) enhances anti-viral, but fails to induce anti-Aβ antibody responses. This inhibition is associated with expression of Aβ(1-10) within the context of an inactivated influenza virus vaccine. These results demonstrate that the use of an inactivated influenza virus as a carrier for AD vaccine may not be applicable due to the possible inhibition of anti-Aβ antibody response in individuals previously vaccinated or infected with influenza. Copyright © 2014 Elsevier B.V. All rights reserved.

  12. CARMA3 Is a Host Factor Regulating the Balance of Inflammatory and Antiviral Responses against Viral Infection

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    Changying Jiang

    2016-03-01

    Full Text Available Host response to RNA virus infection is sensed by RNA sensors such as RIG-I, which induces MAVS-mediated NF-κB and IRF3 activation to promote inflammatory and antiviral responses, respectively. Here, we have found that CARMA3, a scaffold protein previously shown to mediate NF-κB activation induced by GPCR and EGFR, positively regulates MAVS-induced NF-κB activation. However, our data suggest that CARMA3 sequesters MAVS from forming high-molecular-weight aggregates, thereby suppressing TBK1/IRF3 activation. Interestingly, following NF-κB activation upon virus infection, CARMA3 is targeted for proteasome-dependent degradation, which releases MAVS to activate IRF3. When challenged with vesicular stomatitis virus or influenza A virus, CARMA3-deficient mice showed reduced disease symptoms compared to those of wild-type mice as a result of less inflammation and a stronger ability to clear infected virus. Altogether, our results reveal the role of CARMA3 in regulating the balance of host antiviral and pro-inflammatory responses against RNA virus infection.

  13. Effect of maternal antibodies and pig age on the antibody response after vaccination against Glässers disease.

    Science.gov (United States)

    Pomorska-Mól, Małgorzata; Markowska-Daniel, Iwona; Rachubik, Jarosław; Pejsak, Zygmunt

    2011-08-01

    The influence of age and maternal antibodies on the development and duration of postvaccinal antibody response against Glässer's disease were investigated. Pigs born to immune (MDA-positive) and non-immune (MDA-negative) sows were vaccinated with inactivated vaccine. Vaccination was done according to three different protocols: at 1 and 4, at 2 and 5 or at 4 and 7 weeks of age. There were also two control groups for MDA-negative and MDA-positive pigs. The level of Haemophilus parasuis (Hps) specific antibodies were determined using commercial ELISA test. No serological responses were seen in any of the groups after the first vaccination. Maternally derived antibodies (MDA) against Hps were above the positive level until approximately 3 weeks of life in MDA-positive pigs. In those pigs the strongest postvaccinal humoral response was observed in piglets vaccinated at 4 and 7 weeks of age. In the remaining MDA-positive piglets only slight seroconversion was noted but levels of antibodies never exceeded values considered as positive. All MDA-negative pigs produced Hps-specific antibodies after the second vaccination. The results of the present study indicated that MDA may alter the development and duration of active postvaccinal antibody response. Age of pigs at the moment of vaccination was not associated with the significant differences in the magnitude of antibody response, however influenced the kinetics of decline of Hps-specific antibodies.

  14. Novel Role for Protein Inhibitor of Activated STAT 4 (PIAS4) in the Restriction of Herpes Simplex Virus 1 by the Cellular Intrinsic Antiviral Immune Response.

    Science.gov (United States)

    Conn, Kristen L; Wasson, Peter; McFarlane, Steven; Tong, Lily; Brown, James R; Grant, Kyle G; Domingues, Patricia; Boutell, Chris

    2016-05-01

    Small ubiquitin-like modifier (SUMO) is used by the intrinsic antiviral immune response to restrict viral pathogens, such as herpes simplex virus 1 (HSV-1). Despite characterization of the host factors that rely on SUMOylation to exert their antiviral effects, the enzymes that mediate these SUMOylation events remain to be defined. We show that unconjugated SUMO levels are largely maintained throughout infection regardless of the presence of ICP0, the HSV-1 SUMO-targeted ubiquitin ligase. Moreover, in the absence of ICP0, high-molecular-weight SUMO-conjugated proteins do not accumulate if HSV-1 DNA does not replicate. These data highlight the continued importance for SUMO signaling throughout infection. We show that the SUMO ligase protein inhibitor of activated STAT 4 (PIAS4) is upregulated during HSV-1 infection and localizes to nuclear domains that contain viral DNA. PIAS4 is recruited to sites associated with HSV-1 genome entry through SUMO interaction motif (SIM)-dependent mechanisms that are destabilized by ICP0. In contrast, PIAS4 accumulates in replication compartments through SIM-independent mechanisms irrespective of ICP0 expression. Depletion of PIAS4 enhances the replication of ICP0-null mutant HSV-1, which is susceptible to restriction by the intrinsic antiviral immune response. The mechanisms of PIAS4-mediated restriction are synergistic with the restriction mechanisms of a characterized intrinsic antiviral factor, promyelocytic leukemia protein, and are antagonized by ICP0. We provide the first evidence that PIAS4 is an intrinsic antiviral factor. This novel role for PIAS4 in intrinsic antiviral immunity contrasts with the known roles of PIAS proteins as suppressors of innate immunity. Posttranslational modifications with small ubiquitin-like modifier (SUMO) proteins regulate multiple aspects of host immunity and viral replication. The protein inhibitor of activated STAT (PIAS) family of SUMO ligases is predominantly associated with the suppression of

  15. Accelerating Influenza Research: Vaccines, Antivirals, Immunomodulators and Monoclonal Antibodies. The Manufacture of a New Wild-Type H3N2 Virus for the Human Viral Challenge Model.

    Directory of Open Access Journals (Sweden)

    Daniel J Fullen

    Full Text Available Influenza and its associated diseases are a major cause of morbidity and mortality. The United States Advisory Committee on Immunization Practices recommends influenza vaccination for everyone over 6 months of age. The failure of the flu vaccine in 2014-2015 demonstrates the need for a model that allows the rapid development of novel antivirals, universal/intra-seasonal vaccines, immunomodulators, monoclonal antibodies and other novel treatments. To this end we manufactured a new H3N2 influenza virus in compliance with Good Manufacturing Practice for use in the Human Viral Challenge Model.We chose an H3N2 influenza subtype, rather than H1N1, given that this strain has the most substantial impact in terms of morbidity or mortality annually as described by the Centre for Disease Control. We first subjected the virus batch to rigorous adventitious agent testing, confirmed the virus to be wild-type by Sanger sequencing and determined the virus titres appropriate for human use via the established ferret model. We built on our previous experience with other H3N2 and H1N1 viruses to develop this unique model.We conducted an initial safety and characterisation study in healthy adult volunteers, utilising our unique clinical quarantine facility in London, UK. In this study we demonstrated this new influenza (H3N2 challenge virus to be both safe and pathogenic with an appropriate level of disease in volunteers. Furthermore, by inoculating volunteers with a range of different inoculum titres, we established the minimum infectious titre required to achieve reproducible disease whilst ensuring a sensitive model that can be translated to design of subsequent field based studies.ClinicalTrials.gov NCT02525055.

  16. Antibody B cell responses in HIV-1 infection.

    Science.gov (United States)

    Mouquet, Hugo

    2014-11-01

    In rare cases, B cells can supply HIV-1-infected individuals with unconventional antibodies equipped to neutralize the wide diversity of viral variants. Innovations in single-cell cloning, high-throughput sequencing, and structural biology methods have enabled the capture and thorough characterization of these exceptionally potent broadly neutralizing antibodies (bNAbs). Here, I review the recent findings in humoral responses to HIV-1, focusing on the interplay between naturally occurring bNAbs and the virus both at systemic and mucosal levels. In this context, I discuss how an improved understanding of bNAb generation may provide invaluable insight into the fundamental mechanisms governing adaptive B cell responses to viruses, and how this knowledge is currently contributing to the development of vaccine and therapeutic strategies against HIV-1. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Antibody response against gastrointestinal antigens in demyelinating diseases of the central nervous system

    DEFF Research Database (Denmark)

    Banati, M; Csecsei, P; Koszegi, E

    2013-01-01

    BACKGROUND: Antibodies against gastrointestinal antigens may indicate altered microbiota and immune responses in the gut. Recent experimental data suggest a connection between gastrointestinal immune responses and CNS autoimmunity. METHODS: Antibodies against gliadin, tissue transglutaminase (tTG...

  18. T-bet- and STAT4-dependent IL-33 receptor expression directly promotes antiviral Th1 cell responses.

    Science.gov (United States)

    Baumann, Claudia; Bonilla, Weldy V; Fröhlich, Anja; Helmstetter, Caroline; Peine, Michael; Hegazy, Ahmed N; Pinschewer, Daniel D; Löhning, Max

    2015-03-31

    During infection, the release of damage-associated molecular patterns, so-called "alarmins," orchestrates the immune response. The alarmin IL-33 plays a role in a wide range of pathologies. Upon release, IL-33 signals through its receptor ST2, which reportedly is expressed only on CD4(+) T cells of the Th2 and regulatory subsets. Here we show that Th1 effector cells also express ST2 upon differentiation in vitro and in vivo during lymphocytic choriomeningitis virus (LCMV) infection. The expression of ST2 on Th1 cells was transient, in contrast to constitutive ST2 expression on Th2 cells, and marked highly activated effector cells. ST2 expression on virus-specific Th1 cells depended on the Th1-associated transcription factors T-bet and STAT4. ST2 deficiency resulted in a T-cell-intrinsic impairment of LCMV-specific Th1 effector responses in both mixed bone marrow-chimeric mice and adoptive cell transfer experiments. ST2-deficient virus-specific CD4(+) T cells showed impaired expansion, Th1 effector differentiation, and antiviral cytokine production. Consequently, these cells mediated little virus-induced immunopathology. Thus, IL-33 acts as a critical and direct cofactor to drive antiviral Th1 effector cell activation, with implications for vaccination strategies and immunotherapeutic approaches.

  19. Autophagy Proteins in Viral Exocytosis and Anti-Viral Immune Responses

    Directory of Open Access Journals (Sweden)

    Christian Münz

    2017-10-01

    Full Text Available Abstract: Autophagy-related (Atg gene-encoded proteins were originally described for their crucial role in macroautophagy, a catabolic pathway for cytoplasmic constituent degradation in lysosomes. Recently it has become clear that modules of this machinery can also be used to influence endo- and exocytosis. This mini review discusses how these alternative Atg functions support virus replication and viral antigen presentation on major histocompatibility (MHC class I and II molecules. A better understanding of the modular use of the macroautophagy machinery might enable us to manipulate these alternative functions of Atg proteins during anti-viral therapies and to attenuate virus-induced immune pathologies.

  20. Human antibody responses to Schistosoma mansoni: does antigen directed, isotype restriction result in the production of blocking antibodies?

    Directory of Open Access Journals (Sweden)

    David W. Dunne

    1987-01-01

    Full Text Available After treatment young Kenyan schoolchildren are highly susceptible to reinfection with Schistosoma mansoni. Older children and adults are resistant to reinfection. There is no evidence that this age related resistance is due to a slow development of protective immunological mechanisms, rather, it appears that young children are susceptible because of the presence of blocking antibodies which decline with age, thus allowing the expression of protective responses. Correlations between antibody responses to different stages of the parasite life-cycle suggest that, in young children, antigen directed, isotype restriction of the response against cross-reactive polysaccharide egg antigens results in an ineffectual, or even blocking antibody response to the schistosomulum.

  1. Clonal analysis of a human antimouse antibody (HAMA) response.

    Science.gov (United States)

    Thorpe, S J; Turner, C; Heath, A; Feavers, I; Vatn, I; Natvig, J B; Thompson, K M

    2003-01-01

    Circulating human antimouse antibodies (HAMAs) directed to mouse immunoglobulin G (IgG) are clinically significant, compromising mouse antibody therapy and imaging, and interfering in immunological assays. To investigate the HAMA response, 20 stable cell lines secreting human monoclonal antibodies reactive with mouse IgG were established from a donor with a history of exposure to mice. Their subclass and domain specificities were established by solid-phase binding, indirect haemagglutination assays and immunoblotting, using Igs of known subclass and Ig fragments. The heavy-chain variable region gene usage was determined for 12 HAMAs. Eight HAMAs were IgM, 11 HAMAs were IgG4 and one HAMA was IgG1, indicating an IgG4-dominated response. All of the IgG HAMAs reacted with epitopes present on the Fc portion; one was subclass-specific, nine were subclass-restricted and two were pan-IgG-reactive. Measurement of their affinities gave dissociation constants typically in the nanomolar range. Seven and five HAMAs were derived from variable heavy-chain 3 (VH3) and VH1 gene segments, respectively. The IgG HAMAs used different VH segments to the IgM HAMAs. JH regions were coded by JH4 in eight HAMAs. DH segment usage appeared to be restricted in the IgM HAMAs. Two IgG HAMAs were clonally related. These monoclonal HAMAs are potentially useful as reagents for detecting mouse IgG and as reference reagents for the investigation of the HAMA response in patients undergoing mouse monoclonal antibody therapy and for the investigation of the influence of HAMAs on immunodiagnostic tests.

  2. Guanylate-binding protein 1 participates in cellular antiviral response to dengue virus

    Directory of Open Access Journals (Sweden)

    Pan Wen

    2012-11-01

    Full Text Available Abstract Background Dengue virus (DENV, the causative agent of human Dengue hemorrhagic fever, is a mosquito-borne virus found in tropical and sub-tropical regions around the world. Vaccines against DENV are currently unavailable. Guanylate-binding protein 1 (GBP1 is one of the Interferon (IFN stimulated genes (ISGs and has been shown important for host immune defense against various pathogens. However, the role of GBP1 during DENV infection remains unclarified. In this study, we evaluated the relevance of GBP1 to DENV infection in in vitro model. Findings Quantitative RT-PCR (qRT-PCR and Western blot showed that the expression of mouse Gbp1 was dramatically upregulated in DENV-infected RAW264.7 cells. The intracellular DENV loads were significantly higher in Gbp1 silenced cells compared with controls. The expression levels of selective anti-viral cytokines were decreased in Gbp1 siRNA treated cells, while the transcription factor activity of NF-κB was impaired upon GBP1 silencing during infection. Conclusions Our data suggested that GBP1 plays an antiviral role during DENV infection.

  3. HIV-1 proteins in infected cells determine the presentation of viral peptides by HLA class I and class II molecules and the nature of the cellular and humoral antiviral immune responses--a review.

    Science.gov (United States)

    Becker, Y

    1994-07-01

    The goals of molecular virology and immunology during the second half of the 20th century have been to provide the conceptual approaches and the tools for the development of safe and efficient virus vaccines for the human population. The success of the vaccination approach to prevent virus epidemics was attributed to the ability of inactivated and live virus vaccines to induce a humoral immune response and to produce antiviral neutralizing antibodies in the vaccinees. The successful development of antiviral vaccines and their application to most of the human population led to a marked decrease in virus epidemics around the globe. Despite this remarkable achievement, the developing epidemics of HIV-caused AIDS (accompanied by activation of latent herpesviruses in AIDS patients), epidemics of Dengue fever, and infections with respiratory syncytial virus may indicate that conventional approaches to the development of virus vaccines that induce antiviral humoral responses may not suffice. This may indicate that virus vaccines that induce a cellular immune response, leading to the destruction of virus-infected cells by CD8+ cytotoxic T cells (CTLs), may be needed. Antiviral CD8+ CTLs are induced by viral peptides presented within the peptide binding grooves of HLA class I molecules present on the surface of infected cells. Studies in the last decade provided an insight into the presentation of viral peptides by HLA class I molecules to CD8+ T cells. These studies are here reviewed, together with a review of the molecular events of virus replication, to obtain an overview of how viral peptides associate with the HLA class I molecules. A similar review is provided on the molecular pathway by which viral proteins, used as subunit vaccines or inactivated virus particles, are taken up by endosomes in the endosome pathway and are processed by proteolytic enzymes into peptides that interact with HLA class II molecules during their transport to the plasma membrane of antigen

  4. The antibody response against human and chimeric anti-TNF therapeutic antibodies primarily targets the TNF binding region

    NARCIS (Netherlands)

    van Schie, K. A.; Hart, M. H.; de Groot, E. R.; Kruithof, S.; Aarden, L. A.; Wolbink, G. J.; Rispens, T.

    2015-01-01

    In a subset of patients, anti tumour necrosis factor (TNF) therapeutic antibodies are immunogenic, resulting in the formation of antidrug antibodies (ADAs). Neutralising ADAs compete with TNF for its binding site and reduces the effective serum concentration, causing clinical non-response. It is

  5. Immunity to rhabdoviruses in rainbow trout: the antibody response

    DEFF Research Database (Denmark)

    Lorenzen, Niels; Lapatra, S.E.

    1999-01-01

    Interactions between host and pathogen, as in the case of fish pathogenic viruses, represent interesting models for analyses of the relationships between structure and function of the teleost immune system. Two salmonid rhabdoviruses, IHNV and VHSV, have received special attention due......, have demonstrated that rainbow trout can produce specific and highly functional antibodies that are able to neutralise virus pathogenicity in vitro as well as in vivo. The apparently more restricted antibody response to IHNV and VHSV antigens in fish compared to mammals could possibly be explained...... by different kinds of epitopes being differently immunogenic in fish and in mammals. Also, it may be assumed that the requirements for the assay-antigens in terms of antigenicity, may differ for mammals and fish. The present text includes an initial presentation of the pathogens, followed by basic and applied...

  6. Synergistic effects of thymoquinone and curcumin on immune response and anti-viral activity against avian influenza virus (H9N2) in turkeys.

    Science.gov (United States)

    Umar, S; Shah, M A A; Munir, M T; Yaqoob, M; Fiaz, M; Anjum, S; Kaboudi, K; Bouzouaia, M; Younus, M; Nisa, Q; Iqbal, M; Umar, W

    2016-07-01

    The main objective of this study was to determine the possible effects of thymoquinone (TQ) and curcumin (Cur) on immune-response and pathogenesis of H9N2 avian influenza virus (AIV) in turkeys. The experiment was performed on 75 non-vaccinated mixed-sex turkey poults, divided into 5 experimental groups (A, B, C, D, and E) of 15 birds each. Group A was kept as non-infected and a non-treated negative control (ctrl group) while group B was kept as infected and non-treated positive control (H9N2 group). Turkeys in groups A and B received normal commercial feed while turkeys in groups C and D received TQ, and Cur respectively, and group E concurrently received TQ and Cur from d one through the entire experiment period. All groups were challenged intra-nasally with H9N2 AIV (A/chicken/Pakistan/10RS3039-284-48/2010) at the fourth wk of age except group A. Infected turkeys showed clinical signs of different severity, showing the most prominent disease signs in turkeys in group B. All infected turkeys showed positive results for virus shedding; however, the pattern of virus shedding was different, and with turkeys in group B showing more pronounced virus secretion than the turkeys in the other groups receiving different levels of TQ and Cur. Moreover, significantly higher antibody titer against H9N2 AIV in turkeys shows the immunomodulatory nature of TQ and Cur. Similarly, increased cytokine gene expression suggests antiviral behavior of TQ and Cur especially in combination, leading to suppressed pathogenesis of H9N2 viruses. However, reduced virus shedding and enhanced immune responses were more pronounced in those turkeys receiving TQ and Cur concurrently. This study showed that supplements of TQ and Cur in combination would significantly enhance immune responsiveness and suppress pathogenicity of influenza viruses in turkeys. © 2016 Poultry Science Association Inc.

  7. Comparisons of the effect of naturally acquired maternal pertussis antibodies and antenatal vaccination induced maternal tetanus antibodies on infant's antibody secreting lymphocyte responses and circulating plasma antibody levels.

    Science.gov (United States)

    Ahmad, Shaikh Meshbahuddin; Alam, Jahangir; Afsar, Nure Alam; Huda, Nazmul; Kabir, Yearul; Qadri, Firdausi; Raqib, Rubhana; Stephensen, Charles B

    2016-04-02

    The goal of this study was to explore the effects of trans-placental tetanus toxoid (TT) and pertussis (PT) antibodies on an infant's response to vaccination in the context of antenatal immunization with tetanus but not with pertussis. 38 mothers received a single dose of TT vaccine during pregnancy. Infants received tetanus and pertussis vaccines at 6, 10 and 14 wk of age. TT and PT anti-IgG secretion by infant lymphocytes was measured at 15 wk. Plasma antibodies were measured at 6 wk (pre-vaccination), 15 wk and 1 y of age. Prior to vaccination, TT and PT antibody were detected in 94.6% and 15.2% of infants. At 15 wk anti-TT-IgG and anti-PT-IgG in plasma was increased by 7-9 fold over pre-vaccination levels, while at 1 y plasma anti-TT-IgG was decreased by approximately 5-fold from the peak and had returned to near the pre-vaccination level. At 1 y plasma anti-PT-IgG was decreased by 2-fold 1 yfrom the 15 wk level. However, 89.5% and 82.3% of infants at 1 y had protective levels of anti-TT and anti-PT IgG, respectively. Pre-vaccination plasma IgG levels were associated with lower vaccine-specific IgG secretion by infant lymphocytes at 15 wk (p < 0.10). This apparent inhibition was seen for anti-TT-IgG at both 15 wk (p < 0.05) and t 1 y (p < 0.10) of age. In summary, we report an apparent inhibitory effect of passively derived maternal antibody on an infants' own antibody response to the same vaccine. However, since the cut-off values for protective titers are low, infants had protective antibody levels throughout infancy.

  8. Response to antiviral therapy in haematopoietic stem cell transplant recipients with cytomegalovirus (CMV) reactivation according to the donor CMV serological status.

    Science.gov (United States)

    Servais, S; Dumontier, N; Biard, L; Schnepf, N; Resche-Rigon, M; Peffault de Latour, R; Scieux, C; Robin, M; Meunier, M; Xhaard, A; Sicre de Fontbrune, F; Le Goff, J; Socié, G; Simon, F; Mazeron, M-C

    2016-03-01

    Pre-emptive antiviral treatment efficiently prevents occurrence of cytomegalovirus (CMV) disease in allogeneic stem cell transplant recipients. However, successive treatment courses can be necessary. The current study was aimed at determining factors that could influence the response to antiviral treatment, in particular the donor CMV serostatus. A total of 147 consecutive CMV-seropositive recipients (R+) were included and prospectively monitored for 6 months after transplantation. Reactivation of CMV occurred in 111 patients, 61 of 78 with a CMV-positive donor (D+) and in 50 of 69 with a CMV-negative donor (D-) (p 0.45). Baseline viral loads and initial viral doubling times did not differ between D+/R+ and D-/R+. Fifteen D+/R+ and four D-/R+ had self-resolving CMV infections. A total of 92 patients received antiviral treatment and 81 (88%) had a significant decrease in CMV load under therapy. Repeated CMV episodes were observed in 67% of those and were significantly more frequent in D-/R+ than in D+/R+ (p antivirals were found in two D-/R+. Donor CMV serostatus influenced neither CMV reactivation occurrence nor the kinetics of CMV DNA load in the early phase of CMV replication but had a significant impact on response to antiviral therapy. Virological drug-resistance remained rare. Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  9. Keratinocyte antiviral response to Poly(dA:dT stimulation and papillomavirus infection in a canine model of X-linked severe combined immunodeficiency.

    Directory of Open Access Journals (Sweden)

    Jennifer A Luff

    Full Text Available X-linked severe combined immunodeficiency (XSCID is caused by a genetic mutation within the common gamma chain (γc, an essential component of the cytokine receptors for interleukin (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. XSCID patients are most commonly treated with bone marrow transplants (BMT to restore systemic immune function. However, BMT-XSCID humans and dogs remain at an increased risk for development of cutaneous papillomavirus (PV infections and their associated neoplasms, most typically cutaneous papillomas. Since basal keratinocytes are the target cell for the initial PV infection, we wanted to determine if canine XSCID keratinocytes have a diminished antiviral cytokine response to poly(dA:dT and canine papillomavirus-2 (CPV-2 upon initial infection. We performed quantitative RT-PCR for antiviral cytokines and downstream interferon stimulated genes (ISG on poly(dA:dT stimulated and CPV-2 infected monolayer keratinocyte cultures derived from XSCID and normal control dogs. We found that XSCID keratinocytes responded similarly to poly(dA:dT as normal keratinocytes by upregulating antiviral cytokines and ISGs. CPV-2 infection of both XSCID and normal keratinocytes did not result in upregulation of antiviral cytokines or ISGs at 2, 4, or 6 days post infection. These data suggest that the antiviral response to initial PV infection of basal keratinocytes is similar between XSCID and normal patients, and is not the likely source for the remaining immunodeficiency in XSCID patients.

  10. Keratinocyte antiviral response to Poly(dA:dT) stimulation and papillomavirus infection in a canine model of X-linked severe combined immunodeficiency.

    Science.gov (United States)

    Luff, Jennifer A; Yuan, Hang; Kennedy, Douglas; Schlegel, Richard; Felsburg, Peter; Moore, Peter F

    2014-01-01

    X-linked severe combined immunodeficiency (XSCID) is caused by a genetic mutation within the common gamma chain (γc), an essential component of the cytokine receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. XSCID patients are most commonly treated with bone marrow transplants (BMT) to restore systemic immune function. However, BMT-XSCID humans and dogs remain at an increased risk for development of cutaneous papillomavirus (PV) infections and their associated neoplasms, most typically cutaneous papillomas. Since basal keratinocytes are the target cell for the initial PV infection, we wanted to determine if canine XSCID keratinocytes have a diminished antiviral cytokine response to poly(dA:dT) and canine papillomavirus-2 (CPV-2) upon initial infection. We performed quantitative RT-PCR for antiviral cytokines and downstream interferon stimulated genes (ISG) on poly(dA:dT) stimulated and CPV-2 infected monolayer keratinocyte cultures derived from XSCID and normal control dogs. We found that XSCID keratinocytes responded similarly to poly(dA:dT) as normal keratinocytes by upregulating antiviral cytokines and ISGs. CPV-2 infection of both XSCID and normal keratinocytes did not result in upregulation of antiviral cytokines or ISGs at 2, 4, or 6 days post infection. These data suggest that the antiviral response to initial PV infection of basal keratinocytes is similar between XSCID and normal patients, and is not the likely source for the remaining immunodeficiency in XSCID patients.

  11. Cocoa Diet and Antibody Immune Response in Preclinical Studies

    Directory of Open Access Journals (Sweden)

    Mariona Camps-Bossacoma

    2017-06-01

    Full Text Available The ability of cocoa to interact with the immune system in vitro and in vivo has been described. In the latter context, a cocoa-enriched diet in healthy rats was able to modify the immune system’s functionality. This fact could be observed in the composition and functionality of lymphoid tissues, such as the thymus, spleen, and lymph nodes. Consequently, immune effector mechanisms, such as antibody synthesis, were modified. A cocoa-enriched diet in young rats was able to attenuate the serum levels of immunoglobulin (Ig G, IgM, and IgA and also the intestinal IgM and IgA secretion. Moreover, in immunized rats, the intake of cocoa decreased specific IgG1, IgG2a, IgG2c, and IgM concentrations in serum. This immune-regulator potential was then tested in disease models in which antibodies play a pathogenic role. A cocoa-enriched diet was able to partially prevent the synthesis of autoantibodies in a model of autoimmune arthritis in rats and was also able to protect against IgE and T helper 2-related antibody synthesis in two rat models of allergy. Likewise, a cocoa-enriched diet prevented an oral sensitization process in young rats. In this review, we will focus on the influence of cocoa on the acquired branch of the immune function. Therefore, we will focus on how a cocoa diet influences lymphocyte function both in the systemic and intestinal immune system. Likewise, its potential role in preventing some antibody-induced immune diseases is also included. Although further studies must characterize the particular cocoa components responsible for such effects and nutritional studies in humans need to be carried out, cocoa has potential as a nutraceutical agent in some hypersensitivity status.

  12. Unabated adenovirus replication following activation of the cGAS/STING-dependent antiviral response in human cells.

    Science.gov (United States)

    Lam, Eric; Falck-Pedersen, Erik

    2014-12-01

    The cGAS/STING DNA sensing complex has recently been established as a predominant pathogen recognition receptor (PRR) for DNA-directed type I interferon (IFN) innate immune activation. Using replication-defective adenovirus vectors and replication-competent wild-type adenovirus, we have modeled the influence of the cGAS/STING cascade in permissive human cell lines (A549, HeLa, ARPE19, and THP1). Wild-type adenovirus induced efficient early activation of the cGAS/STING cascade in a cell-specific manner. In all responsive cell lines, cGAS/STING short hairpin RNA (shRNA) knockdown resulted in a loss of TBK1 and interferon response factor 3 (IRF3) activation, a lack of beta interferon transcript induction, loss of interferon-dependent STAT1 activation, and diminished induction of interferon-stimulated genes (ISGs). Adenoviruses that infect through the coxsackievirus-adenovirus receptor (CAR) (Ad2 and Ad5) and the CD46 (Ad35) and desmoglein-2 (Ad7) viral receptors all induce the cGAS/STING/TBK1/IRF3 cascade. The magnitude of the IRF3/IFN/ISG antiviral response was strongly influenced by serotype, with Ad35>Ad7>Ad2. For each serotype, no enhancement of viral DNA replication or virus production occurred in cGAS or STING shRNA-targeted cell line pools. We found no replication advantage in permissive cell lines that do not trigger the cGAS/STING cascade following infection. The cGAS/STING/TBK1/IRF3 cascade was not a direct target of viral antihost strategies, and we found no evidence that Ad stimulation of the cGAS/STING DNA response had an impact on viral replication efficiency. This study shows for the first time that the cGAS DNA sensor directs a dominant IRF3/IFN/ISG antiviral response to adenovirus in human cell lines. Activation of cGAS occurs with viruses that infect through different high-affinity receptors (CAR, CD46, and desmoglein-2), and the magnitude of the cGAS/STING DNA response cascade is influenced by serotype-specific functions. Furthermore, activation of

  13. Serum and intestinal isotype antibody responses to Wa human rotavirus in gnotobiotic pigs are modulated by maternal antibodies.

    Science.gov (United States)

    Parreño, V; Hodgins, D C; de Arriba, L; Kang, S Y; Yuan, L; Ward, L A; Tô, T L; Saif, L J

    1999-06-01

    The effects of passive antibodies on protection and active immune responses to human rotavirus were studied in gnotobiotic pigs. Pigs were injected at birth with saline or sow serum of high (immunized) or low (control) antibody titre and subsets of pigs were fed colostrum and milk from immunized or control sows. Pigs were inoculated at 3-5 days of age and challenged at 21 days post-inoculation (p.i.) with virulent Wa human rotavirus. Pigs receiving immune serum with or without immune colostrum/milk were partially protected against diarrhoea and virus shedding after inoculation, but had significantly lower IgA antibody titres in serum and small intestinal contents at 21 days p.i. and lower protection rates after challenge compared with pigs given control or no maternal antibodies. IgG antibody titres were consistently higher in small than in large intestinal contents. Pigs given control serum with control colostrum/milk had lower rates of virus shedding after inoculation than those given control serum alone. In summary, high titres of circulating maternal antibodies with or without local (milk) antibodies provided passive protection after inoculation but suppressed active mucosal antibody responses. These findings may have implications for the use of live, oral rotavirus vaccines in breast-fed infants.

  14. Vaccine and Wild-Type Strains of Yellow Fever Virus Engage Distinct Entry Mechanisms and Differentially Stimulate Antiviral Immune Responses

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    Maria Dolores Fernandez-Garcia

    2016-02-01

    Full Text Available The live attenuated yellow fever virus (YFV vaccine 17D stands as a “gold standard” for a successful vaccine. 17D was developed empirically by passaging the wild-type Asibi strain in mouse and chicken embryo tissues. Despite its immense success, the molecular determinants for virulence attenuation and immunogenicity of the 17D vaccine are poorly understood. 17D evolved several mutations in its genome, most of which lie within the envelope (E protein. Given the major role played by the YFV E protein during virus entry, it has been hypothesized that the residues that diverge between the Asibi and 17D E proteins may be key determinants of attenuation. In this study, we define the process of YFV entry into target cells and investigate its implication in the activation of the antiviral cytokine response. We found that Asibi infects host cells exclusively via the classical clathrin-mediated endocytosis, while 17D exploits a clathrin-independent pathway for infectious entry. We demonstrate that the mutations in the 17D E protein acquired during the attenuation process are sufficient to explain the differential entry of Asibi versus 17D. Interestingly, we show that 17D binds to and infects host cells more efficiently than Asibi, which culminates in increased delivery of viral RNA into the cytosol and robust activation of the cytokine-mediated antiviral response. Overall, our study reveals that 17D vaccine and Asibi enter target cells through distinct mechanisms and highlights a link between 17D attenuation, virus entry, and immune activation.

  15. Elevation of intact and proteolytic fragments of acute phase proteins constitutes the earliest systemic antiviral response in HIV-1 infection.

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    Holger B Kramer

    2010-05-01

    Full Text Available The earliest immune responses activated in acute human immunodeficiency virus type 1 infection (AHI exert a critical influence on subsequent virus spread or containment. During this time frame, components of the innate immune system such as macrophages and DCs, NK cells, beta-defensins, complement and other anti-microbial factors, which have all been implicated in modulating HIV infection, may play particularly important roles. A proteomics-based screen was performed on a cohort from whom samples were available at time points prior to the earliest positive HIV detection. The ability of selected factors found to be elevated in the plasma during AHI to inhibit HIV-1 replication was analyzed using in vitro PBMC and DC infection models. Analysis of unique plasma donor panels spanning the eclipse and viral expansion phases revealed very early alterations in plasma proteins in AHI. Induction of acute phase protein serum amyloid A (A-SAA occurred as early as 5-7 days prior to the first detection of plasma viral RNA, considerably prior to any elevation in systemic cytokine levels. Furthermore, a proteolytic fragment of alpha-1-antitrypsin (AAT, termed virus inhibitory peptide (VIRIP, was observed in plasma coincident with viremia. Both A-SAA and VIRIP have anti-viral activity in vitro and quantitation of their plasma levels indicated that circulating concentrations are likely to be within the range of their inhibitory activity. Our results provide evidence for a first wave of host anti-viral defense occurring in the eclipse phase of AHI prior to systemic activation of other immune responses. Insights gained into the mechanism of action of acute-phase reactants and other innate molecules against HIV and how they are induced could be exploited for the future development of more efficient prophylactic vaccine strategies.

  16. Cell adhesion molecules and hyaluronic acid as markers of inflammation, fibrosis and response to antiviral therapy in chronic hepatitis C patients

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    Esther Granot

    2001-01-01

    Full Text Available Objective: Cell adhesion molecules (intracellular adhesion molecule-1 (ICAM-1, vascular cell adhesion molecule-1 (VCAM-1 and hyaluronic acid, markers of inflammation and fibrosis were monitored in hepatitis C patients to determine whether changes in plasma levels, during antiviral treatment, can predict long-term response to therapy.

  17. Depletion of elongation initiation factor 4E binding proteins by CRISPR/Cas9 genome editing enhances antiviral response in porcine cells

    Science.gov (United States)

    Type I interferons (IFN) are key mediators of the innate antiviral response in mammalian cells. Elongation initiation factor 4E binding proteins (4E-BPs) are translational controllers of interferon regulatory factor 7 (IRF7), the master regulator of IFN transcription. The role of 4EBPs in the negat...

  18. Antiviral Type I and Type III Interferon Responses in the Central Nervous System

    Science.gov (United States)

    Sorgeloos, Frédéric; Kreit, Marguerite; Hermant, Pascale; Lardinois, Cécile; Michiels, Thomas

    2013-01-01

    The central nervous system (CNS) harbors highly differentiated cells, such as neurons that are essential to coordinate the functions of complex organisms. This organ is partly protected by the blood-brain barrier (BBB) from toxic substances and pathogens carried in the bloodstream. Yet, neurotropic viruses can reach the CNS either by crossing the BBB after viremia, or by exploiting motile infected cells as Trojan horses, or by using axonal transport. Type I and type III interferons (IFNs) are cytokines that are critical to control early steps of viral infections. Deficiencies in the IFN pathway have been associated with fatal viral encephalitis both in humans and mice. Therefore, the IFN system provides an essential protection of the CNS against viral infections. Yet, basal activity of the IFN system appears to be low within the CNS, likely owing to the toxicity of IFN to this organ. Moreover, after viral infection, neurons and oligodendrocytes were reported to be relatively poor IFN producers and appear to keep some susceptibility to neurotropic viruses, even in the presence of IFN. This review addresses some trends and recent developments concerning the role of type I and type III IFNs in: i) preventing neuroinvasion and infection of CNS cells; ii) the identity of IFN-producing cells in the CNS; iii) the antiviral activity of ISGs; and iv) the activity of viral proteins of neurotropic viruses that target the IFN pathway. PMID:23503326

  19. Antiviral Type I and Type III Interferon Responses in the Central Nervous System

    Directory of Open Access Journals (Sweden)

    Thomas Michiels

    2013-03-01

    Full Text Available The central nervous system (CNS harbors highly differentiated cells, such as neurons that are essential to coordinate the functions of complex organisms. This organ is partly protected by the blood-brain barrier (BBB from toxic substances and pathogens carried in the bloodstream. Yet, neurotropic viruses can reach the CNS either by crossing the BBB after viremia, or by exploiting motile infected cells as Trojan horses, or by using axonal transport. Type I and type III interferons (IFNs are cytokines that are critical to control early steps of viral infections. Deficiencies in the IFN pathway have been associated with fatal viral encephalitis both in humans and mice. Therefore, the IFN system provides an essential protection of the CNS against viral infections. Yet, basal activity of the IFN system appears to be low within the CNS, likely owing to the toxicity of IFN to this organ. Moreover, after viral infection, neurons and oligodendrocytes were reported to be relatively poor IFN producers and appear to keep some susceptibility to neurotropic viruses, even in the presence of IFN. This review addresses some trends and recent developments concerning the role of type I and type III IFNs in: i preventing neuroinvasion and infection of CNS cells; ii the identity of IFN-producing cells in the CNS; iii the antiviral activity of ISGs; and iv the activity of viral proteins of neurotropic viruses that target the IFN pathway.

  20. Antiviral type I and type III interferon responses in the central nervous system.

    Science.gov (United States)

    Sorgeloos, Frédéric; Kreit, Marguerite; Hermant, Pascale; Lardinois, Cécile; Michiels, Thomas

    2013-03-15

    The central nervous system (CNS) harbors highly differentiated cells, such as neurons that are essential to coordinate the functions of complex organisms. This organ is partly protected by the blood-brain barrier (BBB) from toxic substances and pathogens carried in the bloodstream. Yet, neurotropic viruses can reach the CNS either by crossing the BBB after viremia, or by exploiting motile infected cells as Trojan horses, or by using axonal transport. Type I and type III interferons (IFNs) are cytokines that are critical to control early steps of viral infections. Deficiencies in the IFN pathway have been associated with fatal viral encephalitis both in humans and mice. Therefore, the IFN system provides an essential protection of the CNS against viral infections. Yet, basal activity of the IFN system appears to be low within the CNS, likely owing to the toxicity of IFN to this organ. Moreover, after viral infection, neurons and oligodendrocytes were reported to be relatively poor IFN producers and appear to keep some susceptibility to neurotropic viruses, even in the presence of IFN. This review addresses some trends and recent developments concerning the role of type I and type III IFNs in: i) preventing neuroinvasion and infection of CNS cells; ii) the identity of IFN-producing cells in the CNS; iii) the antiviral activity of ISGs; and iv) the activity of viral proteins of neurotropic viruses that target the IFN pathway.

  1. Mx Is Not Responsible for the Antiviral Activity of Interferon-α against Japanese Encephalitis Virus

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    Jing Zhou

    2017-01-01

    Full Text Available Mx proteins are interferon (IFN-induced dynamin-like GTPases that are present in all vertebrates and inhibit the replication of myriad viruses. However, the role Mx proteins play in IFN-mediated suppression of Japanese encephalitis virus (JEV infection is unknown. In this study, we set out to investigate the effects of Mx1 and Mx2 expression on the interferon-α (IFNα restriction of JEV replication. To evaluate whether the inhibitory activity of IFNα on JEV is dependent on Mx1 or Mx2, we knocked down Mx1 or Mx2 with siRNA in IFNα-treated PK-15 cells and BHK-21 cells, then challenged them with JEV; the production of progeny virus was assessed by plaque assay, RT-qPCR, and Western blotting. Our results demonstrated that depletion of Mx1 or Mx2 did not affect JEV restriction imposed by IFNα, although these two proteins were knocked down 66% and 79%, respectively. Accordingly, expression of exogenous Mx1 or Mx2 did not change the inhibitory activity of IFNα to JEV. In addition, even though virus-induced membranes were damaged by Brefeldin A (BFA, overexpressing porcine Mx1 or Mx2 did not inhibit JEV proliferation. We found that BFA inhibited JEV replication, not maturation, suggesting that BFA could be developed into a novel antiviral reagent. Collectively, our findings demonstrate that IFNα inhibits JEV infection by Mx-independent pathways.

  2. HIV-1, interferon and the interferon regulatory factor system: an interplay between induction, antiviral responses and viral evasion.

    Science.gov (United States)

    Marsili, Giulia; Remoli, Anna Lisa; Sgarbanti, Marco; Perrotti, Edvige; Fragale, Alessandra; Battistini, Angela

    2012-01-01

    Thirty years after the first isolation of the etiological agent of AIDS, the virus HIV-1 is still a major threat worldwide with millions of individuals currently infected. Although current combination therapies allow viral replication to be controlled, HIV-1 is not eradicated and persists in drug- and immune system-insensitive reservoirs and a cure is still lacking. Pathogens such as HIV-1 that cause chronic infections are able to adapt to the host in a manner that ensures long term residence and survival, via the evolution of numerous mechanisms that evade various aspects of the innate and adaptive immune response. One such mechanism is targeted to members of the interferon (IFN) regulatory factor (IRF) family of proteins. These transcription factors regulate a variety of biological processes including interferon induction, immune cell activation and downstream pattern recognition receptors (PRRs). HIV-1 renders IRFs harmless and hijacks them to its own advantage in order to facilitate its replication and evasion of immune responses. Type I interferon (IFN), the canonical antiviral innate response, can be induced in both acute and chronic HIV-1 infection in vivo, but in the majority of individuals this initial response is not protective and can contribute to disease progression. Type I IFN expression is largely inhibited in T cells and macrophages in order to successfully establish productive infection, whereas sustained IFN production by plasmacytoid dendritic cells is considered an important source of chronic immune activation, a hallmark to AIDS progression. Copyright © 2012 Elsevier Ltd. All rights reserved.

  3. Metabolic syndrome is associated with poor treatment response to antiviral therapy in chronic hepatitis C genotype 3 patients.

    Science.gov (United States)

    Aziz, Hafsa; Gill, Uzma; Raza, Abida; Gill, Muzaffar L

    2014-05-01

    Hepatitis C viral (HCV) infection is caused by an RNA virus. HCV infection is considered to induce systemic disease that causes steatosis, alters lipid metabolism, and results in metabolic syndrome. This study aimed to investigate the therapeutic outcome in HCV genotype 3 patients with metabolic syndrome. A total of 621 HCV-positive patients who visited the hospital for treatment were screened. Among these, 441 patients were enrolled for antiviral therapy. These enrolled patients were assessed for metabolic syndrome according to the International Diabetes Federation criteria. Group A included patients with metabolic syndrome and group B included patients without metabolic syndrome. All patients received peginterferon-α2a (180 μg/week) and ribavirin (10 mg/kg/day) for 6 months. The prevalence of metabolic syndrome in chronic HCV patients was 37.9%. We observed that metabolic syndrome was more common among female compared with male participants (43.9 vs. 28.8%, P=0.005). It was found that sustained virologic response (SVR) rates were significantly higher in the patients in group B (without metabolic syndrome) compared with the patients in group A who had metabolic syndrome (72.2 vs. 43.7%, Pmetabolic syndrome and a correlation of metabolic syndrome with nonresponse to antiviral therapy was observed. An interesting correlation among metabolic syndrome, age, and SVR was found: with age, SVR decreases, while metabolic syndrome increases. Metabolic syndrome has an influence on therapeutic outcomes in terms of SVR. Moreover, this information can identify patients who might have a low chance of attaining an SVR and a timely decision may protect the patients from the adverse effects of therapy.

  4. Nasally administered Lactobacillus rhamnosus strains differentially modulate respiratory antiviral immune responses and induce protection against respiratory syncytial virus infection.

    Science.gov (United States)

    Tomosada, Yohsuke; Chiba, Eriko; Zelaya, Hortensia; Takahashi, Takuya; Tsukida, Kohichiro; Kitazawa, Haruki; Alvarez, Susana; Villena, Julio

    2013-08-15

    Some studies have shown that nasally administered immunobiotics had the potential to improve the outcome of influenza virus infection. However, the capacity of immunobiotics to improve protection against respiratory syncytial virus (RSV) infection was not investigated before. The aims of this study were: a) to evaluate whether the nasal administration of Lactobacillus rhamnosus CRL1505 (Lr05) and L. rhamnosus CRL1506 (Lr06) are able to improve respiratory antiviral defenses and beneficially modulate the immune response triggered by TLR3/RIG-I activation; b) to investigate whether viability of Lr05 or Lr06 is indispensable to modulate respiratory immunity and; c) to evaluate the capacity of Lr05 and Lr06 to improve the resistance of infant mice against RSV infection. Nasally administered Lr05 and Lr06 differentially modulated the TLR3/RIG-I-triggered antiviral respiratory immune response. Lr06 administration significantly modulated the production of IFN-α, IFN-β and IL-6 in the response to poly(I:C) challenge, while nasal priming with Lr05 was more effective to improve levels of IFN-γ and IL-10. Both viable Lr05 and Lr06 strains increased the resistance of infant mice to RSV infection while only heat-killed Lr05 showed a protective effect similar to those observed with viable strains. The present work demonstrated that nasal administration of immunobiotics is able to beneficially modulate the immune response triggered by TLR3/RIG-I activation in the respiratory tract and to increase the resistance of mice to the challenge with RSV. Comparative studies using two Lactobacillus rhamnosus strains of the same origin and with similar technological properties showed that each strain has an specific immunoregulatory effect in the respiratory tract and that they differentially modulate the immune response after poly(I:C) or RSV challenges, conferring different degree of protection and using distinct immune mechanisms. We also demonstrated in this work that it is possible

  5. MERS-CoV Antibody Responses 1 Year after Symptom Onset, South Korea, 2015.

    Science.gov (United States)

    Choe, Pyoeng Gyun; Perera, R A P M; Park, Wan Beom; Song, Kyoung-Ho; Bang, Ji Hwan; Kim, Eu Suk; Kim, Hong Bin; Ko, Long Wei Ronald; Park, Sang Won; Kim, Nam-Joong; Lau, Eric H Y; Poon, Leo L M; Peiris, Malik; Oh, Myoung-Don

    2017-07-01

    We investigated the kinetics of the Middle East respiratory syndrome coronavirus (MERS-CoV) neutralizing and spike protein antibody titers over the course of 1 year in 11 patients who were confirmed by reverse transcription PCR to have been infected during the outbreak in South Korea in 2015. Robust antibody responses were detected in all survivors who had severe disease; responses remained detectable, albeit with some waning, for <1 year. The duration of viral RNA detection (but not viral load) in sputum significantly correlated with the antibody response magnitude. The MERS S1 ELISA antibody titers correlated well with the neutralizing antibody response. Antibody titers in 4 of 6 patients who had mild illness were undetectable even though most had evidence of pneumonia. This finding implies that MERS-CoV seroepidemiologic studies markedly underestimate the extent of mild and asymptomatic infection. Obtaining convalescent-phase plasma with high antibody titers to treat MERS will be challenging.

  6. Immunity to rhabdoviruses in rainbow trout: the antibody response

    DEFF Research Database (Denmark)

    Lorenzen, Niels; Lapatra, S.E.

    1999-01-01

    in detail so far. Analysis of the specificity of anti-virus trout antibodies has been complicated by a generally insufficient ability of the antibodies to bind the viral proteins in assays such as immunoblotting. However, other assays, specifically designed for detection of fish anti IHNV/VHSV antibodies...

  7. B cells and functional antibody responses to combat influenza

    Directory of Open Access Journals (Sweden)

    Giuseppe eLofano

    2015-06-01

    Full Text Available Vaccination against influenza (Flu is the most effective way to protect the population. Current vaccines provide protection by stimulating functional B- and T-cell responses, however, they are poorly immunogenic in particular segments of the population and need to be reformulated almost every year due to the genetic instability of the virus. Next generation Flu vaccines should be designed to induce cross-reactivity, confer protection against pandemic outbreaks, and promote long-lasting immune responses among individuals at higher risk of infection. Multiple strategies are being developed for the induction of broad functional humoral immunity, including the use of adjuvants, heterologous prime-boost strategies, and epitope-based antigen design. The basic approach is to mimic natural responses to influenza virus infection by promoting cross-reactive neutralizing antibodies that directly prevent the infection. This review provides an overview of the mechanisms underlying humoral responses to influenza vaccination or natural infection, and discusses promising strategies to control influenza virus.

  8. Depletion of elongation initiation factor 4E binding proteins by CRISPR/Cas9 enhances the antiviral response in porcine cells.

    Science.gov (United States)

    Ramírez-Carvajal, Lisbeth; Singh, Neetu; de los Santos, Teresa; Rodríguez, Luis L; Long, Charles R

    2016-01-01

    Type I interferons (IFNs) are key mediators of the innate antiviral response in mammalian cells. Elongation initiation factor 4E binding proteins (4E-BPs) are translational controllers of interferon regulatory factor 7 (IRF-7), the "master regulator" of IFN transcription. Previous studies have suggested that mouse cells depleted of 4E-BPs are more sensitive to IFNβ treatment and had lower viral loads as compared to wild type (WT) cells. However, such approach has not been tested as an antiviral strategy in livestock species. In this study, we tested the antiviral activity of porcine cells depleted of 4E-BP1 by a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) genome engineering system. We found that 4E-BP1 knockout (KO) porcine cells had increased expression of IFNα and β, IFN stimulated genes, and significant reduction in vesicular stomatitis virus titer as compare to WT cells. No phenotypical changes associated with CRISPR/Cas9 manipulation were observed in 4E-BP1 KO cells. This work highlights the use of the CRISPR/Cas9 system to enhance the antiviral response in porcine cells. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Regulation of Polysaccharide- and Protein- Specific Antibody Responses to Intact Extracellular Bacteria

    Science.gov (United States)

    2016-03-11

    1 | P a g e “Regulation of polysaccharide- and protein- specific antibody responses to intact extracellular bacteria ” By Swagata Kar...the thesis manuscript entitled: “Regulation of polysaccharide- and protein- specific antibody responses to intact extracellular bacteria ” Is...polysaccharide- and protein- specific antibody responses to intact extracellular bacteria ” Author: Swagata Kar, Ph.D., 2016. Uniformed Services University

  10. Dual antibody therapy to harness the innate anti-tumor immune response to enhance antibody targeting of tumors.

    Science.gov (United States)

    Chester, Cariad; Marabelle, Aurelien; Houot, Roch; Kohrt, Holbrook E

    2015-04-01

    Cancer immunotherapy is a rapidly evolving field that offers a novel paradigm for cancer treatment: therapies focus on enhancing the immune system's innate and adaptive anti-tumor response. Early immunotherapeutics have achieved impressive clinical outcomes and monoclonal antibodies are now integral to therapeutic strategies in a variety of cancers. However, only recently have antibodies targeting innate immune cells entered clinical development. Innate immune effector cells play important roles in generating and maintaining antitumor immunity. Antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) are important innate immune mechanisms for tumor eradication. These cytolytic processes are initiated by the detection of a tumor-targeting antibody and can be augmented by activating co-stimulatory pathways or blocking inhibitory signals on innate immune cells. The combination of FDA-approved monoclonal antibodies with innate effector-targeting antibodies has demonstrated potent preclinical therapeutic synergy and early-phase combinatorial clinical trials are ongoing. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Oral antibiotics enhance antibody responses to keyhole limpet hemocyanin in orally but not muscularly immunized chickens.

    Science.gov (United States)

    Murai, Atsushi; Kitahara, Kazuki; Okumura, Shouta; Kobayashi, Misato; Horio, Fumihiko

    2016-02-01

    Recent studies have emphasized the crucial role of gut microbiota in triggering and modulating immune response. We aimed to determine whether the modification of gut microbiota by oral co-administration of two antibiotics, ampicillin and neomycin, would lead to changes in the antibody response to antigens in chickens. Neonatal chickens were given or not given ampicillin and neomycin (0.25 and 0.5 g/L, respectively) in drinking water. At 2 weeks of age, the chicks were muscularly or orally immunized with antigenic keyhole limpet hemocyanin (KLH), and then serum anti-KLH antibody levels were examined by ELISA. In orally immunized chicks, oral antibiotics treatment enhanced antibody responses (IgM, IgA, IgY) by 2-3-fold compared with the antibiotics-free control, while the antibiotics did not enhance antibody responses in the muscularly immunized chicks. Concomitant with their enhancement of antibody responses, the oral antibiotics also lowered the Lactobacillus species in feces. Low doses of antibiotics (10-fold and 100-fold lower than the initial trial), which failed to change the fecal Lactobacillus population, did not modify any antibody responses when chicks were orally immunized with KLH. In conclusion, oral antibiotics treatment enhanced the antibody response to orally exposed antigens in chickens. This enhancement of antibody response was associated with a modification of the fecal Lactobacillus content, suggesting a possible link between gut microbiota and antibody response in chickens. © 2015 Japanese Society of Animal Science.

  12. Longitudinal study of interferon-gamma, serum antibody and milk antibody responses in cattle infected with Mycobacterium avium subsp paratuberculosis

    DEFF Research Database (Denmark)

    Huda, A.; Jungersen, Gregers; Lind, Peter

    2004-01-01

    -blood lymphocytes (IFN-gamma test), and measurement of antibody responses against M. paratuberculosis in serum and milk by an in-house absorbed ELISA. The IFN-gamma test diagnosed higher proportions of infected and exposed animals than the antibody ELISAs. The highest sensitivity of IFN-gamma test was in infected...... cattle of 2+ years of age. Receiver-operating characteristic (ROC) analyses supported the assumption that the IFN-gamma test had a better performance than antibody tests of animals of 1+ and 2+ years of age. However, for animals of 3+ years all tests performed equally well. Application of single sampling...... compared with repeated samplings showed better performance of the IFN-gamma test by repeated samplings, and the milk antibody ELISA in animals of 3+ years of age performed significantly better with repeated sampling compared with single sampling. In conclusion, the IFN-gamma test may be applied...

  13. MHC and non-MHC genes regulate elimination of lymphocytic choriomeningitis virus and antiviral cytotoxic T lymphocyte and delayed-type hypersensitivity mediating T lymphocyte activity in parallel

    DEFF Research Database (Denmark)

    Thomsen, Allan Randrup; Marker, O

    1989-01-01

    responsiveness measured in terms of virus-specific cytotoxicity and delayed-type hypersensitivity, whereas no correlation was found with regard to NK cell activity and antiviral antibody response. Analysis of F1 progeny between H-2 identical high and low responder strains showed that low responsiveness...

  14. Epstein-Barr Virus Specific Antibody Response in Multiple Sclerosis Patients during 21 Months of Natalizumab Treatment

    Directory of Open Access Journals (Sweden)

    Massimiliano Castellazzi

    2015-01-01

    Full Text Available Multiple sclerosis (MS is a chronic inflammatory autoimmune disease of the central nervous system. Natalizumab, a humanized anti-α4 integrin monoclonal antibody, is a highly effective treatment approved for MS. An association between MS and an exposure to Epstein-Barr Virus (EBV sustained by the levels of antiviral capsid antigen (VCA and anti-Epstein-Barr nuclear antigen-1 (EBNA-1 IgG has been described. Our goal was to verify the utility of EBV-specific IgG as a marker in Natalizumab treated MS. Twenty patients (17 female and 3 male in treatment with Natalizumab were enrolled. Serum levels of anti-VCA and anti-EBNA-1 IgG were determined and expressed as arbitrary units (AU before treatment and every three months for 21 months of therapy. Anti-VCA IgG levels were increased at the 15th month (235410 ± 196712 AU comparing with the 3rd (98146 ± 47145 AU and the 6th (109866 ± 52270 AU months of therapy p<0.05. No significant differences were found for serum anti-EBNA-1 IgG levels. Our data indicate that a transient, self-limited, EBV reactivation can occur in MS during Natalizumab therapy but our results do not support the use of serum EBV-specific antibody levels as biomarkers for monitoring therapeutic response to Natalizumab in the course of MS.

  15. Rapid decrease in hepatitis C viremia by direct acting antivirals improves the natural killer cell response to IFNα.

    Science.gov (United States)

    Serti, Elisavet; Park, Heiyoung; Keane, Meghan; O'Keefe, Ashley C; Rivera, Elenita; Liang, T Jake; Ghany, Marc; Rehermann, Barbara

    2017-04-01

    Chronic HCV infection is characterised by innate immune activation with increased interferon-stimulated genes (ISG) expression and by an altered phenotype of interferon-responsive natural killer (NK) cells. Here, we asked whether a rapid reduction in viremia by daclatasvir (DCV) and asunaprevir (ASV) improves the response to pegylated interferon (PegIFN) in patients who had previously failed a standard course of PegIFN/ribavirin (RBV) therapy. Twenty-two HCV-infected non-responders to previous PegIFN/RBV therapy were studied for IFN-responsiveness of NK cells during quadruple (QUAD) therapy with DCV, ASV, PegIFN and RBV. A direct comparison of early NK cell responses in PegIFN/RBV therapy and QUAD therapy was performed for seven patients using paired cryopreserved peripheral blood mononuclear cells (PBMC) from both treatment courses. As a validation cohort, nine DCV/ASV-treated patients were studied for their NK cell response to in vitro stimulation with IFNα. The 24 h virological response to QUAD therapy correlated with an increase in signal transducer and activator of transcription 1 (STAT1), phosphorylated STAT1 (pSTAT1) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in NK cells, and the STAT1/pSTAT1/TRAIL induction was greater during QUAD therapy than during previous PegIFN/RBV therapy. Successful QUAD therapy as well as successful IFN-free DCV/ASV regimen resulted in an improved functional NK cell response (degranulation and TRAIL expression) to in vitro stimulation with IFNα. IFN-responsiveness can be improved by inhibiting HCV replication and reducing the HCV-induced activation of the innate immune response. This may provide a rationale for clinical trials of a brief period of direct acting antiviral therapy followed by PegIFN/RBV therapy to reduce the overall treatment costs in low-income and middle-income countries. NCT01888900 and NCT00718172. Published by the BMJ Publishing Group Limited. For permission to use (where

  16. Immune response in mice to ingested soya protein: antibody production, oral tolerance and maternal transfer

    DEFF Research Database (Denmark)

    Christensen, Hanne Risager; Pedersen, Susanne Brix; Frøkiær, Hanne

    2004-01-01

    by ELISA, and to the presence of oral tolerance detected as a suppressed antibody and cell-proliferation response upon immunisation with soya protein. F0 mice generated soya-specific antibodies, while oral tolerance to the same soya proteins was also clearly induced. When F0 dams were transferred to soya...... antibody response in the offspring, bat in this case in the absence of oral tolerance. This indicates that, under certain conditions, factors involved in spontaneous antibody production can be transmitted from mother to offspring. Understanding the immune response to soya protein ingested under healthy...

  17. The interferon-inducible DNA-sensor protein IFI16: a key player in the antiviral response.

    Science.gov (United States)

    Dell'Oste, Valentina; Gatti, Deborah; Giorgio, Alessandro G; Gariglio, Marisa; Landolfo, Santo; De Andrea, Marco

    2015-01-01

    IFI16, a member of the IFN-inducible PYHIN-200 gene family, displays multifaceted activity due to its ability to bind to various target proteins and, in turn, modulate a variety cell functions including proliferation, differentiation, apoptosis/pyroptosis, senescence, and in? ammation. The last few year have seen major advances in our knowledge of IFI16 antiviral activity and its role in the immune response. Indeed, a wealth of evidence now supports a key role of IFI16 in the activation of innate immunity and viral restriction against Herpesviruses and Lentiviruses, such that the definition of IFI16 as a "restriction factor" is now widely accepted. However, most viruses have developed their own unique strategy to antagonize IFI16, leading to a modification or disruption of its function. This review summarizes our current understanding of how viral replication is sensed and then inhibited by IFI16 protein and the viral strategies employed to defeat this host defense mechanism. We will focus mainly on Herpesviruses, although recent discoveries on the role of IFI16 in lentiviral infection will also be considered.

  18. Comprehensive Profiling of Immune Responses in MARV Survivors Demonstrates Robust Th1-Skewing with Short Lived Neutralizing Antibody Responses

    Science.gov (United States)

    2017-03-29

    infection would be highly valuable for the evaluation of candidate vaccines that would seek to be broadly protective. Results and Discussion T...survivors (Sobarzo et al., 2015). Neutralizing antibody responses have been achieved through vaccination against MARV GP in mouse, guinea pig and...neutralizing antibodies elicited by vaccination against filoviruses is a coveted immune response, functions of non-neutralizing antibodies have been

  19. Virus-host interplay in chronic hepatitis B: Predicting response to immunomodulating antiviral therapy

    NARCIS (Netherlands)

    Jansen, L.

    2016-01-01

    It is of great importance to optimize pegylated interferon alfa (Peg-IFNα) based treatment strategies for patients with chronic Hepatitis B, as only a minority of patients achieves a favorable response. In Chapter 2, we describe a cohort of 92 patients with chronic Hepatitis B (44 HBeAg-positive and

  20. Porcine humoral immune responses to multiple injections of murine monoclonal antibodies

    DEFF Research Database (Denmark)

    Lohse, Louise; Nielsen, Jens; Kamstrup, Søren

    2005-01-01

    In humans and cattle, multiple injections of murine monoclonal antibodies (m-mAbs) induce anti-mouse antibody responses. The objectives of the present. study were to investigate whether a similar response could be seen when pigs were subjected to m-mAb therapy, and to study the kinetics of such a...

  1. Screening response to hepatitis c virus antibodies among diabetic ...

    African Journals Online (AJOL)

    ... is a debilitating disease condition, especially in individuals above 30 years of age, these results highlight the need for screening to determine the presence of HCV among diabetic patients. Keywords: Hepatitis C virus, antibodies, type 2 diabetics, antibodies, Nigeria International Journal of Natural and Applied Sciences, ...

  2. Evaluation of Vaccine-induced Antibody Responses: Impact of New Technologies

    Science.gov (United States)

    Zaccaro, Daniel J.; Wagener, Diane K.; Whisnant, Carol C.; Staats, Herman F.

    2013-01-01

    Host response to vaccination has historically been evaluated based on a change in antibody titer that compares the post-vaccination titer to the pre-vaccination titer. A four-fold or greater increase in antigen-specific antibody has been interpreted to indicate an increase in antibody production in response to vaccination. New technologies, such as the bead-based assays, provide investigators and clinicians with precise antibody levels (reported as concentration per mL) in ranges below and above those previously available through standard assays such as ELISA. Evaluations of bead assay data to determine host response to vaccination using fold change and absolute change, witha general linear models used to calculate adjusted statistics, present very different pictures of the antibody response when pre-vaccination antibody levels are low. Absolute changes in bead assay values, although not a standard computation, appears to more accurately reflect the host response to vaccination for those individuals with extremely low pre-vaccination antibody levels. Conversely, for these same individuals, fold change may be very high while post-vaccination antibodies do not achieve seroprotective levels. Absolute change provides an alternate method to characterize host response to vaccination, especially when pre-vaccination levels are very low, and may be useful in studies designed to determine associations between host genotypes and response to vaccination. PMID:23583812

  3. Characterization of isotypes of antibody response against leishmania parasite

    International Nuclear Information System (INIS)

    Elassad, Asma M.S.; Ghalib, Hashim W.; Younis, Saddia A.

    1994-01-01

    In this study an enzyme linked immunosorbent assay (ELIZA) was developed to detect IgG,IgM and IgA response in visceral leishmaniasis patients (VL) against L.donovain and L. major antigens compared to control groups; cutaneous leishmaniasis patients (CL), mucosal leishmaniasis patients (ML), patients with other tropical diseases and healthy controls.Highly specific IgG were found in VL patients with test specificity (93.7%) and sensitivity(93.4%). A moderate IgG were found in VL patients but non-specific while no IgA were detected in all studied groups. Also VL patients showed high specificity and sensitivity (95.2 and 96.6% respectively) against L.major antigen.The distribution of IgG subclasses (IgG1,IgG2,IgG3 and IgG4) antibodies in VL patients were assayed.IgG3 showed the highest specificity and sensitivity and titers followed by IgG1.Also the diagnostic value of ELIZA test for different leishmaniasis forms were discussed. (Author)

  4. Human immunological response to mouse monoclonal antibodies in the treatment or diagnosis of malignant diseases.

    Science.gov (United States)

    Van Kroonenburgh, M J; Pauwels, E K

    1988-11-01

    An overview of the literature is presented concerning the formation, detection, incidence and effect of the human immunoglobulin response on immunoscintigraphy. The following conclusions are drawn. The production of human anti-mouse antibodies (HAMAs) is associated with a diminished therapeutic response; adequate prevention of HAMA production is not yet possible; high HAMA titres give rise to rapid clearance of MoAb into the liver and marked reduction of tumour uptake which results in reduced image quality on immunoscintigraphy; alteration of antibody biodistribution is likely to be related to the in vivo formation of antibody-antibody complexes which could interfere with image quality when sequential imaging is carried out.

  5. Phase I clinical and pharmacological study of suppression of human antimouse antibody response to monoclonal antibody L6 by deoxyspergualin.

    Science.gov (United States)

    Dhingra, K; Fritsche, H; Murray, J L; LoBuglio, A F; Khazaeli, M B; Kelley, S; Tepper, M A; Grasela, D; Buzdar, A; Valero, V

    1995-07-15

    Development of human antimouse antibody (HAMA) is a major limiting factor in the application of murine mAb for clinical use. A novel immunomodulatory drug, deoxyspergualin (DSG), has shown potential to suppress antimouse antibody response in preclinical model systems. We conducted a Phase I trial to determine the effect of DSG on HAMA response to murine mAb L6 administered to patients with advanced cancers (in previous trials, this antibody elicited HAMA in two-thirds of the treated patients). L6 mAb was administered at a fixed dose of 200 mg/m2 on days 1-5. DSG was administered at doses of 50 mg/m2 [dose level (dl) 1] or 150 mg/m2 (dls II and III) on days 1-7. Treatment courses were repeated every 6 weeks (dls I and II) or every 3 weeks (dl III). HAMAs were quantitated by a commercially available ELISA assay (ImmuSTRIP; anti-isotypic antibodies) and a radiometric assay (antiisotypic and anti-idiotypic antibodies). Pharmacokinetics of L6 and DSG was also studied in all consenting patients. Among 24 evaluable patients, 2 patients developed detectable HAMAs using the ELISA (one each at dls I and II) after a median follow-up of 122 days (P = 0.0001 as compared to historical controls). Even in the two patients who developed HAMA, the HAMA levels were quite low (160 and 181 ng/ml; historical experience, 70-38,744 ng/ml). The radiometric assay detected anti-L6 antibodies in 13 patients (4, 6, and 3 at dls I-III, respectively) after a median of 82 days. The median highest anti-L6 antibody level was 129 ng/ml (range, 21-2150). The highest anti-L6 antibody level at dl III was only 44 ng/ml. The results suggest suppression of anti-idiotypic response also. No clinical antitumor activity was observed, and no significant changes in T4/T8 subsets or immunoglobulins occurred (suggesting a lack of generalized immunosuppression). We conclude that DSG can suppress HAMA response to L6. A starting dose of 150 mg/m2/day is recommended for Phase II trials to confirm this observation.

  6. An antiviral response directed by PKR phosphorylation of the RNA helicase A.

    Directory of Open Access Journals (Sweden)

    Anthony J Sadler

    2009-02-01

    Full Text Available The double-stranded RNA-activated protein kinase R (PKR is a key regulator of the innate immune response. Activation of PKR during viral infection culminates in phosphorylation of the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2alpha to inhibit protein translation. A broad range of regulatory functions has also been attributed to PKR. However, as few additional PKR substrates have been identified, the mechanisms remain unclear. Here, PKR is shown to interact with an essential RNA helicase, RHA. Moreover, RHA is identified as a substrate for PKR, with phosphorylation perturbing the association of the helicase with double-stranded RNA (dsRNA. Through this mechanism, PKR can modulate transcription, as revealed by its ability to prevent the capacity of RHA to catalyze transactivating response (TAR-mediated type 1 human immunodeficiency virus (HIV-1 gene regulation. Consequently, HIV-1 virions packaged in cells also expressing the decoy RHA peptides subsequently had enhanced infectivity. The data demonstrate interplay between key components of dsRNA metabolism, both connecting RHA to an important component of innate immunity and delineating an unanticipated role for PKR in RNA metabolism.

  7. "HIV-peplotion vaccine"--a novel approach to protection against AIDS by transepithelial transport of viral peptides to Langerhans cells for long-term antiviral CTL response. (A review).

    Science.gov (United States)

    Becker, Y

    1996-01-01

    Viral vaccines which stimulate the humoral immune response in humans have been successful in preventing most of the known virus diseases except dengue fever, respiratory syncytial virus infections and HIV-1-related AIDS. Burke [1] raised a concern that anti-HIV-1 antibodies may add a risk factor to immunized individuals infected with HIV-1. An approach to develop HIV-1 vaccines capable of stimulating anti-HIV-1 cytotoxic T cells requires an understanding of the importance of epidermal and epithelial Langerhans cells (LC). These cells are professional antigen-presenting cells which express HLA class I and class II molecules. Epithelial LC are present in a specific layer in the skin, genitalia and gut and may be accessible to viral antigens by local application in a vehicle for transepithelial transport of viral proteins/peptides (designated "HIV-1 Peplotion vaccine"). This approach is supported by the reports that HIV-1 gp160 in ISCOM induced MHC class I CTL response [2], mixing of cationic lipids with viral proteins formed complexes which were delivered to cell cytoplasm and the degraded peptides stimulated CTLs by HLA class I mechanism [3] and viral proteins encapsulated in pH-sensitive liposomes administered to LC induced primary antiviral CTLs [4]. Current studies in our laboratory deal with (a) selection of the vehicle for transepidermal transport of peptides and the conditions for selective uptake by epidermal LC [5]; (b) computer analysis of HIV-1 proteins to detect the putative proteolytic cleavage peptides with amino acid motifs which allow association with different known HLA class I haplotype molecules on LCs and synthetic peptide uptake from "without" by LC. The "HIV-1 Peplotion vaccine", when developed, will be useful for continual stimulation of antiviral CTLs in uninfected individuals and HIV-1 carriers by repetitive application to skin, genitalia and gut. The "Peplotion vaccine" will be applied by vaccinees, will be affordable for all human

  8. Induction of Antiviral Immune Response through Recognition of the Repeating Subunit Pattern of Viral Capsids Is Toll-Like Receptor 2 Dependent.

    Science.gov (United States)

    Shepardson, Kelly M; Schwarz, Benjamin; Larson, Kyle; Morton, Rachelle V; Avera, John; McCoy, Kimberly; Caffrey, Alayna; Harmsen, Ann; Douglas, Trevor; Rynda-Apple, Agnieszka

    2017-11-14

    Although viruses and viral capsids induce rapid immune responses, little is known about viral pathogen-associated molecular patterns (PAMPs) that are exhibited on their surface. Here, we demonstrate that the repeating protein subunit pattern common to most virus capsids is a molecular pattern that induces a Toll-like-receptor-2 (TLR2)-dependent antiviral immune response. This early antiviral immune response regulates the clearance of subsequent bacterial superinfections, which are a primary cause of morbidities associated with influenza virus infections. Utilizing this altered susceptibility to subsequent bacterial challenge as an outcome, we determined that multiple unrelated, empty, and replication-deficient capsids initiated early TLR2-dependent immune responses, similar to intact influenza virus or murine pneumovirus. These TLR2-mediated responses driven by the capsid were not dependent upon the capsid's shape, size, origin, or amino acid sequence. However, they were dependent upon the multisubunit arrangement of the capsid proteins, because unlike intact capsids, individual capsid subunits did not enhance bacterial clearance. Further, we demonstrated that even a linear microfilament protein built from repeating protein subunits (F-actin), but not its monomer (G-actin), induced similar kinetics of subsequent bacterial clearance as did virus capsid. However, although capsids and F-actin induced similar bacterial clearance, in macrophages they required distinct TLR2 heterodimers for this response (TLR2/6 or TLR2/1, respectively) and different phagocyte populations were involved in the execution of these responses in vivo Our results demonstrate that TLR2 responds to invading viral particles that are composed of repeating protein subunits, indicating that this common architecture of virus capsids is a previously unrecognized molecular pattern. IMPORTANCE Rapid and precise pathogen identification is critical for the initiation of pathogen-specific immune responses

  9. Abbott RealTime PCR assay is useful for evaluating virological response to antiviral treatment for chronic hepatitis C.

    Science.gov (United States)

    Ikezaki, Hiroaki; Furusyo, Norihiro; Ihara, Takeshi; Hayashi, Takeo; Ogawa, Eiichi; Toyoda, Kazuhiro; Taniai, Hiroaki; Kainuma, Mosaburo; Murata, Masayuki; Hayashi, Jun

    2011-12-01

    This study was done to evaluate the utility of the Abbott RealTime PCR assay (ART) for the monitoring of chronic hepatitis C patients. The serum samples of 183 patients infected with hepatitis C virus (HCV) genotype 1b who had completed a 48-week period of pegylated interferon (PEG-IFN) alpha-2b plus ribavirin treatment were prospectively analyzed. Serum HCV RNA levels were measured both by ART and by the Roche COBAS Amplicor Monitor test, version2.0 (CAM) at baseline and at weeks 4, 12, 24, 36, and 48 of treatment, and at 24 weeks after the end of treatment (EOT). A significant positive correlation of pretreatment HCV RNA levels was found between ART and CAM (r = 0.595, P HCV RNA level from the pretreatment level determined by ART in SVR patients was significantly higher than that in non-SVR patients at all time points tested. The logarithmic decline determined by CAM in SVR patients was significantly higher than that in non-SVR patients only at week 4, but there was no significant difference at other weeks. Of 124 patients who were HCV RNA-negative at EOT by ART, 58 (46.8%) had a relapse of viremia at 24 weeks after EOT, whereas 77 of 143 patients (53.8%) who were HCV RNA-negative at EOT by CAM had a relapse. The relapse rate was lower when determined by ART than by CAM, but not significantly so. ART is more useful than CAM for evaluating the virological response to antiviral treatment for chronic hepatitis C.

  10. Monoclonal antibodies for the measurement of class-specific antibody responses in the green turtle, Chelonia mydas.

    Science.gov (United States)

    Herbst, L H; Klein, P A

    1995-06-01

    Monoclonal antibodies (Mabs) were developed against the known immunoglobulin classes of the green turtle, Chelonia mydas. Plasma protein fractions enriched for 5.7S IgY, 7S IgY, and IgM turtle immunoglobulins were used to immunize Balb/c mice for hybridoma production and for hybridoma screening. Fifteen hybridomas produced Mabs with specificity for turtle immunoglobulins and for affinity purified dinitrophenol (DNP) specific turtle antibodies. Three Mabs specific for either turtle 5.7S IgY heavy chain (HL814), 7S IgY heavy chain (HL857), or IgM heavy chain (HL846) were purified and used in an enzyme-linked immunosorbent assay (ELISA) to measure antibody responses in two turtles immunized with 2,4-dinitrophenylated bovine serum albumin (DNP-BSA) over a 10 month period. In both turtles the 7S IgY antibody response developed within 5 weeks of the first inoculation and remained high over the following 9 months. The 5.7S IgY antibody response was detected in one turtle at 3-4 months and in the other at 8 months, and reached high levels in both individuals by 10 months. The IgM responses were difficult to interpret. One turtle had pre-inoculation anti-DNP IgM antibody in its plasma and the other developed only a weak, transient response at about 4 months. The class-specific antibody activity in immune turtle plasma could be strongly inhibited by soluble DNP or by rabbit anti-DNP specific antiserum, showing that these antibody responses were directed predominantly to the DNP hapten on the DNP-BSA antigen. Antibody responses to the BSA carrier could not be detected in either turtle over the course of the immunization. Mab HL814, specific for an epitope on the 5.7S green turtle immunoglobulin heavy chain, will be useful for characterizing the molecular relationships of 5.7S, 7S and IgM heavy chains and the role of 5.7S antibody in humoral immunity in this species. All anti-turtle Ig Mabs were screened against the plasma globulins of Loggerhead (Caretta caretta), Olive

  11. Immunoglobulin E Antileishmanial Antibody Response in Cutaneous Leishmaniasis

    Science.gov (United States)

    Sousa-Atta, Maria L. B.; Salamé, Gregório S.; D’Oliveira, Argemiro; Almeida, Roque P.; Atta, Ajax M.; Carvalho, Edgar M.

    2002-01-01

    High levels of antileishmanial immunoglobulin E (IgE) antibodies are associated with disease activity in visceral leishmaniasis. Herein, we report our observations about the relationship between antileishmanial IgE antibodies and clinical aspects of cutaneous leishmaniasis. This study was carried out with 45 patients (29 male and 16 female), with ages ranging from 11 to 48 years. All subjects were from an area to which leishmaniasis is endemic, Corte de Pedra (Bahia, Brazil), and the duration of the illness was ≤30 days. The patients were classified as positive or negative for IgE serology in enzyme-linked immunosorbent assay with leishmanial antigens. IgE antibodies were detected in 18 patients (optical density, 0.421 ± 0.30; 95% confidence interval, 0.27 to 0.57), and only 3 (17%) had more than one ulcer. In this group the diameter of Montenegro’s reaction was 18 ± 12.2 mm. In the group with negative IgE serology, 11 of 27 patients (48%) presented two or more cutaneous ulcers, and the mean of the skin test result was 9 ± 6.9 mm. There was a positive correlation between IgE antibody levels and Montenegro’s reaction size and an inverse correlation between IgE antileishmanial antibodies and the number of skin ulcers. The presence of antileishmanial IgE antibodies in cutaneous leishmaniasis may be a result of immunoregulatory events with clinical implications. PMID:11777837

  12. Different levels of natural antibodies in chickens divergently selected for specific antibody responses

    NARCIS (Netherlands)

    Parmentier, H.K.; Lammers, A.; Hoekman, J.J.; Vries Reilingh, de G.; Zaanen, I.T.A.; Savelkoul, H.F.J.

    2004-01-01

    We studied the presence of Natural antibodies in plasma samples from individual birds from selected chicken lines at young and old age. Binding, specificity, and relative affinity to various antigens were determined in plasma from non-immunized female chickens at 5 weeks of age, and in plasma

  13. In-Depth Analysis of the Antibody Response of Individuals Exposed to Primary Dengue Virus Infection

    Science.gov (United States)

    de Alwis, Ruklanthi; Beltramello, Martina; Messer, William B.; Sukupolvi-Petty, Soila; Wahala, Wahala M. P. B.; Kraus, Annette; Olivarez, Nicholas P.; Pham, Quang; Brian, James; Tsai, Wen-Yang; Wang, Wei-Kung; Halstead, Scott; Kliks, Srisakul; Diamond, Michael S.; Baric, Ralph; Lanzavecchia, Antonio; Sallusto, Federica; de Silva, Aravinda M.

    2011-01-01

    Humans who experience a primary dengue virus (DENV) infection develop antibodies that preferentially neutralize the homologous serotype responsible for infection. Affected individuals also generate cross-reactive antibodies against heterologous DENV serotypes, which are non-neutralizing. Dengue cross-reactive, non-neutralizing antibodies can enhance infection of Fc receptor bearing cells and, potentially, exacerbate disease. The actual binding sites of human antibody on the DENV particle are not well defined. We characterized the specificity and neutralization potency of polyclonal serum antibodies and memory B-cell derived monoclonal antibodies (hMAbs) from 2 individuals exposed to primary DENV infections. Most DENV-specific hMAbs were serotype cross-reactive and weakly neutralizing. Moreover, many hMAbs bound to the viral pre-membrane protein and other sites on the virus that were not preserved when the viral envelope protein was produced as a soluble, recombinant antigen (rE protein). Nonetheless, by modifying the screening procedure to detect rare antibodies that bound to rE, we were able to isolate and map human antibodies that strongly neutralized the homologous serotype of DENV. Our MAbs results indicate that, in these two individuals exposed to primary DENV infections, a small fraction of the total antibody response was responsible for virus neutralization. PMID:21713020

  14. Liver stiffness predicts the response to direct-acting antiviral-based therapy against chronic hepatitis C in cirrhotic patients.

    Science.gov (United States)

    Neukam, K; Morano-Amado, L E; Rivero-Juárez, A; Macías, J; Granados, R; Romero-Palacios, A; Márquez, M; Merino, D; Ortega, E; Alados-Arboledas, J C; Cucurull, J; Omar, M; Ryan-Murua, P; Pineda, J A

    2017-05-01

    The purpose of this investigation was to evaluate the impact of liver stiffness (LS) on the response to direct-acting antiviral (DAA)-based therapy against hepatitis C virus (HCV) infection in cirrhotic patients. Those patients included in two Spanish prospective cohorts of patients receiving therapy based on at least one DAA, who showed a baseline LS ≥ 12.5 kPa and who had reached the scheduled time point for sustained virological response evaluation 12 weeks after completing therapy (SVR12) were analysed. Pegylated interferon/ribavirin-based therapy plus an HCV NS3/4A protease inhibitor (PR-PI group) was administered to 198 subjects, while 146 received interferon-free regimens (IFN-free group). The numbers of patients with SVR12 according to an LS < 21 kPa versus ≥21 kPa were 59/99 (59.6%) versus 46/99 (46.5%) in the PR-PI group (p = 0.064) and 41/43 (95.3%) versus 90/103 (87.4%) in the IFN-free group (p = 0.232). Corresponding figures for the relapse rates in those who presented end-of-treatment response (ETR) were 3/62 (4.8%) versus 10/56 (17.9%, p = 0.024) and 1/42 (2.4%) versus 8/98 (8.2%, p = 0.278), respectively. In a multivariate analysis adjusted for age, sex and use of interferon, a baseline LS ≥ 21 kPa was identified as an independent predictor of relapse [adjusted odds ratio, AOR (95% confidence interval, CI): 4.228 (1.344-13.306); p = 0.014] in those patients with ETR. LS above 21 kPa is associated with higher rates of relapse to DAA-based therapy in HCV-infected patients with cirrhosis in clinical practice. LS could help us to tailor the duration and composition of DAA-based combinations in cirrhotic subjects, in order to minimise the likelihood of relapse.

  15. Vaccination of horses with Lyme vaccines for dogs induces short-lasting antibody responses.

    Science.gov (United States)

    Guarino, Cassandra; Asbie, Sanda; Rohde, Jennifer; Glaser, Amy; Wagner, Bettina

    2017-07-24

    Borrelia burgdorferi can induce Lyme disease. Approved Lyme vaccines for horses are currently not available. In an effort to protect horses, veterinarians are using Lyme vaccines licensed for dogs. However, data to assess the response of horses to, or determine the efficacy of this off-label vaccine use are missing. Here, antibodies against outer surface protein A (OspA), OspC, and OspF were quantified in diagnostic serum submissions from horses with a history of vaccination with canine Lyme vaccines. The results suggested that many horses respond with low and often short-lasting antibody responses. Subsequently, four experimental vaccination trials were performed. First, we investigated antibody responses to three canine vaccines in B. burgdorferi-naïve horses. One killed bacterin vaccine induced antibodies against OspC. OspA antibodies were low for all three vaccines and lasted less than 16weeks. The second trial tested the impact of the vaccine dose using the OspA/OspC inducing bacterin vaccine in horses. A 2mL dose produced higher OspA and OspC antibody values than a 1mL dose. However, the antibody response again quickly declined, independent of dose. Third, the horses were vaccinated with 2 doses of a recombinant OspA vaccine. Previous vaccination and/or environmental exposure enhanced the magnitude and longevity of the OspA antibody response to about 20weeks. Last, the influence of intramuscular versus subcutaneous vaccine administration was investigated for the recombinant OspA vaccine. OspA antibody responses were not influenced by injection route. The current work highlights that commercial Lyme vaccines for dogs induce only transient antibody responses in horses which can also be of low magnitude. Protection from infection with B. burgdorferi should not be automatically assumed after vaccinating horses with Lyme vaccines for dogs. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  16. The potential of antiviral agents to control classical swine fever: a modelling study.

    Science.gov (United States)

    Backer, Jantien A; Vrancken, Robert; Neyts, Johan; Goris, Nesya

    2013-09-01

    Classical swine fever (CSF) represents a continuous threat to pig populations that are free of disease without vaccination. When CSF virus is introduced, the minimal control strategy imposed by the EU is often insufficient to mitigate the epidemic. Additional measures such as preemptive culling encounter ethical objections, whereas emergency vaccination leads to prolonged export restrictions. Antiviral agents, however, provide instantaneous protection without inducing an antibody response. The use of antiviral agents to contain CSF epidemics is studied with a model describing within- and between-herd virus transmission. Epidemics are simulated in a densely populated livestock area in The Netherlands, with farms of varying sizes and pig types (finishers, piglets and sows). Our results show that vaccination and/or antiviral treatment in a 2 km radius around an infected herd is more effective than preemptive culling in a 1 km radius. However, the instantaneous but temporary protection provided by antiviral treatment is slightly less effective than the delayed but long-lasting protection offered by vaccination. Therefore, the most effective control strategy is to vaccinate animals when allowed (finishers and piglets) and to treat with antiviral agents when vaccination is prohibited (sows). As independent control measure, antiviral treatment in a 1 km radius presents an elevated risk of epidemics running out of control. A 2 km control radius largely eliminates this risk. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Bacille Calmette-Guérin (BCG) vaccination at birth and antibody responses to childhood vaccines

    DEFF Research Database (Denmark)

    Nissen, Thomas Nørrelykke; Birk, Nina Marie; Smits, Gaby

    2017-01-01

    Introduction BCG vaccination has been associated with beneficial non-specific effects on child health. Some immunological studies have reported heterologous effects of vaccines on antibody responses to heterologous vaccines. Within a randomised clinical trial of Bacille Calmette-Guérin (BCG......) vaccination at birth, The Danish Calmette Study, we investigated the effect of BCG at birth on the antibody response to the three routine vaccines against DiTeKiPol/Act-Hib and Prevenar 13 in a subgroup of participants. Methods Within 7 days after birth, children were randomised 1:1 to BCG vaccination...... included children (178 BCG; 122 controls), almost all children (>96%) had antibody responses above the protective levels. Overall BCG vaccination at birth did not affect the antibody level. When stratifying by ‘age at randomisation’ we found a possible inducing effect of BCG on antibodies against B...

  18. Antibody response to pneumococcal vaccine in patients with early stage Hodgkin's disease

    DEFF Research Database (Denmark)

    Frederiksen, B.; Specht, L.; Henrichsen, J.

    1989-01-01

    Antibody response to pneumococcal vaccination was studied in 76 patients with Hodgkin's disease (HD) before, during and at different time intervals after cessation of therapy. All patients were in pathological stage I and II following explorative laparatomy with splenectomy. The increase in antib......Antibody response to pneumococcal vaccination was studied in 76 patients with Hodgkin's disease (HD) before, during and at different time intervals after cessation of therapy. All patients were in pathological stage I and II following explorative laparatomy with splenectomy. The increase...... in antibody response was compared to the findings in 12 healthy volunteers with the aim of establishing the optimal time for vaccination. Serum antibodies against 6 of the pneumococcal polysaccharide antigens (types 1, 4, 7F, 14, 18C and 23F) contained in the vaccine were determined by an ELISA. Antibody...

  19. Protective Capacity of the Human Anamnestic Antibody Response during Acute Dengue Virus Infection.

    Science.gov (United States)

    Xu, Meihui; Züst, Roland; Toh, Ying Xiu; Pfaff, Jennifer M; Kahle, Kristen M; Davidson, Edgar; Doranz, Benjamin J; Velumani, Sumathy; Tukijan, Farhana; Wang, Cheng-I; Fink, Katja

    2016-12-15

    Half of the world's population is exposed to the risk of dengue virus infection. Although a vaccine for dengue virus is now available in a few countries, its reported overall efficacy of about 60% is not ideal. Protective immune correlates following natural dengue virus infection remain undefined, which makes it difficult to predict the efficacy of new vaccines. In this study, we address the protective capacity of dengue virus-specific antibodies that are produced by plasmablasts a few days after natural secondary infection. Among a panel of 18 dengue virus-reactive human monoclonal antibodies, four groups of antibodies were identified based on their binding properties. While antibodies targeting the fusion loop of the glycoprotein of dengue virus dominated the antibody response, two smaller groups of antibodies bound to previously undescribed epitopes in domain II of the E protein. The latter, largely serotype-cross-reactive antibodies, demonstrated increased stability of binding at pH 5. These antibodies possessed weak to moderate neutralization capacity in vitro but were the most efficacious in promoting the survival of infected mice. Our data suggest that the cross-reactive anamnestic antibody response has a protective capacity despite moderate neutralization in vitro and a moderate decrease of viremia in vivo IMPORTANCE: Antibodies can protect from symptomatic dengue virus infection. However, it is not easy to assess which classes of antibodies provide protection because in vitro assays are not always predictive of in vivo protection. During a repeat infection, dengue virus-specific immune memory cells are reactivated and large amounts of antibodies are produced. By studying antibodies cloned from patients with heterologous secondary infection, we tested the protective value of the serotype-cross-reactive "recall" or "anamnestic" response. We found that results from in vitro neutralization assays did not always correlate with the ability of the antibodies to

  20. Suppression of the immune response to ovalbumin in vivo by anti-idiotypic antibodies

    International Nuclear Information System (INIS)

    Grinevich, A.S.; Pinegin, B.V.

    1986-01-01

    Conditions of suppression of the immune response to a food allergin (ovalbumin) were studied with the aid of anti-idiotypic (AID) antibodies. Hen ovalbumin was used and the experiments were performed on mice. Antibodies were isolated from the resulting protein fractions and tested for inhibitor activity by the method of direct radioimmunologic analysis. The test system consisted of the reaction of binding the globulin fraction to the total preparation of antibodies to ovalbumin from mice and a 125 I-labeled total preparation of antibodies to ovalbumin of the same animals

  1. Glutathione Fine-Tunes the Innate Immune Response toward Antiviral Pathways in a Macrophage Cell Line Independently of Its Antioxidant Properties.

    Science.gov (United States)

    Diotallevi, Marina; Checconi, Paola; Palamara, Anna Teresa; Celestino, Ignacio; Coppo, Lucia; Holmgren, Arne; Abbas, Kahina; Peyrot, Fabienne; Mengozzi, Manuela; Ghezzi, Pietro

    2017-01-01

    Glutathione (GSH), a major cellular antioxidant, is considered an inhibitor of the inflammatory response involving reactive oxygen species (ROS). However, evidence is largely based on experiments with exogenously added antioxidants/reducing agents or pro-oxidants. We show that depleting macrophages of 99% of GSH does not exacerbate the inflammatory gene expression profile in the RAW264 macrophage cell line or increase expression of inflammatory cytokines in response to the toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS); only two small patterns of LPS-induced genes were sensitive to GSH depletion. One group, mapping to innate immunity and antiviral responses (Oas2, Oas3, Mx2, Irf7, Irf9, STAT1, il1b), required GSH for optimal induction. Consequently, GSH depletion prevented the LPS-induced activation of antiviral response and its inhibition of influenza virus infection. LPS induction of a second group of genes (Prdx1, Srxn1, Hmox1, GSH synthase, cysteine transporters), mapping to nrf2 and the oxidative stress response, was increased by GSH depletion. We conclude that the main function of endogenous GSH is not to limit inflammation but to fine-tune the innate immune response to infection.

  2. An unexpected antibody response to an engineered influenza virus modifies CD8+ T cell responses.

    Science.gov (United States)

    Thomas, Paul G; Brown, Scott A; Yue, Wen; So, Jenny; Webby, Richard J; Doherty, Peter C

    2006-02-21

    The ovalbumin(323-339) peptide that binds H2I-A(b) was engineered into the globular heads of hemagglutinin (H) molecules from serologically non-cross-reactive H1N1 and H3N2 influenza A viruses, the aim being to analyze recall CD4+ T cell responses in a virus-induced respiratory disease. Prime/challenge experiments with these H1ova and H3ova viruses in H2(b) mice gave the predicted, ovalbumin-specific CD4+ T cell response but showed an unexpectedly enhanced, early expansion of viral epitope-specific CD8+ T cells in spleen and a greatly diminished inflammatory process in the virus-infected respiratory tract. At the same time, the primary antibody response to the H3N2 challenge virus was significantly reduced, an effect that has been associated with preexisting neutralizing antibody in other experimental systems. Analysis of serum from the H1ova-primed mice showed low-level binding to H3ova but not to the wild-type H3N2 virus. Experiments with CD4+ T cell-depleted and Ig-/- mice indicated that this cross-reactive Ig is indeed responsible for the modified pathogenesis after respiratory challenge. Furthermore, the effect does not seem to be virus-dose related, although it does require infection. These findings suggest intriguing possibilities for vaccination and, at the same time, emphasize that engineered modifications in viruses may have unintended immunological consequences.

  3. Tissue tropisms, infection kinetics, histologic lesions, and antibody response of the MR766 strain of Zika virus in a murine model.

    Science.gov (United States)

    Kawiecki, Anna B; Mayton, E Handly; Dutuze, M Fausta; Goupil, Brad A; Langohr, Ingeborg M; Del Piero, Fabio; Christofferson, Rebecca C

    2017-04-18

    The appearance of severe Zika virus (ZIKV) disease in the most recent outbreak has prompted researchers to respond through the development of tools to quickly characterize transmission and pathology. We describe here another such tool, a mouse model of ZIKV infection and pathogenesis using the MR766 strain of virus that adds to the growing body of knowledge regarding ZIKV kinetics in small animal models. We infected mice with the MR766 strain of ZIKV to determine infection kinetics via serum viremia. We further evaluated infection-induced lesions via histopathology and visualized viral antigen via immunohistochemical labeling. We also investigated the antibody response of recovered animals to both the MR766 and a strain from the current outbreak (PRVABC59). We demonstrate that the IRF3/7 DKO mouse is a susceptible, mostly non-lethal model well suited for the study of infection kinetics, pathological progression, and antibody response. Infected mice presented lesions in tissues that have been associated with ZIKV infection in the human population, such as the eyes, male gonads, and central nervous system. In addition, we demonstrate that infection with the MR766 strain produces cross-neutralizing antibodies to the PRVABC59 strain of the Asian lineage. This model provides an additional tool for future studies into the transmission routes of ZIKV, as well as for the development of antivirals and other therapeutics, and should be included in the growing list of available tools for investigations of ZIKV infection and pathogenesis.

  4. Serum and skin surface antibody responses in merino sheep given three successive inoculations with Dermatophilus congolensis.

    Science.gov (United States)

    Sutherland, S S; Ellis, T M; Robertson, G M; Gregory, A R

    1987-11-01

    Three antigens prepared from different phases of the life cycle of Dermatophilus congolensis were used in an enzyme-linked immunosorbent assay to measure serum and skin surface antibody responses in sheep after a first, second and third inoculation with D. congolensis. After the first inoculation, a strong antibody response to the flagella, filament and soluble antigens was detected after 7-21 days in the sera from sheep that were regularly biopsied; the antibody response at the skin surface was detected 28-42 days after inoculation, when the lesions were resolving. Strong anamnestic responses were detected in the serum of sheep that were biopsied and some of the nonbiopsied sheep after the second and third inoculations, but the skin surface antibody response at these times was variable.

  5. Antibody response to equine coronavirus in horses inoculated with a bovine coronavirus vaccine.

    Science.gov (United States)

    Nemoto, Manabu; Kanno, Toru; Bannai, Hiroshi; Tsujimura, Koji; Yamanaka, Takashi; Kokado, Hiroshi

    2017-11-17

    A vaccine for equine coronavirus (ECoV) is so far unavailable. Bovine coronavirus (BCoV) is antigenically related to ECoV; it is therefore possible that BCoV vaccine will induce antibodies against ECoV in horses. This study investigated antibody response to ECoV in horses inoculated with BCoV vaccine. Virus neutralization tests showed that antibody titers against ECoV increased in all six horses tested at 14 days post inoculation, although the antibody titers were lower against ECoV than against BCoV. This study showed that BCoV vaccine provides horses with antibodies against ECoV to some extent. It is unclear whether antibodies provided by BCoV vaccine are effective against ECoV, and therefore ECoV challenge studies are needed to evaluate efficacy of the vaccine in the future.

  6. Antibody response of sandhill and whooping cranes to an eastern equine encephalitis virus vaccine

    Science.gov (United States)

    Clark, G.G.; Dein, F.J.; Crabbs, C.L.; Carpenter, J.W.; Watts, D.M.

    1987-01-01

    As a possible strategy to protect whooping cranes (Grus americana) from fatal eastern equine encephalitis (EEE) viral infection, studies were conducted to determine the immune response of this species and sandhill cranes (Grus canadensis) to a formalin-inactivated EEE viral vaccine. Viral-specific neutralizing antibody was elicited in both species after intramuscular (IM) vaccination. Subcutaneous and intravenous routes of vaccination failed to elicit detectable antibody in sandhill cranes. Among the IM vaccinated cranes, the immune response was characterized by nondetectable or low antibody titers that waned rapidly following primary exposure to the vaccine. However, one or more booster doses consistently elicited detectable antibody and/or increased antibody titers in the whooping cranes. In contrast, cranes with pre-existing EEE viral antibody, apparently induced by natural infection, exhibited a rapid increase and sustained high-antibody titers. Even though EEE virus vaccine induced neutralizing antibody and produced no adverse side effects, further studies will be required to determine the protective efficacy of the antibody.

  7. Antibody response to the lipopolysaccharide and protein antigens of Salmonella typhi during typhoid infection

    International Nuclear Information System (INIS)

    Tsang, R.S.W.; Chau, P.Y.; Lam, S.K.

    1981-01-01

    Serum antibody responses to the lipopolysaccharide and protein antigens of S. typhi in typhoid patients were studied using a solid-phase radioimmunoassay technique with 125 I labelled anti-immunoglobulin antibody. Sera from 24 adult typhoid patients and 20 non-typhoid adult controls were compared. As a group, sera from typhoid patients showed increased IgA, IgG and IgM immunoglobulin levels and gave significantly higher anti-LPS and anti-protein antibody titres in all three major immunoglobulin classes than did non-typhoid controls. Levels of antibodies against LPS or protein in sera of typhoid patients were highly variable with a skew distribution. A good correlation was found between antibody titres to the LPS antigen and those to a protein antigen. No correlation, however, was found between the anti-LPS antibody titres measured by radioimmunoassay and the anti-O antibody titres measured by the Widal agglutination test. Titration of anti-LPS or anti-protein antibodies by radioimmunoassay was found to be more sensitive and specific than Widal test for the serological diagnosis of typhoid fever. The advantages of measuring antibody response by radioimmunoassay over conventional Widal test are discussed. (author)

  8. Human anti-mouse antibody response induced by anti-CD4 monoclonal antibody therapy in patients with rheumatoid arthritis.

    Science.gov (United States)

    Horneff, G; Winkler, T; Kalden, J R; Emmrich, F; Burmester, G R

    1991-04-01

    The development of human anti-mouse monoclonal antibodies (HAMAs) was investigated in 10 patients with rheumatoid arthritis (RA) who had undergone an experimental therapeutic trial with an anti-CD4 monoclonal antibody. In this patient group, the antibody 16H5 of the IgG1 isotype had been administered in a median total dosage of 140 mg per treatment cycle. Four patients took part in a second treatment regimen 6-8 weeks later. After the first treatment cycle, detectable HAMAs developed in 5 out of 10 patients. In 4 individuals undergoing a second course of therapy, increases of HAMAs were evident only in the 3 patients with previous HAMA responses. HAMAs were primarily of the IgG isotype, while the presence of rheumatoid factors usually interfered with the detectability of IgM HAMAs. However, using isolated F(ab)2 fragments of the monoclonal reagent used for therapy, HAMAs of the IgM isotype were also detectable. HAMAs of the IgG isotype did not exceed levels of 2.0 mg/liter after a single treatment cycle and 2.2 mg/liter after a repeated cycle. No IgE responses were detectable. Absorption experiments indicated that approximately 25% of the HAMA activity was directed against specific determinants of the 16H5 monoclonal antibody, presumably including anti-idiotypic reactivities. These data demonstrate that HAMAs developed only in a proportion of RA patients treated with the anti-CD4 monoclonal antibody 16H5. However, the amounts were rather low compared to other monoclonal reagents used in cancer patients and were therefore allowed for repeated applications without an apparent loss of efficacy.

  9. Antibody response to Mycoplasma hyopneumoniae infection in vaccinated pigs with or without maternal antibodies induced by sow vaccination.

    Science.gov (United States)

    Martelli, P; Terreni, M; Guazzetti, S; Cavirani, S

    2006-06-01

    Vaccination with bacterins is an important tool for the control of Mycoplasma hyopneumoniae infection of pigs. Because such vaccination often involves piglets that have suckled M. hyopneumoniae antibody-positive dams it is important to understand the effect of pre-existing (passively acquired) antibody on vaccine-induced immunity. To investigate this issue experimentally, 20 sows that were seronegative for M. hyopneumoniae were selected from a M. hyopneumoniae-infected herd and then randomly allocated to one of four treatment groups (five sows/group): Group A, vaccinated sows/vaccinated piglets; Group B, vaccinated sows/non-vaccinated piglets; Group C, non-vaccinated sows/vaccinated piglets; Group D, non-vaccinated sows/non-vaccinated piglets. Sows (Groups A and B) were vaccinated 14 days before farrowing and seroconverted within the next 14 days. Conversely, none of the non-vaccinated sows was seropositive at farrowing. Piglets (Groups A and C) were vaccinated when they were 7 days of age. Regardless of treatments none of the piglets had any evidence of an active immune response until many of those of Groups A and C and a few of those of Groups B and D seroconverted after it had been shown that at least some pigs of all groups had been naturally infected with a field strain of M. hyopneumoniae. This pattern of immune responsiveness (i.e. the collective results of Groups A, B, C and D) suggested that vaccination of pigs had primed their immune system for subsequent exposure to M. hyopneumoniae, and that passively acquired antibody had little or no effect on either a vaccine-induced priming or a subsequent anamnestic response. According to the statistical analysis sow serological status did not interfere with the antibody response in early vaccinated piglets. In conclusion, the results pointed out that early vaccination of piglets may assist M. hyopneumoniae control independently from the serological status of sows.

  10. Protective immunization with B16 melanoma induces antibody response and not cytotoxic T cell response

    International Nuclear Information System (INIS)

    Sarzotti, M.; Sriyuktasuth, P.; Klimpel, G.R.; Cerny, J.

    1986-01-01

    C57BL/6 mice immunized with three intraperitoneal injections of syngeneic, irradiated B16 melanoma cells, became resistant to B16 tumor challenge. Immunized mice had high levels of serum antibody against a membrane antigen of B16 cells. The B16 antigen recognized by the anti-B16 sera formed a major band of 90 KD in gel electrophoresis. The anti-B16 antibody was partially protective when mixed with B16 cells and injected into normal recipient mice. Surprisingly, B16 resistance mice were incapable of generating cytotoxic T cells (CTL) specific for the B16 tumor. Both spleen and lymph node cell populations from immunized mice did not generate B16-specific CTL. Allogeneic mice (DBA/2 or C3H) were also unable to generate B16-specific CTL: however, alloreactive CTL produced in these strains of mice by immunization with C57BL/6 lymphocytes, did kill B16 target cells. Interestingly, spleen cells from syngeneic mice immunized with B16 tumor produced 6-fold more interleukin-2 (IL-2) than normal spleen cells, in vitro. These data suggest that immunization with B16 tumor activates a helper subset of T cells (for antibody and IL-2 production) but not the effector CTL response

  11. A review of human anti-globulin antibody (HAGA, HAMA, HACA, HAHA) responses to monoclonal antibodies. Not four letter words.

    Science.gov (United States)

    Mirick, G R; Bradt, B M; Denardo, S J; Denardo, G L

    2004-12-01

    The United States Food and Drug Administration (FDA) has approved unconjugated monoclonal antibodies (MAbs) for immunotherapy (IT) of B-cell lymphoma, breast cancer and acute myeloid leukemia. More recently, approval has been given for conjugated ZevalinTM ((90)yttrium ibritumomab tiuxetan, IDEC-Y2B8, Biogen Idec, Cambridge, MA) and BexxarTM ((131)I-tositumomab, Corixa, Corp., Seattle, WA and GlaxoSmithKline, Philadelphia, PA) anti-CD20 MAbs for use in radioimmunotherapy (RIT) of non-Hodgkin's lymphoma (NHL), thus redefining the standard care of cancer patients. Because of, and despite a lack of basis for concern about allergic reactions due to human antibody responses to these foreign proteins, assays were developed to determine HAGA (human anti-globulin antibody) levels that developed in patient sera following treatment with MAbs. Strategies were also devised to ''humanize'' MAbs and to temporarily block patient immune function with drugs in order to decrease the seroconversion rates, with considerable success. On the other hand, a survival advantage has been observed in some patients who developed a HAGA following treatment. This correlates with development of an anti-idiotype antibody cascade directed toward the MAbs used to treat these patients. What follows is a selective review of HAGA and its effect on cancer treatment over the past 2 decades.

  12. A review of human anti-globulin antibody (HAGA, HAMA, HACA, HAHA) responses to monoclonal antibodies. Not four letter words

    International Nuclear Information System (INIS)

    Mirick, G. R.; Bradt, B. M.; Denardo, S. J.; Denardo, G. L.

    2004-01-01

    The United States Food and Drugs Administration (FDA) has approved unconjugated monoclonal antibodies (MAbs) for immunotherapy (IT) of B-cell lymphoma, breast cancer and acute myeloid leukemia. More recently, approval has been given for conjugated ZevalinTM ( 9 0yttrium ibritumomab tiuxetan, IDEC-Y2B8, Biogen Idec, Cambridge, MA) and BexxarTM ( 1 31I-tositumomab, Corixa, Corp., Seattle, WA and GlaxoSmithKline, Philadelphia, PA) antiCD20 MAns for use in radioimmunotherapy (RIT) of non-Hodgikin's lymphoma (NHL), thus redefining the standard care of cancer patients. Because of, and despite a lack of basis for concern about allergic reactions due to human antibody responses to these foreign proteins, essays were developed to determine HAGE (human anti-globulin antibody) levels that developed in patient sera following treatment with MAbs. Strategies were also devised to humanize MAbs and to temporarily block patient immune function with drugs in order to decrease the seroconversion rates, with considerable success. On the other hand, a survival advantage has been observed in some patients who developed a HAGA following treatment. This correlates with development of an anti-idiotype antibody cascade directed toward the MAbs used to treat these patients. What follows is a selective review of HAGA and its effect on cancer treatment over the past 2 decades

  13. A review of human anti-globulin antibody (HAGA, HAMA, HACA, HAHA) responses to monoclonal antibodies. Not four letter words

    Energy Technology Data Exchange (ETDEWEB)

    Mirick, G. R.; Bradt, B. M.; Denardo, S. J.; Denardo, G. L. [Calfornia Univ., Sacramento (United States). Davis Medical Center

    2004-12-01

    The United States Food and Drugs Administration (FDA) has approved unconjugated monoclonal antibodies (MAbs) for immunotherapy (IT) of B-cell lymphoma, breast cancer and acute myeloid leukemia. More recently, approval has been given for conjugated ZevalinTM ({sup 9}0yttrium ibritumomab tiuxetan, IDEC-Y2B8, Biogen Idec, Cambridge, MA) and BexxarTM ({sup 1}31I-tositumomab, Corixa, Corp., Seattle, WA and GlaxoSmithKline, Philadelphia, PA) antiCD20 MAns for use in radioimmunotherapy (RIT) of non-Hodgikin's lymphoma (NHL), thus redefining the standard care of cancer patients. Because of, and despite a lack of basis for concern about allergic reactions due to human antibody responses to these foreign proteins, essays were developed to determine HAGE (human anti-globulin antibody) levels that developed in patient sera following treatment with MAbs. Strategies were also devised to humanize MAbs and to temporarily block patient immune function with drugs in order to decrease the seroconversion rates, with considerable success. On the other hand, a survival advantage has been observed in some patients who developed a HAGA following treatment. This correlates with development of an anti-idiotype antibody cascade directed toward the MAbs used to treat these patients. What follows is a selective review of HAGA and its effect on cancer treatment over the past 2 decades.

  14. Correlated effects of selection for immunity in White Leghorn chicken lines on natural antibodies and specific antibody responses to KLH and M. butyricum

    OpenAIRE

    Minozzi, Giulietta; Parmentier, Henk K; Mignon-Grasteau, Sandrine; Nieuwland, Mike GB; Bed'hom, Bertrand; Gourichon, David; Minvielle, Francis; Pinard-van der Laan, Marie-Helen

    2008-01-01

    Background - The effect of selection for three general immune response traits on primary antibody responses (Ab) to Mycobacterium butyricum or keyhole limpet hemocyanin (KLH) was studied in four experimental lines of White Leghorn chicken. Birds underwent 12 generations of selection for one of three different general immune criteria; high antibody response to Newcastle disease virus 3 weeks after vaccination (ND3), high cell-mediated immune response, using the wing web response to phytohemglu...

  15. Meningitis Caused by Toscana Virus Is Associated with Strong Antiviral Response in the CNS and Altered Frequency of Blood Antigen-Presenting Cells

    Science.gov (United States)

    Varani, Stefania; Gelsomino, Francesco; Bartoletti, Michele; Viale, Pierluigi; Mastroianni, Antonio; Briganti, Elisabetta; Ortolani, Patrizia; Albertini, Francesco; Calzetti, Carlo; Prati, Francesca; Cenni, Patrizia; Castellani, Gastone; Morini, Silvia; Rossini, Giada; Landini, Maria Paola; Sambri, Vittorio

    2015-01-01

    Toscana virus (TOSV) is a Phlebotomus-transmitted RNA virus and a frequent cause of human meningitis and meningoencephalitis in Southern Europe during the summer season. While evidence for TOSV-related central nervous system (CNS) cases is increasing, little is known about the host defenses against TOSV. We evaluated innate immune response to TOSV by analyzing frequency and activation of blood antigen-presenting cells (APCs) and cytokine levels in plasma and cerebrospinal fluid (CSF) from patients with TOSV neuroinvasive infection and controls. An altered frequency of different blood APC subsets was observed in TOSV-infected patients, with signs of monocytic deactivation. Nevertheless, a proper or even increased responsiveness of toll-like receptor 3 and 7/8 was observed in blood APCs of these patients as compared to healthy controls. Systemic levels of cytokines remained low in TOSV-infected patients, while levels of anti-inflammatory and antiviral mediators were significantly higher in CSF from TOSV-infected patients as compared to patients with other infectious and noninfectious neurological diseases. Thus, the early host response to TOSV appears effective for viral clearance, by proper response to TLR3 and TLR7/8 agonists in peripheral blood and by a strong and selective antiviral and anti-inflammatory response in the CNS. PMID:26569288

  16. Meningitis Caused by Toscana Virus Is Associated with Strong Antiviral Response in the CNS and Altered Frequency of Blood Antigen-Presenting Cells

    Directory of Open Access Journals (Sweden)

    Stefania Varani

    2015-11-01

    Full Text Available Toscana virus (TOSV is a Phlebotomus-transmitted RNA virus and a frequent cause of human meningitis and meningoencephalitis in Southern Europe during the summer season. While evidence for TOSV-related central nervous system (CNS cases is increasing, little is known about the host defenses against TOSV. We evaluated innate immune response to TOSV by analyzing frequency and activation of blood antigen-presenting cells (APCs and cytokine levels in plasma and cerebrospinal fluid (CSF from patients with TOSV neuroinvasive infection and controls. An altered frequency of different blood APC subsets was observed in TOSV-infected patients, with signs of monocytic deactivation. Nevertheless, a proper or even increased responsiveness of toll-like receptor 3 and 7/8 was observed in blood APCs of these patients as compared to healthy controls. Systemic levels of cytokines remained low in TOSV-infected patients, while levels of anti-inflammatory and antiviral mediators were significantly higher in CSF from TOSV-infected patients as compared to patients with other infectious and noninfectious neurological diseases. Thus, the early host response to TOSV appears effective for viral clearance, by proper response to TLR3 and TLR7/8 agonists in peripheral blood and by a strong and selective antiviral and anti-inflammatory response in the CNS.

  17. Serum antibody response to human and bovine IRBP in uveitis

    NARCIS (Netherlands)

    Hoekzema, R.; Hwan, S. B.; Rothova, A.; van Haren, M. A.; Donoso, L. A.; Kijlstra, A.

    1990-01-01

    Interphotoreceptor retinoid binding protein (IRBP) is a 136,000 molecular weight photoreceptor cell protein capable of inducing an experimental autoimmune uveitis (EAU) in susceptible animal strains. The occurrence of serum antibodies against human (Hu) or bovine (Bo) IRBP was investigated in

  18. Are anticardiolipin antibodies responsible for some of the ...

    African Journals Online (AJOL)

    Abstract. What were first called simply false-positive Wassermann reactions and then lupus anticoagulant are now known as antiphospholipid or anticardiolipin antibodies (ACA). These are known to cause a tendency to thrombosis and are frequently present in many neurological conditions and infections. The pathological ...

  19. Evaluation of antibody response by dogs vaccinated with low egg ...

    African Journals Online (AJOL)

    Twelve dogs were immunized with live attenuated flury strain antirabies vaccine using single, double and triple inoculation sites of the recommended dose, but in divided doses for the double and triple sites. All the dogs were screened for neutralizing antibodies against rabies before immunization, while sera were collected ...

  20. [The IgG antibody response in patients colonized by Helicobacter pylori].

    Science.gov (United States)

    Figueroa, G; Acuña, R; Jashés, M; Troncoso, M; Toledo, M S; Arellano, L

    1990-11-01

    The IgG antibody response specific to Helicobacter pylori was evaluated through ELISA in a group of 92 gastric patients colonized by this bacteria. 74 had gastritis and 19 gastroduodenal ulcer. Three control groups were studied in a similar way: normal adult volunteers (n = 17), adults with E coli or S typhi bacteremia (n = 30) and normal infants (n = 30). IgG antibody response to H pylori was demonstrated in 98% of colonized patients and 0% of infants. Asymptomatic individuals and those with bacteremia had high rates of antibody response (76 and 90% respectively), although this rate and also the titers of antibody response were significantly lower than that of colonized patients (p pylori in the majority of colonized gastric patients and asymptomatic adults suggests that this infection is very common in our population.

  1. Demonstration of the salmonid humoral response to Renibacterium salmoninarum using a monoclonal antibody against salmonid immunoglobulin

    Science.gov (United States)

    Bartholomew, J.L.; Arkoosh , M.R.; Rohovec, J.S.

    1991-01-01

    The specificity of the antibody response of salmonids to Renibacterium salmoninarum antigens was demonstrated by western blotting techniques that utilized a monoclonal antibody against salmonid immunoglobulin. In this study, the specificity of the response in immunized chinook salmon Oncorhynchus tshawytschawas compared with the response in naturally infected chinook salmon and coho salmon O. kisutch, and immunized rabbits. The antibody response in immunized salmon and rabbits and the naturally infected fish was primarily against the 57–58kilodalton protein complex. In addition to recognizing these proteins in the extracellular fraction and whole-cell preparations, antibody from the immunized salmon and rabbits detected four proteins with lower molecular masses. Western blotting techniques allow identification of the specific antigens recognized and are a useful tool for comparing the immunogenicity of different R. salmoninarumpreparations. Immunofluorescent techniques with whole bacteria were less sensitive than western blotting in detecting salmonid anti-R. salmoninarumantibody.

  2. Selective enhancement of radiation response of herpes simplex virus thymidine kinase transduced 9L gliosarcoma cells in vitro and in vivo by antiviral agents

    International Nuclear Information System (INIS)

    Jae, Ho Kim; Sang, Hie Kim; Kolozsvary, Andrew; Brown, Stephen L.; Ok, Bae Kim; Freytag, Svend O.

    1995-01-01

    Purpose: To demonstrate in a well-characterized tumor model that the radiosensitivity of tumor cells transduced with a herpes simplex virus thymidine kinase gene (HS-tk) would be selectively enhanced by antiviral agents. Methods and Materials: Rat 9L gliosarcoma cells transduced with a retroviral vector containing an HS-tk gene, 9L-tk cells were exposed to various doses of irradiation under either in vitro or in vivo conditions. The radiation sensitizing potential of two antiviral drugs, bromovinyl deoxyuridine (BVdU) and dihydroxymethyl ethyl methyl guanine (acyclovir), was evaluated in vitro. The radiosensitizing ability of BVdU was also evaluated with a 9L-tk tumor growing in the rat brain. Tumors growing in the right hemisphere of rat brains were irradiated stereotactically with single-dose irradiation. Results: The radiation response of 9L-tk cells was selectively enhanced by antiviral agents relative to nontransduced cells. In the cell culture, when a 24-h drug exposure (20 μg/ml) preceded radiation, the sensitizer enhancement ratio (SER) for BVdU and acyclovir was 1.4 ± 0.1 and 1.3 ± 0.1, respectively. Exposure of cells to 10 μg/ml acyclovir for two 24-h periods both pre- and postirradiation resulted in a SER of 1.6 ± 0.1. In vivo, a significant increase in median survival time of rats with 9L-tk tumors was found when BVdU was administered prior to single-dose irradiation relative to the survival time of similar rats receiving radiation alone. Conclusion: An antiviral agent can enhance cell killing by radiation with selective action in cells transduced with the herpes simplex virus thymidine kinase gene. The results suggest that the three-pronged therapy of HS-tk gene transduction, systemically administered antiviral drug, and stereotactically targeted radiation therapy will improve the effectiveness of radiation therapy for the treatment of radioresistant tumors

  3. Smoking and periodontal disease: discrimination of antibody responses to pathogenic and commensal oral bacteria.

    Science.gov (United States)

    Hayman, L; Steffen, M J; Stevens, J; Badger, E; Tempro, P; Fuller, B; McGuire, A; Al-Sabbagh, Mohanad; Thomas, M V; Ebersole, J L

    2011-04-01

    Smoking is an independent risk factor for the initiation, extent and severity of periodontal disease. This study examined the ability of the host immune system to discriminate commensal oral bacteria from pathogens at mucosal surfaces, i.e. oral cavity. Serum immunoglobulin (Ig)G antibody reactive with three pathogenic and five commensal oral bacteria in 301 current smokers (age range 21-66 years) were examined by enzyme-linked immunosorbent assay. Clinical features of periodontal health were used as measures of periodontitis. Antibody to the pathogens and salivary cotinine levels were related positively to disease severity; however, the antibody levels were best described by the clinical disease unrelated to the amount of smoking. The data showed a greater immune response to pathogens than commensals that was related specifically to disease extent, and most noted in black males. Significant correlations in individual patient responses to the pathogens and commensals were lost with an increasing extent of periodontitis and serum antibody to the pathogens. Antibody to Porphyromonas gingivalis was particularly distinct with respect to the discriminatory nature of the immune responses in recognizing the pathogens. Antibody responses to selected pathogenic and commensal oral microorganisms differed among racial groups and genders. The antibody response to the pathogens was related to disease severity. The level of antibody to the pathogens, and in particular P. gingivalis, was correlated with disease severity in black and male subsets of patients. The amount of smoking did not appear to impact directly serum antibody levels to these oral bacteria. © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.

  4. Plants as sources of antiviral agents | Abonyi | African Journal of ...

    African Journals Online (AJOL)

    Antivirals are substances other than a virus or virus containing vaccine or specific antibody which can produce either a protective or therapeutic effect to the clear detectable advantage of the virus infected host. The search for antiviral agents began in earnest in the 1950s but this was directed mainly by chance, with little or ...

  5. Cytokine profiles and antibody responses to Plasmodium falciparum ...

    African Journals Online (AJOL)

    Estimated higher ratios of IFN-γ/IL-10 and IFN-γ/IL-12 were also observed in the symptomatic children while the asymptomatic controls had higher IL-12/IL-10 ratio. The mean concentration levels of anti-P. falciparum IgG1, IgG2, IgG3 antibodies were statistically significantly higher in the individuals >5 years of age than <5 ...

  6. Mechanisms of equine infectious anemia virus escape from neutralizing antibody responses define epitope specificity.

    Science.gov (United States)

    Sponseller, Brett A; Clark, Sandra K; Friedrich, Rachel A

    2012-08-01

    Determining mechanisms of viral escape to particular epitopes recognized by virus-neutralizing antibody can facilitate characterization of host-neutralizing antibody responses as type- versus group-specific, and provides necessary information for vaccine development. Our study reveals that a single N-glycan located in the 5' region of the Wyoming wild-type equine infectious anemia virus (EIAV) principal neutralizing domain (PND) accounts for the differences in neutralization phenotype observed between PND variants, while variations in charged amino acids within the PND do not appear to play a key role in viral escape. Site-directed mutagenesis and peptide mapping of a conserved epitope to neutralizing antibody in the 3' region of the PND showed rapid selective pressure for acquisition of a 5' PND N-glycan responsible for defining the specificity of the neutralizing-antibody response.

  7. Glucose-6-Phosphate Dehydrogenase Enhances Antiviral Response through Downregulation of NADPH Sensor HSCARG and Upregulation of NF-κB Signaling

    Directory of Open Access Journals (Sweden)

    Yi-Hsuan Wu

    2015-12-01

    Full Text Available Glucose-6-phosphate dehydrogenase (G6PD-deficient cells are highly susceptible to viral infection. This study examined the mechanism underlying this phenomenon by measuring the expression of antiviral genes—tumor necrosis factor alpha (TNF-α and GTPase myxovirus resistance 1 (MX1—in G6PD-knockdown cells upon human coronavirus 229E (HCoV-229E and enterovirus 71 (EV71 infection. Molecular analysis revealed that the promoter activities of TNF-α and MX1 were downregulated in G6PD-knockdown cells, and that the IκB degradation and DNA binding activity of NF-κB were decreased. The HSCARG protein, a nicotinamide adenine dinucleotide phosphate (NADPH sensor and negative regulator of NF-κB, was upregulated in G6PD-knockdown cells with decreased NADPH/NADP+ ratio. Treatment of G6PD-knockdown cells with siRNA against HSCARG enhanced the DNA binding activity of NF-κB and the expression of TNF-α and MX1, but suppressed the expression of viral genes; however, the overexpression of HSCARG inhibited the antiviral response. Exogenous G6PD or IDH1 expression inhibited the expression of HSCARG, resulting in increased expression of TNF-α and MX1 and reduced viral gene expression upon virus infection. Our findings suggest that the increased susceptibility of the G6PD-knockdown cells to viral infection was due to impaired NF-κB signaling and antiviral response mediated by HSCARG.

  8. Longitudinal studies of neutralizing antibody responses to rotavirus in stools and sera of children following severe rotavirus gastroenteritis.

    Science.gov (United States)

    Coulson, B S

    1998-11-01

    Rotavirus-neutralizing antibody responses in sera and stools of children hospitalized with rotavirus gastroenteritis and then monitored longitudinally were optimally detected by using local rotavirus strains. Stool responses were highest on days 5 to 8 after the onset of diarrhea. Longitudinal monitoring suggested that serum neutralizing antibody responses were a more useful measure of severely symptomatic rotavirus infection than stool responses but that stool antibody responses may be a useful measure of rotavirus immunity.

  9. Longitudinal Studies of Neutralizing Antibody Responses to Rotavirus in Stools and Sera of Children following Severe Rotavirus Gastroenteritis

    OpenAIRE

    Coulson, Barbara S.

    1998-01-01

    Rotavirus-neutralizing antibody responses in sera and stools of children hospitalized with rotavirus gastroenteritis and then monitored longitudinally were optimally detected by using local rotavirus strains. Stool responses were highest on days 5 to 8 after the onset of diarrhea. Longitudinal monitoring suggested that serum neutralizing antibody responses were a more useful measure of severely symptomatic rotavirus infection than stool responses but that stool antibody responses may be a use...

  10. A Rapid-Response Humoral Vaccine Platform Exploiting Pre-Existing Non-Cognate Populations of Anti-Vaccine or Anti-Viral CD4+ T Helper Cells to Confirm B Cell Activation.

    Science.gov (United States)

    Hills, Thomas; Jakeman, Phillip G; Carlisle, Robert C; Klenerman, Paul; Seymour, Leonard W; Cawood, Ryan

    2016-01-01

    The need for CD4+ T cell responses to arise de novo following vaccination can limit the speed of B cell responses. Populations of pre-existing vaccine-induced or anti-viral CD4+ T cells recognising distinct antigens could be exploited to overcome this limitation. We hypothesise that liposomal vaccine particles encapsulating epitopes that are recognised, after processing and B cell MHCII presentation, by pre-existing CD4+ T cells will exploit this pre-existing T cell help and result in improved antibody responses to distinct target antigens displayed on the particle surface. Liposomal vaccine particles were engineered to display the malaria circumsporozoite (CSP) antigen on their surface, with helper CD4+ epitopes from distinct vaccine or viral antigens contained within the particle core, ensuring the B cell response is raised but focused against CSP. In vivo vaccination studies were then conducted in C57Bl/6 mice as models of either vaccine-induced pre-existing CD4+ T cell immunity (using ovalbumin-OVA) or virus-induced pre-existing CD4+ T cell immunity (murine cytomegalovirus-MCMV). Following the establishment of pre-existing by vaccination (OVA in the adjuvant TiterMax® Gold) or infection with MCMV, mice were administered CSP-coated liposomal vaccines containing the relevant OVA or MCMV core CD4+ T cell epitopes. In mice with pre-existing anti-OVA CD4+ T cell immunity, these vaccine particles elicited rapid, high-titre, isotype-switched CSP-specific antibody responses-consistent with the involvement of anti-OVA T helper cells in confirming activation of anti-CSP B cells. Responses were further improved by entrapping TLR9 agonists, combining humoral vaccination signals 'one', 'two' and 'three' within one particle. Herpes viruses can establish chronic infection and elicit significant, persistent cellular immune responses. We then demonstrate that this principle can be extended to re-purpose pre-existing anti-MCMV immunity to enhance anti-CSP vaccine responses

  11. Maternal antibodies: clinical significance, mechanism of interference with immune responses, and possible vaccination strategies

    Directory of Open Access Journals (Sweden)

    Stefan eNiewiesk

    2014-09-01

    Full Text Available Neonates have an immature immune system which cannot adequately protect against infectious diseases. Early in life, immune protection is accomplished by maternal antibodies transferred from mother to offspring. However, decaying maternal antibodies inhibit vaccination as is examplified by the inhibition of seroconversion after measles vaccination. This phenomenon has been described in both human and veterinary medicine and is independent of the type of vaccine being used. This review will discuss the use of animal models for vaccine research. I will review clinical solutions for inhibition of vaccination by maternal antibodies, and the testing and development of potentially effective vaccines. These are based on new mechanistic insight about the inhibitory mechanism of maternal antibodies. Maternal antibodies inhibit the generation of antibodies whereas the T cell response is usually unaffected. B cell inhibition is mediated through a cross-link between B-cell receptor (BCR with the Fcg receptor IIB (FcgRIIB by a vaccine-antibody complex. In animal experiments, this inhibition can be partially overcome by injection of a vaccine-specific monoclonal IgM antibody. IgM stimulates the B-cell directly through cross-linking the BCR via complement protein C3d and antigen to the complement receptor 2 (CR2 signaling complex. In addition, it was shown that interferon alpha binds to the CD21 chain of CR2 as well as the interferon receptor and that this dual receptor usage drives B cell responses in the presence of maternal antibodies. In lieu of immunizing the infant the concept of maternal immunization as a strategy to protect neonates has been proposed. This approach would still not solve the question of how to immunize in the presence of maternal antibodies but would defer the time of infection to an age where infection might not have such a detrimental outcome as in neonates. I will review successful examples and potential challenges of implementing

  12. The germinal center antibody response in health and disease [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Anthony L. DeFranco

    2016-05-01

    Full Text Available The germinal center response is the delayed but sustained phase of the antibody response that is responsible for producing high-affinity antibodies of the IgG, IgA and/or IgE isotypes. B cells in the germinal center undergo re-iterative cycles of somatic hypermutation of immunoglobulin gene variable regions, clonal expansion, and Darwinian selection for cells expressing higher-affinity antibody variants. Alternatively, selected B cells can terminally differentiate into long-lived plasma cells or into a broad diversity of mutated memory B cells; the former secrete the improved antibodies to fight an infection and to provide continuing protection from re-infection, whereas the latter may jumpstart immune responses to subsequent infections with related but distinct infecting agents. Our understanding of the molecules involved in the germinal center reaction has been informed by studies of human immunodeficiency patients with selective defects in the production of antibodies. Recent studies have begun to reveal how innate immune recognition via Toll-like receptors can enhance the magnitude and selective properties of the germinal center, leading to more effective control of infection by a subset of viruses. Just as early insights into the nature of the germinal center found application in the development of the highly successful conjugate vaccines, more recent insights may find application in the current efforts to develop new generations of vaccines, including vaccines that can induce broadly protective neutralizing antibodies against influenza virus or HIV-1.

  13. Induction of Antiviral Immune Response through Recognition of the Repeating Subunit Pattern of Viral Capsids Is Toll-Like Receptor 2 Dependent

    Directory of Open Access Journals (Sweden)

    Kelly M. Shepardson

    2017-11-01

    Full Text Available Although viruses and viral capsids induce rapid immune responses, little is known about viral pathogen-associated molecular patterns (PAMPs that are exhibited on their surface. Here, we demonstrate that the repeating protein subunit pattern common to most virus capsids is a molecular pattern that induces a Toll-like-receptor-2 (TLR2-dependent antiviral immune response. This early antiviral immune response regulates the clearance of subsequent bacterial superinfections, which are a primary cause of morbidities associated with influenza virus infections. Utilizing this altered susceptibility to subsequent bacterial challenge as an outcome, we determined that multiple unrelated, empty, and replication-deficient capsids initiated early TLR2-dependent immune responses, similar to intact influenza virus or murine pneumovirus. These TLR2-mediated responses driven by the capsid were not dependent upon the capsid’s shape, size, origin, or amino acid sequence. However, they were dependent upon the multisubunit arrangement of the capsid proteins, because unlike intact capsids, individual capsid subunits did not enhance bacterial clearance. Further, we demonstrated that even a linear microfilament protein built from repeating protein subunits (F-actin, but not its monomer (G-actin, induced similar kinetics of subsequent bacterial clearance as did virus capsid. However, although capsids and F-actin induced similar bacterial clearance, in macrophages they required distinct TLR2 heterodimers for this response (TLR2/6 or TLR2/1, respectively and different phagocyte populations were involved in the execution of these responses in vivo. Our results demonstrate that TLR2 responds to invading viral particles that are composed of repeating protein subunits, indicating that this common architecture of virus capsids is a previously unrecognized molecular pattern.

  14. [Antibody response to Ascaris lumbricoides among the children population in the Ustí Region].

    Science.gov (United States)

    Richter, J; Stiborová, I; Pohorská, J; Dobiásová, L; Král, V

    2005-11-01

    A group of 156 children aged between 10 and 12 years were screened for IgG and IgE antibodies to Ascaris lumbricoides. The study subjects were 64 children of Romany origin and 92 children from the majority population. IgG antibodies to Ascaris lumbricoides were detected in 112 (71.8%) children. No difference in the prevalence of IgG antibodies was found between Romany children and those from the majority population. As many as 34.1% of the study subjects had IgE antibodies to Ascaris lumbricoides, again with no difference between the two ethnic groups. Children with IgG antibodies to Ascaris lumbricoides had significantly higher total IgE levels compared to those who had tested IgG negative. To demonstrate induction of a non-specific IgE response was one of the study objectives. The high prevalence rates of IgG and IgE antibodies to Ascaris lumbricoides are suggestive of a high frequency of cross- and non-specific reactions. Possible effect of cross-reactivity to other antigens on the specific IgG and IgE antibody response to Ascaris lumbricoides is discussed.

  15. TRIM25 Identification in the Chinese Goose: Gene Structure, Tissue Expression Profiles, and Antiviral Immune Responses In Vivo and In Vitro

    Directory of Open Access Journals (Sweden)

    Yunan Wei

    2016-01-01

    Full Text Available The retinoic acid-inducible gene I (RIG-I and the RIG-I-like receptor (RLR protein play a critical role in the interferon (IFN response during RNA virus infection. The tripartite motif containing 25 proteins (TRIM25 was reported to modify caspase activation and RIG-I recruitment domains (CARDs via ubiquitin. These modifications allow TRIM25 to interact with mitochondrial antiviral signaling molecules (MAVs and form CARD-CARD tetramers. Goose TRIM25 was cloned from gosling lungs, which possess a 1662 bp open reading flame (ORF. This ORF encodes a predicted 554 amino acid protein consisting of a B-box domain, a coiled-coil domain, and a PRY/SPRY domain. The protein sequence has 89.25% sequence identity with Anas platyrhynchos TRIM25, 78.57% with Gallus gallus TRIM25, and 46.92% with Homo sapiens TRIM25. TRIM25 is expressed in all gosling and adult goose tissues examined. QRT-PCR revealed that goose TRIM25 transcription could be induced by goose IFN-α, goose IFN-γ, and goose IFN-λ, as well as a35 s polyinosinic-polycytidylic acid (poly(I:C, oligodeoxynucleotides 2006 (ODN 2006, and resiquimod (R848 in vitro; however, it is inhibited in H9N2 infected goslings for unknown reasons. These data suggest that goose TRIM25 might play a positive role in the regulation of the antiviral immune response.

  16. TRIM25 Identification in the Chinese Goose: Gene Structure, Tissue Expression Profiles, and Antiviral Immune Responses In Vivo and In Vitro.

    Science.gov (United States)

    Wei, Yunan; Zhou, Hao; Wang, Anqi; Sun, Lipei; Wang, Mingshu; Jia, Renyong; Zhu, Dekang; Liu, Mafeng; Yang, Qiao; Wu, Ying; Sun, Kunfeng; Chen, Xiaoyue; Cheng, Anchun; Chen, Shun

    2016-01-01

    The retinoic acid-inducible gene I (RIG-I) and the RIG-I-like receptor (RLR) protein play a critical role in the interferon (IFN) response during RNA virus infection. The tripartite motif containing 25 proteins (TRIM25) was reported to modify caspase activation and RIG-I recruitment domains (CARDs) via ubiquitin. These modifications allow TRIM25 to interact with mitochondrial antiviral signaling molecules (MAVs) and form CARD-CARD tetramers. Goose TRIM25 was cloned from gosling lungs, which possess a 1662 bp open reading flame (ORF). This ORF encodes a predicted 554 amino acid protein consisting of a B-box domain, a coiled-coil domain, and a PRY/SPRY domain. The protein sequence has 89.25% sequence identity with Anas platyrhynchos TRIM25, 78.57% with Gallus gallus TRIM25, and 46.92% with Homo sapiens TRIM25. TRIM25 is expressed in all gosling and adult goose tissues examined. QRT-PCR revealed that goose TRIM25 transcription could be induced by goose IFN- α , goose IFN- γ , and goose IFN- λ , as well as a35 s polyinosinic-polycytidylic acid (poly(I:C)), oligodeoxynucleotides 2006 (ODN 2006), and resiquimod (R848) in vitro; however, it is inhibited in H9N2 infected goslings for unknown reasons. These data suggest that goose TRIM25 might play a positive role in the regulation of the antiviral immune response.

  17. TRIM32 protein modulates type I interferon induction and cellular antiviral response by targeting MITA/STING protein for K63-linked ubiquitination.

    Science.gov (United States)

    Zhang, Jing; Hu, Ming-Ming; Wang, Yan-Yi; Shu, Hong-Bing

    2012-08-17

    Viral infection activates several transcription factors including NF-κB and IRF3, which collaborate to induce type I interferons (IFNs) and innate antiviral response. MITA (also called STING) is a critical adaptor protein that links virus-sensing receptors to IRF3 activation upon infection by both RNA and DNA pathogens. Here we show that the E3 ubiquitin ligase tripartite motif protein 32 (TRIM32) ubiquitinated MITA and dramatically enhanced MITA-mediated induction of IFN-β. Overexpression of TRIM32 potentiated virus-triggered IFNB1 expression and cellular antiviral response. Consistently, knockdown of TRIM32 had opposite effects. TRIM32 interacted with MITA, and was located at the mitochondria and endoplasmic reticulum. TRIM32 targeted MITA for K63-linked ubiquitination at K20/150/224/236 through its E3 ubiquitin ligase activity, which promoted the interaction of MITA with TBK1. These findings suggest that TRIM32 is an important regulatory protein for innate immunity against both RNA and DNA viruses by targeting MITA for K63-linked ubiquitination and downstream activation.

  18. De novo characterization of the spleen transcriptome of the large yellow croaker (Pseudosciaena crocea and analysis of the immune relevant genes and pathways involved in the antiviral response.

    Directory of Open Access Journals (Sweden)

    Yinnan Mu

    Full Text Available The large yellow croaker (Pseudosciaena crocea is an economically important marine fish in China. To understand the molecular basis for antiviral defense in this species, we used Illumia paired-end sequencing to characterize the spleen transcriptome of polyriboinosinic:polyribocytidylic acid [poly(I:C]-induced large yellow croakers. The library produced 56,355,728 reads and assembled into 108,237 contigs. As a result, 15,192 unigenes were found from this transcriptome. Gene ontology analysis showed that 4,759 genes were involved in three major functional categories: biological process, cellular component, and molecular function. We further ascertained that numerous consensus sequences were homologous to known immune-relevant genes. Kyoto Encyclopedia of Genes and Genomes orthology mapping annotated 5,389 unigenes and identified numerous immune-relevant pathways. These immune-relevant genes and pathways revealed major antiviral immunity effectors, including but not limited to: pattern recognition receptors, adaptors and signal transducers, the interferons and interferon-stimulated genes, inflammatory cytokines and receptors, complement components, and B-cell and T-cell antigen activation molecules. Moreover, the partial genes of Toll-like receptor signaling pathway, RIG-I-like receptors signaling pathway, Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT signaling pathway, and T-cell receptor (TCR signaling pathway were found to be changed after poly(I:C induction by real-time polymerase chain reaction (PCR analysis, suggesting that these signaling pathways may be regulated by poly(I:C, a viral mimic. Overall, the antivirus-related genes and signaling pathways that were identified in response to poly(I:C challenge provide valuable leads for further investigation of the antiviral defense mechanism in the large yellow croaker.

  19. De novo characterization of the spleen transcriptome of the large yellow croaker (Pseudosciaena crocea) and analysis of the immune relevant genes and pathways involved in the antiviral response

    KAUST Repository

    Mu, Yinnan

    2014-05-12

    The large yellow croaker (Pseudosciaena crocea) is an economically important marine fish in China. To understand the molecular basis for antiviral defense in this species, we used Illumia paired-end sequencing to characterize the spleen transcriptome of polyriboinosinic:polyribocytidylic acid [poly(I:C)]-induced large yellow croakers. The library produced 56,355,728 reads and assembled into 108,237 contigs. As a result, 15,192 unigenes were found from this transcriptome. Gene ontology analysis showed that 4,759 genes were involved in three major functional categories: biological process, cellular component, and molecular function. We further ascertained that numerous consensus sequences were homologous to known immune-relevant genes. Kyoto Encyclopedia of Genes and Genomes orthology mapping annotated 5,389 unigenes and identified numerous immune-relevant pathways. These immune-relevant genes and pathways revealed major antiviral immunity effectors, including but not limited to: pattern recognition receptors, adaptors and signal transducers, the interferons and interferon-stimulated genes, inflammatory cytokines and receptors, complement components, and B-cell and T-cell antigen activation molecules. Moreover, the partial genes of Toll-like receptor signaling pathway, RIG-I-like receptors signaling pathway, Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signaling pathway, and T-cell receptor (TCR) signaling pathway were found to be changed after poly(I:C) induction by real-time polymerase chain reaction (PCR) analysis, suggesting that these signaling pathways may be regulated by poly(I:C), a viral mimic. Overall, the antivirus-related genes and signaling pathways that were identified in response to poly(I:C) challenge provide valuable leads for further investigation of the antiviral defense mechanism in the large yellow croaker. © 2014 Mu et al.

  20. La respuesta inmune antiviral

    Directory of Open Access Journals (Sweden)

    Rainel Sánchez de la Rosa

    1998-02-01

    Full Text Available Se expone que los virus son parásitos intracelulares obligados, puesto que no tienen metabolismo propio; esto obliga al sistema inmune a poner en marcha sus mecanismos más especializados para reconocer y eliminar, tanto a los virus libres, como a las células infectadas. Se señala que las células presentadoras de antígenos, los linfocitos B y los T unidos al complejo mayor de histocompatibilidad, forman parte de la organización de la respuesta inmune antiviral; la inducción de esta respuesta con proteínas, péptidos y ADN desnudo, son alternativas actuales tanto en la prevención como en el tratamiento de las infecciones viralesIt is explained that viruses are compulsory intracellular parasites, since they don't have their own metabolism, which makes the immune system to start its mest specialized mechanisms to recognize and eliminate the free viruses and the infected cells. It is stated that the cells presenting antigens, and the B and T lymphocytes together with the major histocompatibility complex, are part of the organization of the immune antiviral response. The induction of this response with proteins, peptides and naked DNA are the present alternatives for the prevention and treatment of viral infections

  1. Staphylococcus aureus nasal carriage in rheumatoid arthritis: antibody response to toxic shock syndrome toxin-1.

    OpenAIRE

    Tabarya, D; Hoffman, W L

    1996-01-01

    OBJECTIVE: To determine the prevalence of Staphylococcus aureus nasal carriage and to compare antibody responses to two superantigens, staphylococcal toxic shock syndrome toxin-1 (TSST-1) and staphylococcal enterotoxin A (SEA), in rheumatoid arthritis patients and normal subjects. METHODS: 88 rheumatoid arthritis patients and 110 control subjects were cultured for nasal carriage of S aureus; 62 isolates were bacteriophage typed. Twenty five patients and 11 spouses were tested for antibodies t...

  2. Circulating CXCR5+PD-1+ response predicts influenza vaccine antibody responses in young adults but not elderly adults

    OpenAIRE

    Herati, Ramin Sedaghat; Reuter, Morgan A.; Dolfi, Douglas V.; Mansfield, Kathleen D.; Aung, Htin; Badwan, Osama Z.; Kurupati, Raj K.; Kannan, Senthil; Ertl, Hildegund; Schmader, Kenneth E.; Betts, Michael R.; Canaday, David H.; Wherry, E. John

    2014-01-01

    Although influenza vaccination is recommended for all adults annually, the incidence of vaccine failure, defined as weak or absent increase in neutralizing antibody titers, is increased in the elderly compared to young adults. The T follicular helper subset of CD4 T cells (Tfh) provides B cell help in germinal centers and is necessary for class-switched antibody responses. Previous studies suggested a role for circulating T follicular helper cells (cTfh) following influenza vaccination in adu...

  3. Ontogeny of adaptive antibody response to a model antigen in captive altricial zebra finches.

    Directory of Open Access Journals (Sweden)

    Tess L Killpack

    Full Text Available Based on studies from the poultry literature, all birds are hypothesized to require at least 4 weeks to develop circulating mature B-cell lineages that express functionally different immunoglobulin specificities. However, many altricial passerines fledge at adult size less than four weeks after the start of embryonic development, and therefore may experience a period of susceptibility during the nestling and post-fledging periods. We present the first study, to our knowledge, to detail the age-related changes in adaptive antibody response in an altricial passerine. Using repeated vaccinations with non-infectious keyhole limpet hemocyanin (KLH antigen, we studied the ontogeny of specific adaptive immune response in altricial zebra finches Taeniopygia guttata. Nestling zebra finches were first injected at 7 days (7d, 14 days (14d, or 21 days post-hatch (21d with KLH-adjuvant emulsions, and boosted 7 days later. Adults were vaccinated in the same manner. Induced KLH-specific IgY antibodies were measured using ELISA. Comparisons within age groups revealed no significant increase in KLH-specific antibody levels between vaccination and boost in 7d birds, yet significant increases between vaccination and boost were observed in 14d, 21d, and adult groups. There was no significant difference among age groups in KLH antibody response to priming vaccination, yet KLH antibody response post-boost significantly increased with age among groups. Post-boost antibody response in all nestling age groups was significantly lower than in adults, indicating that mature adult secondary antibody response level was not achieved in zebra finches prior to fledging (21 days post-hatch in zebra finches. Findings from this study contribute fundamental knowledge to the fields of developmental immunology and ecological immunology and strengthen the utility of zebra finches as a model organism for future studies of immune ontogeny.

  4. Protective Effect of Panax notoginseng Root Water Extract against Influenza A Virus Infection by Enhancing Antiviral Interferon-Mediated Immune Responses and Natural Killer Cell Activity

    Directory of Open Access Journals (Sweden)

    Jang-Gi Choi

    2017-11-01

    Full Text Available Influenza is an acute respiratory illness caused by the influenza A virus, which causes economic losses and social disruption mainly by increasing hospitalization and mortality rates among the elderly and people with chronic diseases. Influenza vaccines are the most effective means of preventing seasonal influenza, but can be completely ineffective if there is an antigenic mismatch between the seasonal vaccine virus and the virus circulating in the community. In addition, influenza viruses resistant to antiviral drugs are emerging worldwide. Thus, there is an urgent need to develop new vaccines and antiviral drugs against these viruses. In this study, we conducted in vitro and in vivo analyses of the antiviral effect of Panax notoginseng root (PNR, which is used as an herbal medicine and nutritional supplement in Korea and China. We confirmed that PNR significantly prevented influenza virus infection in a concentration-dependent manner in mouse macrophages. In addition, PNR pretreatment inhibited viral protein (PB1, PB2, HA, NA, M1, PA, M2, and NP and viral mRNA (NS1, HA, PB2, PA, NP, M1, and M2 expression. PNR pretreatment also increased the secretion of pro-inflammatory cytokines [tumor necrosis factor alpha and interleukin 6] and interferon (IFN-beta and the phosphorylation of type-I IFN-related proteins (TANK-binding kinase 1, STAT1, and IRF3 in vitro. In mice exposed to the influenza A H1N1 virus, PNR treatment decreased mortality by 90% and prevented weight loss (by approximately 10% compared with the findings in untreated animals. In addition, splenocytes from PNR-administered mice displayed significantly enhanced natural killer (NK cell activity against YAC-1 cells. Taking these findings together, PNR stimulates an antiviral response in murine macrophages and mice that protects against viral infection, which may be attributable to its ability to stimulate NK cell activity. Further investigations are needed to reveal the molecular

  5. Effects of deceleration on the humoral antibody response in rats

    Science.gov (United States)

    Barone, R. P.; Caren, L. D.; Oyama, J.

    1985-01-01

    Effects of hypergravity, simulated by chronic centrifugation, followed by a return to normal G (deceleration) on the immune system of rats were investigated. Two groups of male rats (28 days at 2.1 G, and 3.1 G) were compared to the control group (1.0 G). The animals were immunized by i.p. injections of sheep red blood cells on days 29, 42, and 57, and bled on days 36, 47, and 62. While the centrifuged rats ate and gainedsignificantly less than the control rats, the antibody titers and the organ/body mass ratios for the adrenal glands, kidneys, lungs, heart, and thymus were unaffected by gravity exposures, as were the values of the hematocrit and the white blood cell counts. It is concluded that deceleration does not adversely affect these particular aspects of the immune system.

  6. Activated human nasal epithelial cells modulate specific antibody response against bacterial or viral antigens.

    Directory of Open Access Journals (Sweden)

    Chiou-Yueh Yeh

    Full Text Available Nasal mucosa is an immune responsive organ evidenced by eliciting both specific local secretory IgA and systemic IgG antibody responses with intra-nasal administration of antigens. Nevertheless, the role of nasal epithelial cells in modulating such responses is unclear. Human nasal epithelial cells (hNECs obtained from sinus mucosa of patients with chronic rhinosinusitis were cultured in vitro and firstly were stimulated by Lactococcus lactis bacterium-like particles (BLPs in order to examine their role on antibody production. Secondly, both antigens of immunodominant protein IDG60 from oral Streptococcus mutans and hemagglutinin (HA from influenza virus were tested to evaluate the specific antibody response. Stimulated hNECs by BLPs exhibited a significant increase in the production of interleukin-6 (IL-6, and thymic stromal lymphopoietin (TSLP. Conditioned medium of stimulated hNECs has effects on enhancing the proliferation of CD4+ T cells together with interferon-γ and IL-5 production, increasing the costimulatory molecules on dendritic cells and augmenting the production of IDG60 specific IgA, HA specific IgG, IgA by human peripheral blood lymphocytes. Such production of antigen specific IgG and IgA is significantly counteracted in the presence of IL-6 and TSLP neutralizing antibodies. In conclusion, properly stimulated hNECs may impart immuno-modulatory effects on the antigen-specific antibody response at least through the production of IL-6 and TSLP.

  7. Anti-HERV-K (HML-2) capsid antibody responses in HIV elite controllers.

    Science.gov (United States)

    de Mulder, Miguel; SenGupta, Devi; Deeks, Steven G; Martin, Jeffrey N; Pilcher, Christopher D; Hecht, Frederick M; Sacha, Jonah B; Nixon, Douglas F; Michaud, Henri-Alexandre

    2017-08-22

    Human endogenous retroviruses (HERVs) comprise approximately 8% of the human genome and while the majority are transcriptionally silent, the most recently integrated HERV, HERV-K (HML-2), remains active. During HIV infection, HERV-K (HML-2) specific mRNA transcripts and viral proteins can be detected. In this study, we aimed to understand the antibody response against HERV-K (HML-2) Gag in the context of HIV-1 infection. We developed an ELISA assay using either recombinant protein or 164 redundant "15mer" HERV-K (HML-2) Gag peptides to test sera for antibody reactivity. We identified a total of eight potential HERV-K (HML-2) Gag immunogenic domains: two on the matrix (peptides 16 and 31), one on p15 (peptide 85), three on the capsid (peptides 81, 97 and 117), one on the nucleocapsid (peptide 137) and one on the QP1 protein (peptide 157). Four epitopes (peptides 16, 31, 85 and 137) were highly immunogenic. No significant differences in antibody responses were found between HIV infected participants (n = 40) and uninfected donors (n = 40) for 6 out of the 8 epitopes tested. The antibody response against nucleocapsid (peptide 137) was significantly lower (p K (HML-2) capsid recombinant peptide in gamma interferon (IFN-γ) enzyme immunospot (Elispot) assays. We found that the HERV-K (HML-2) Gag antibody and T cell response by Elispot were significantly correlated. HIV elite controllers had a strong cellular and antibody response against HERV-K (HML-2) Gag directed mainly against the Capsid region. Collectively, these data suggest that anti-HERV-K (HML-2) antibodies targeting capsid could have an immunoprotective effect in HIV infection.

  8. Delivering HIV Gagp24 to DCIR Induces Strong Antibody Responses In Vivo.

    Directory of Open Access Journals (Sweden)

    Anne-Laure Flamar

    Full Text Available Targeting dendritic cell-specific endocytic receptors using monoclonal antibodies fused to desired antigens is an approach widely used in vaccine development to enhance the poor immunogenicity of protein-based vaccines and to induce immune responses. Here, we engineered an anti-human DCIR recombinant antibody, which cross-reacts with the homologous cynomolgous macaque receptor and was fused via the heavy chain C-terminus to HIV Gagp24 protein (αDCIR.Gagp24. In vitro, αDCIR.Gagp24 expanded multifunctional antigen-specific memory CD4+ T cells recognizing multiple Gagp24 peptides from HIV-infected patient peripheral blood mononuclear cells. In non human primates, priming with αDCIR.Gagp24 without adjuvant elicited a strong anti-Gagp24 antibody response after the second immunization, while in the non-targeted HIV Gagp24 protein control groups the titers were weak. The presence of the double-stranded RNA poly(I:C adjuvant significantly enhanced the anti-Gagp24 antibody response in all the groups and reduced the discrimination between the different vaccine groups. The avidity of the anti-Gagp24 antibody responses was similar with either αDCIR.Gagp24 or Gagp24 immunization, but increased from medium to high avidity in both groups when poly(I:C was co-administered. This data provides a comparative analysis of DC-targeted and non-targeted proteins for their capacity to induce antigen-specific antibody responses in vivo. This study supports the further development of DCIR-based DC-targeting vaccines for protective durable antibody induction, especially in the absence of adjuvant.

  9. Direct Probing of Germinal Center Responses Reveals Immunological Features and Bottlenecks for Neutralizing Antibody Responses to HIV Env Trimer

    NARCIS (Netherlands)

    Havenar-Daughton, Colin; Carnathan, Diane G.; Torrents de la Peña, Alba; Pauthner, Matthias; Briney, Bryan; Reiss, Samantha M.; Wood, Jennifer S.; Kaushik, Kirti; van Gils, Marit J.; Rosales, Sandy L.; van der Woude, Patricia; Locci, Michela; Le, Khoa M.; de Taeye, Steven W.; Sok, Devin; Mohammed, Ata Ur Rasheed; Huang, Jessica; Gumber, Sanjeev; Garcia, AnaPatricia; Kasturi, Sudhir P.; Pulendran, Bali; Moore, John P.; Ahmed, Rafi; Seumois, Grégory; Burton, Dennis R.; Sanders, Rogier W.; Silvestri, Guido; Crotty, Shane

    2016-01-01

    Generating tier 2 HIV-neutralizing antibody (nAb) responses by immunization remains a challenging problem, and the immunological barriers to induction of such responses with Env immunogens remain unclear. Here, some rhesus monkeys developed autologous tier 2 nAbs upon HIV Env trimer immunization

  10. The bright and the dark side of human antibody responses to flaviviruses: lessons for vaccine design.

    Science.gov (United States)

    Rey, Félix A; Stiasny, Karin; Vaney, Marie-Christine; Dellarole, Mariano; Heinz, Franz X

    2018-02-01

    Zika and dengue viruses belong to the Flavivirus genus, a close group of antigenically related viruses that cause significant arthropod-transmitted diseases throughout the globe. Although infection by a given flavivirus is thought to confer lifelong protection, some of the patient's antibodies cross-react with other flaviviruses without cross-neutralizing. The original antigenic sin phenomenon may amplify such antibodies upon subsequent heterologous flavivirus infection, potentially aggravating disease by antibody-dependent enhancement (ADE). The most striking example is provided by the four different dengue viruses, where infection by one serotype appears to predispose to more severe disease upon infection by a second one. A similar effect was postulated for sequential infections with Zika and dengue viruses. In this review, we analyze the molecular determinants of the dual antibody response to flavivirus infection or vaccination in humans. We highlight the role of conserved partially cryptic epitopes giving rise to cross-reacting and poorly neutralizing, ADE-prone antibodies. We end by proposing a strategy for developing an epitope-focused vaccine approach to avoid eliciting undesirable antibodies while focusing the immune system on producing protective antibodies only. © 2017 Institut Pasteur. Published under the terms of the CC BY NC ND 4.0 license.

  11. Identification, production, and use of polyol-responsive monoclonal antibodies for immunoaffinity chromatography.

    Science.gov (United States)

    Thompson, Nancy E; Foley, Katherine M; Stalder, Elizabeth S; Burgess, Richard R

    2009-01-01

    Immunoaffinity chromatography is a powerful tool for purification of proteins and protein complexes. The availability of monoclonal antibodies (mAbs) has revolutionized the field of immunoaffinity chromatography by providing a continuous supply of highly uniform antibody. Before the availability of mAbs, the recovery of the target protein from immobilized polyclonal antibodies usually required very harsh, often denaturing conditions. Although harsh conditions are often still used to disrupt the antigen-antibody interaction when using a mAb, various methods have been developed to exploit the uniformity of the antigen-antibody reaction in order to identify agents or conditions that gently disrupt this interaction and thus result in higher recovery of active protein from immunoaffinity chromatography. We discuss here the use of a specific type of monoclonal antibody that we have designated "polyol-responsive monoclonal antibodies" (PR-mAbs). These are naturally occurring mAbs that have high affinity for the antigen under binding conditions, but have low affinity in the presence of a combination of low molecular weight hydroxylated compounds (polyols) and nonchaotropic salts. Therefore, these PR-mAbs can be used for gentle immunoaffinity chromatography. PR-mAbs can be easily identified and adapted to a powerful protein purification method for a target protein.

  12. Cyclosporin A is an adjuvant in murine IgE antibody responses

    Energy Technology Data Exchange (ETDEWEB)

    Chen, S.S.; Stanescu, G.; Magalski, A.E.; Qian, Y.Y.

    1989-06-15

    Cyclosporin A (CsA) is an undecapeptide fungal metabolite and is generally regarded as a new generation of immunosuppressive drugs. We uncovered a novel immunomodulatory property of CsA as a potent immunologic stimulator in the murine IgE antibody system. The enhancement of IgE responses was observed in mice receiving as few as three daily i.m. injections before Ag priming. Our studies demonstrate the three points listed below. First, CsA potentiates murine IgE responses regardless of Ag specificities in inbred mice. A hierarchy of immunopotentiation by CsA follows the order of low, intermediate, and high IgE responder mice. Second, CsA, when administered along with Ag, exerts a thorough and long lasting impact on the Ag-specific IgE antibody response, and leads to an Ag-specific breakthrough of IgE antibody synthesis in mice rendered tolerant in the IgE antibody system by soluble Ag pretreatment or neonatal IgE treatment. Third, IgE enhancer cells become sensitive to a low dose of irradiation. Two enhancer cellular components are identified, those of the Th cells and B cells, which appear to favor the induction of IgE responses. Understanding the cellular basis of the immunopotentiating effect of CsA will provide further insight into the murine IgE antibody system.

  13. An HIV-1 Env-Antibody Complex Focuses Antibody Responses to Conserved Neutralizing Epitopes.

    Science.gov (United States)

    Chen, Yajing; Wilson, Richard; O'Dell, Sijy; Guenaga, Javier; Feng, Yu; Tran, Karen; Chiang, Chi-I; Arendt, Heather E; DeStefano, Joanne; Mascola, John R; Wyatt, Richard T; Li, Yuxing

    2016-11-15

    Elicitation of broadly neutralizing Ab (bNAb) responses to the conserved elements of the HIV-1 envelope glycoproteins (Env), including the primary receptor CD4 binding site (CD4bs), is a major focus of vaccine development yet to be accomplished. However, a large number of CD4bs-directed bNAbs have been isolated from HIV-1-infected individuals. Comparison of the routes of binding used by the CD4bs-directed bNAbs from patients and the vaccine-elicited CD4bs-directed mAbs indicates that the latter fail to neutralize primary virus isolates because they approach the Env spike with a vertical angle and contact the specific surface residues occluded in the native spike, including the bridging sheet on gp120. To preferentially expose the CD4bs and direct the immune response away from the bridging sheet, resulting in an altered angle of approach, we engineered an immunogen consisting of gp120 core in complex with the prototypic CD4-induced Ab, 17b. This mAb directly contacts the bridging sheet but not the CD4bs. The complex was further stabilized by chemical crosslinking to prevent dissociation. Rabbits immunized with the crosslinked complex displayed earlier affinity maturation, achieving tier 1 virus neutralization compared with animals immunized with gp120 core alone. Immunization with the crosslinked complex induced transient Ab responses with binding specificity similar to the CD4bs-directed bNAbs. mAbs derived from complex-immunized rabbits displayed footprints on gp120 more distal from the bridging sheet as compared with previous vaccine-elicited CD4bs Abs, indicating that Env-Ab complexes effectively dampen immune responses to undesired immunodominant bridging sheet determinants. Copyright © 2016 by The American Association of Immunologists, Inc.

  14. Effect of increased CRM₁₉₇ carrier protein dose on meningococcal C bactericidal antibody response.

    Science.gov (United States)

    Lee, Lucia H; Blake, Milan S

    2012-04-01

    New multivalent CRM(197)-based conjugate vaccines are available for childhood immunization. Clinical studies were reviewed to assess meningococcal group C (MenC) antibody responses following MenC-CRM(197) coadministration with CRM(197)-based pneumococcal or Haemophilus influenzae type b conjugate vaccines. Infants receiving a total CRM(197) carrier protein dose of ∼50 μg and concomitant diphtheria-tetanus-acellular pertussis (DTaP)-containing vaccine tended to have lower MenC geometric mean antibody titers and continued to have low titers after the toddler dose. Nevertheless, at least 95% of children in the reported studies achieved a MenC serum bactericidal antibody (SBA) titer of ≥ 1:8 after the last infant or toddler dose. SBA was measured using an assay with a baby rabbit or human complement source. Additional studies are needed to assess long-term antibody persistence and MenC CRM(197) conjugate vaccine immunogenicity using alternative dosing schedules.

  15. [Study on antibody response to revaccination of hepatitis B vaccine among firstly low-response adults].

    Science.gov (United States)

    Feng, Yi; Yan, Bing-yu; Zhang, Li; Lü, Jing-jing; Liu, Jia-ye; Gong, Xiao-hong; Cui, Fu-qiang; Liang, Xiao-feng; Chen, Shi-yu; Xu, Ai-qiang

    2012-09-01

    To evaluate and compare the antibody to hepatitis B virus (HBV) surface antigen (anti-HBs) response and the influent factors of revaccination of 4 kinds of hepatitis B vaccine (HepB) among firstly low-response adults. A total of 11 590 adults who were 18 - 49 years old, never received HepB vaccination, without HBV infection history, HBs-Ag negative, and had been living at 3 towns of Zhangqiu county in Shandong province Ji'nan city for more than half a year, were selected in the study in July, 2009. Self-designed questionnaire was used to select the basic information of the subjects. The subjects were divided into 4 groups by cluster sampling, and were vaccinated according to the "0-1-6" immune procedure with 10 µg HepB made by recombinant deoxyribonucleic acid techniques in Saccharomyces Cerevisiae (HepB-SC), 10 µg HepB made by recombinant deoxyribonucleic acid techniques in Hansenula Polymorpha (HepB-HP), 20 µg HepB-SC and 20 µg HepB made by recombinant deoxyribonucleic acid techniques in Chinese hamster ovary cell (HepB-CHO), 3 doses respectively. The adults who were low-response to the primary hepatitis B vaccination (10 mU/ml ≤ anti-HBs Anti-HBs was detected by chemiluminescence microparticle immunoassay and compared by the vaccine type. The influence factors about antibody response were also analyzed. Out of the 11 590 subjects, 8592 adults had accepted the primary vaccination of hepatitis B and been collected the blood samples; among whom, 1306 subjects showed low-response, at the rate of 15.20%. A total of 1034 low-response subjects accepted secondary strengthened vaccination and were collected blood samples; 55.13% of them showed anti-HBs seroconversion (anti-HBs ≥ 100 mU/ml); while the seroconversion rate in each group was 44.54% (106/238) in 10 µg HepB-SC group, 57.14% (156/273) in 10 µg HepB-HP group, 56.08% (143/255) in 20 µg HepB-SC group and 61.57% (165/268) in 20 µg HepB-CHO group, respectively. There was significant difference among the

  16. Protein dynamics and the diversity of an antibody response.

    Science.gov (United States)

    Adhikary, Ramkrishna; Yu, Wayne; Oda, Masayuki; Zimmermann, Jörg; Romesberg, Floyd E

    2012-08-03

    The immune system is remarkable in its ability to produce antibodies (Abs) with virtually any specificity from a limited repertoire of germ line precursors. Although the contribution of sequence diversity to this molecular recognition has been studied for decades, recent models suggest that protein dynamics may also broaden the range of targets recognized. To characterize the contribution of protein dynamics to immunological molecular recognition, we report the sequence, thermodynamic, and time-resolved spectroscopic characterization of a panel of eight Abs elicited to the chromophoric antigen 8-methoxypyrene-1,3,6-trisulfonate (MPTS). Based on the sequence data, three of the Abs arose from unique germ line Abs, whereas the remaining five comprise two sets of siblings that arose by somatic mutation of a common precursor. The thermodynamic data indicate that the Abs recognize MPTS via a variety of mechanisms. Although the spectroscopic data reveal small differences in protein dynamics, the anti-MPTS Abs generally show similar levels of flexibility and conformational heterogeneity, possibly representing the convergent evolution of the dynamics necessary for function. However, one Ab is significantly more rigid and conformationally homogeneous than the others, including a sibling Ab from which it differs by only five somatic mutations. This example of divergent evolution demonstrates that point mutations are capable of fixing significant differences in protein dynamics. The results provide unique insight into how high affinity Abs may be produced that bind virtually any target and possibly, from a more general perspective, how new protein functions are evolved.

  17. Protein Dynamics and the Diversity of an Antibody Response*

    Science.gov (United States)

    Adhikary, Ramkrishna; Yu, Wayne; Oda, Masayuki; Zimmermann, Jörg; Romesberg, Floyd E.

    2012-01-01

    The immune system is remarkable in its ability to produce antibodies (Abs) with virtually any specificity from a limited repertoire of germ line precursors. Although the contribution of sequence diversity to this molecular recognition has been studied for decades, recent models suggest that protein dynamics may also broaden the range of targets recognized. To characterize the contribution of protein dynamics to immunological molecular recognition, we report the sequence, thermodynamic, and time-resolved spectroscopic characterization of a panel of eight Abs elicited to the chromophoric antigen 8-methoxypyrene-1,3,6-trisulfonate (MPTS). Based on the sequence data, three of the Abs arose from unique germ line Abs, whereas the remaining five comprise two sets of siblings that arose by somatic mutation of a common precursor. The thermodynamic data indicate that the Abs recognize MPTS via a variety of mechanisms. Although the spectroscopic data reveal small differences in protein dynamics, the anti-MPTS Abs generally show similar levels of flexibility and conformational heterogeneity, possibly representing the convergent evolution of the dynamics necessary for function. However, one Ab is significantly more rigid and conformationally homogeneous than the others, including a sibling Ab from which it differs by only five somatic mutations. This example of divergent evolution demonstrates that point mutations are capable of fixing significant differences in protein dynamics. The results provide unique insight into how high affinity Abs may be produced that bind virtually any target and possibly, from a more general perspective, how new protein functions are evolved. PMID:22685303

  18. Antibody responses of swine following infection with Mycoplasma hyopneumoniae, M. hyorhinis, M. hyosynoviae and M. flocculare.

    Science.gov (United States)

    Gomes Neto, João Carlos; Strait, Erin L; Raymond, Matthew; Ramirez, Alejandro; Minion, F Chris

    2014-11-07

    Several mycoplasma species possessing a range of virulence have been described in swine. The most commonly described are Mycoplasma hyopneumoniae, Mycoplasma hyorhinis, Mycoplasma hyosynoviae, and Mycoplasma flocculare. They are ubiquitious in many pig producing areas of the world, and except for M. hyopneumoniae, commercial antibody-based assays are lacking for most of these. Antibody cross-reactivity among these four mycoplasma species is not well characterized. Recently, the use of pen-based oral fluids for herd surveillance is of increasing interest. Thus, this study sought to measure pig antibody responses and the level of cross-reactivity in serum and pen-based oral fluids after challenge with four species of swine mycoplasmas. Four groups of four mycoplasma-free growing pigs were separately inoculated with the different mycoplasma species. Pen-based oral fluids and serum samples were collected weekly until necropsy. Species-specific Tween 20 ELISAs were used to measure antibody responses along with four other commercial M. hyopneumoniae ELISAs. Animals from all groups seroconverted to the challenge species of mycoplasma and no evidence of cross-contamination was observed. A delayed antibody response was seen with all but M. hyorhinis-infected pigs. Cross-reactive IgG responses were detected in M. hyopneumoniae- and M. flocculare-infected animals by the M. hyorhinis Tween 20 ELISA, while sera from M. hyosynoviae and M. flocculare-infected pigs were positive in one commercial assay. In pen-based oral fluids, specific anti-M. hyopneumoniae IgA responses were detected earlier after infection than serum IgG responses. In summary, while some antibody-based assays may have the potential for false positives, evidence of this was observed in the current study. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Global Stability of Delayed Viral Infection Models with Nonlinear Antibody and CTL Immune Responses and General Incidence Rate

    OpenAIRE

    Miao, Hui; Teng, Zhidong; Li, Zhiming

    2016-01-01

    The dynamical behaviors for a five-dimensional viral infection model with three delays which describes the interactions of antibody, cytotoxic T-lymphocyte (CTL) immune responses, and nonlinear incidence rate are investigated. The threshold values for viral infection, antibody response, CTL immune response, CTL immune competition, and antibody competition, respectively, are established. Under certain assumptions, the threshold value conditions on the global stability of the infection-free, im...

  20. Antibody Responses to Trivalent Inactivated Influenza Vaccine in Health Care Personnel Previously Vaccinated and Vaccinated for The First Time

    OpenAIRE

    Kuan-Ying A. Huang; Shih-Cheng Chang; Yhu-Chering Huang; Cheng-Hsun Chiu; Tzou-Yien Lin

    2017-01-01

    Inactivated influenza vaccination induces a hemagglutinin-specific antibody response to the strain used for immunization. Annual vaccination is strongly recommended for health care personnel. However, it is debatable if repeated vaccination would affect the antibody response to inactivated influenza vaccine through the time. We enrolled health care personnel who had repeated and first trivalent inactivated influenza vaccination in 2005?2008. Serological antibody responses were measured by hem...

  1. Antibody response to pneumococcal vaccine in patients with early stage Hodgkin's disease

    DEFF Research Database (Denmark)

    Frederiksen, B.; Specht, L.; Henrichsen, J.

    1989-01-01

    Antibody response to pneumococcal vaccination was studied in 76 patients with Hodgkin's disease (HD) before, during and at different time intervals after cessation of therapy. All patients were in pathological stage I and II following explorative laparatomy with splenectomy. The increase in antib......Antibody response to pneumococcal vaccination was studied in 76 patients with Hodgkin's disease (HD) before, during and at different time intervals after cessation of therapy. All patients were in pathological stage I and II following explorative laparatomy with splenectomy. The increase...

  2. Functional Antibody Response Against V1V2 and V3 of HIV gp120 in the VAX003 and VAX004 Vaccine Trials.

    Science.gov (United States)

    Balasubramanian, Preetha; Williams, Constance; Shapiro, Mariya B; Sinangil, Faruk; Higgins, Keith; Nádas, Arthur; Totrov, Maxim; Kong, Xiang-Peng; Fiore-Gartland, Andrew J; Haigwood, Nancy L; Zolla-Pazner, Susan; Hioe, Catarina E

    2018-01-11

    Immunization with HIV AIDSVAX gp120 vaccines in the phase III VAX003 and VAX004 trials did not confer protection. To understand the shortcomings in antibody (Ab) responses induced by these vaccines, we evaluated the kinetics of Ab responses to the V1V2 and V3 regions of gp120 and the induction of Ab-mediated antiviral functions during the course of 7 vaccinations over a 30.5-month period. Plasma samples from VAX003 and VAX004 vaccinees and placebo recipients were measured for ELISA-binding Abs and for virus neutralization, Ab-dependent cellular phagocytosis (ADCP), and Ab-dependent cellular cytotoxicity (ADCC). Ab responses to V1V2 and V3 peaked after 3 to 4 immunizations and declined after 5 to 7 immunizations. The deteriorating responses were most evident against epitopes in the underside of the V1V2 β-barrel and in the V3 crown. Correspondingly, vaccinees demonstrated higher neutralization against SF162 pseudovirus sensitive to anti-V1V2 and anti-V3 Abs after 3 or 4 immunizations than after 7 immunizations. Higher levels of ADCP and ADCC were also observed at early or mid-time points as compared with the final time point. Hence, VAX003 and VAX004 vaccinees generated V1V2- and V3-binding Abs and functional Abs after 3 to 4 immunizations, but subsequent boosts did not maintain these responses.

  3. High Affinity Antibodies against Influenza Characterize the Plasmablast Response in SLE Patients After Vaccination.

    Directory of Open Access Journals (Sweden)

    Kaval Kaur

    Full Text Available Breakdown of B cell tolerance is a cardinal feature of systemic lupus erythematosus (SLE. Increased numbers of autoreactive mature naïve B cells have been described in SLE patients and autoantibodies have been shown to arise from autoreactive and non-autoreactive precursors. How these defects, in the regulation of B cell tolerance and selection, influence germinal center (GC reactions that are directed towards foreign antigens has yet to be investigated. Here, we examined the characteristics of post-GC foreign antigen-specific B cells from SLE patients and healthy controls by analyzing monoclonal antibodies generated from plasmablasts induced specifically by influenza vaccination. We report that many of the SLE patients had anti-influenza antibodies with higher binding affinity and neutralization capacity than those from controls. Although overall frequencies of autoreactivity in the influenza-specific plasmablasts were similar for SLE patients and controls, the variable gene repertoire of influenza-specific plasmablasts from SLE patients was altered, with increased usage of JH6 and long heavy chain CDR3 segments. We found that high affinity anti-influenza antibodies generally characterize the plasmablast responses of SLE patients with low levels of autoreactivity; however, certain exceptions were noted. The high-avidity antibody responses in SLE patients may also be correlated with cytokines that are abnormally expressed in lupus. These findings provide insights into the effects of dysregulated immunity on the quality of antibody responses following influenza vaccination and further our understanding of the underlying abnormalities of lupus.

  4. Filamentous phage as an immunogenic carrier to elicit focused antibody responses against a synthetic peptide

    Science.gov (United States)

    van Houten, N.E.; Zwick, M.B.; Menendez, A.; Scott, J.K.

    2007-01-01

    Filamentous bacteriophage are widely used as immunogenic carriers for “phage-displayed” recombinant peptides. Here we report that they are an effective immunogenic carrier for synthetic peptides. The f1.K phage was engineered to have an additional Lys residue near the N-terminus of the major coat protein, pVIII, so as to enhance access to chemical cross-linking agents. The dimeric synthetic peptide, B2.1, was conjugated to f1.K (f1.K/B2.1) in high copy number and compared as an immunogen to B2.1 conjugated to ovalbumin (OVA/B2.1) and to phage-displayed, recombinant B2.1 peptide. All immunogens were administered without adjuvant. The serum antibody titers were measured against: the peptide, the carrier, and, if appropriate, the cross-linker. All immunogens elicited anti-peptide antibody titers, with those elicited by OVA/B2.1 exceeding those by f1.K/B2.1; both titers were greater than that elicited by recombinant B2.1 phage. Comparison of the anti-peptide and anti-carrier antibody responses showed that f1.K/B2.1 elicited a more focused anti-peptide antibody response than OVA/B2.1. The anti-peptide antibody response against f1.K/B2.1 was optimized for the injection route, dose and adjuvant. Dose and adjuvant did not have a significant effect on anti-peptide antibody titers, but a change in injection route from intraperitoneal (IP) to subcutaneous (SC) enhanced anti-peptide antibody titers after seven immunizations. The optimized anti-peptide antibody response exceeded the anti-carrier one by 21-fold, compared to 0.07-fold elicited by OVA/B2.1. This indicates that phage as a carrier can focus the antibody response against the peptide. The results are discussed with respect to the advantages of phage as an alternative to traditional carrier proteins for synthetic peptides, carbohydrates and haptens, and to further improvements in phage as immunogenic carriers. PMID:16488517

  5. Differential effects of preirradiation on adoptive antibody responses in DBA/2 and BALB/c mice

    International Nuclear Information System (INIS)

    Yonkosky, D.; Buffett, R.F.; Bennett, M.

    1978-01-01

    Mice were lethally irradiated on the same day or 3 days prior to the infusion of syngeneic thymus and marrow cells. Mice were immunized with sheep erythrocytes and direct plaque-forming cells per spleen were determined 8 days after cell transfer. Preirradiation of hosts 3 days before cell transfer had varying effects on the level of adoptive antibody responses in mice of different strains: Responses of DBA/2 and DBA/1 were deficient, responses of CD2F1, B10, B10;D2, C3H, C3BF1 and SJL were unaffected, and responses of BALB/c, CBA, and 129 mice were enhanced. The defect in the antibody responses of DBA/2 hosts was dependent on the combination of a DBA/2 host and a DBA/2 cell inoculum. Differentiation of both DBA/2 thymus and marrow cells was deficient in the preirradiated DBA/2 host. This defect did not appear to be the result of loss of adherent cells from the preirradiated DBA/2 host. The enhanced antibody response observed in BALB/c mice appeared to be due to altered activity of BALB/c thymus cells. Preirradiated BALB/c or DBA/2 recipients reconstituted with BALB/c thymus cells and BALB/c or DBA/2 marrow cells showed enhanced antibody responses, while preirradiated BALB/c or DBA/2 recipients reconstituted with BALB/c marrow cells and DBA/2 thymus cells showed no change in degree of antibody responses when compared to control recipients. The preirradiated host had altered its ability to control BALB/c thymus cell activity; this lack of control may be due to loss of regulator cells from the host

  6. [Salmonella typhi vaccination response study reveals defective antibody production selective IgA deficiency patient].

    Science.gov (United States)

    Pleguezuelo, Daniel E; Gianelli, Carla

    2015-01-01

    Selective IgA deficiency (SIgAD) is the most prevalent immunodeficiency worldwide, progressing to common variable immunodeficiency only in few reported cases. We report the case of a Spanish female aged 22 and diagnosed of selective IgA deficiency, a long history of bronchitis, several episodes of pneumonia, bilateral bronchiectasis, normal IgG, IgM, IgG subclasses, and detectable pre-vaccination IgG antibodies against tetanus toxoid and Streptococcus pneumoniae. She was evaluated in our clinic in order to rule out common variable immunodeficiency. We observed good antibody response to tetanus toxoid, absence of circulating switched memory B cells, decreased response to pneumococcal polysaccharide antigens and a lack of response to Salmonella typhi vaccine. Most SIgAD patients presents with upper respiratory tract infections or mild diarrhea. Those with lower tract infections, pneumonia or untreatable diarrhea should follow B-cell subpopulations' study and antibody response to vaccines. Absence of response to Salmonella typhi vaccine allowed us to expose the defective antibody production.

  7. Progressive encephalomyelitis with rigidity and myoclonus: a syndrome with diverse clinical features and antibody responses.

    Science.gov (United States)

    Shugaiv, Erkingül; Leite, Maria Isabel; Şehitoğlu, Elçin; Woodhall, Mark; Çavuş, Filiz; Waters, Patrick; İçöz, Sema; Birişik, Ömer; Uğurel, Elif; Ulusoy, Canan; Kürtüncü, Murat; Vural, Burçak; Vincent, Angela; Akman-Demir, Gulsen; Tüzün, Erdem

    2013-01-01

    To better characterize progressive encephalomyelitis with rigidity and myoclonus (PERM) syndrome and identify novel PERM phenotypes. The clinical features and antibody status of PERM patients were investigated using immunoblots, cell-based assays, RIA, protein macroarray and ELISA. Two patients with supratentorial involvement showed abnormal PET or EEG findings. One patient was discovered to have renal cell carcinoma, and protein macroarray revealed Ma3-antibodies. Another patient with leucine-rich, glioma-inactivated 1 (LGI1) and glutamic acid decarboxylase (GAD) antibodies showed a good response to immunotherapy. The heterogeneity of the immunological features suggests that PERM is caused by diverse pathogenic mechanisms. Seropositivity to well-characterized neuronal cell surface antigens might indicate a good treatment response. Copyright © 2013 S. Karger AG, Basel.

  8. Variable Domain N-Linked Glycans Acquired During Antigen-Specific Immune Responses Can Contribute to Immunoglobulin G Antibody Stability

    Directory of Open Access Journals (Sweden)

    Fleur S. van de Bovenkamp

    2018-04-01

    Full Text Available Immunoglobulin G (IgG can contain N-linked glycans in the variable domains, the so-called Fab glycans, in addition to the Fc glycans in the CH2 domains. These Fab glycans are acquired following introduction of N-glycosylation sites during somatic hypermutation and contribute to antibody diversification. We investigated whether Fab glycans may—in addition to affecting antigen binding—contribute to antibody stability. By analyzing thermal unfolding profiles of antibodies with or without Fab glycans, we demonstrate that introduction of Fab glycans can improve antibody stability. Strikingly, removal of Fab glycans naturally acquired during antigen-specific immune responses can deteriorate antibody stability, suggesting in vivo selection of stable, glycosylated antibodies. Collectively, our data show that variable domain N-linked glycans acquired during somatic hypermutation can contribute to IgG antibody stability. These findings indicate that introducing Fab glycans may represent a mechanism to improve therapeutic/diagnostic antibody stability.

  9. Anti-influenza M2e antibody

    Energy Technology Data Exchange (ETDEWEB)

    Bradbury, Andrew M.

    2013-04-16

    Humanized recombinant and monoclonal antibodies specific for the ectodomain of the influenza virus M2 ion channel protein are disclosed. The antibodies of the invention have anti-viral activity and may be useful as anti-viral therapeutics and/or prophylactic/vaccine agents for inhibiting influenza virus replication and for treating individuals infected with influenza.

  10. Anti-influenza M2e antibody

    Energy Technology Data Exchange (ETDEWEB)

    Bradbury, Andrew M [Santa Fe, NM

    2011-12-20

    Humanized recombinant and monoclonal antibodies specific for the ectodomain of the influenza virus M2 ion channel protein are disclosed. The antibodies of the invention have anti-viral activity and may be useful as anti-viral therapeutics and/or prophylactic/vaccine agents for inhibiting influenza virus replication and for treating individuals infected with influenza.

  11. Antibody Response to Lyme Disease Spirochetes in the Context of VlsE-Mediated Immune Evasion.

    Science.gov (United States)

    Rogovskyy, Artem S; Gillis, David C; Ionov, Yurij; Gerasimov, Ekaterina; Zelikovsky, Alex

    2017-01-01

    Lyme disease (LD), the most prevalent tick-borne illness in North America, is caused by Borrelia burgdorferi The long-term survival of B. burgdorferi spirochetes in the mammalian host is achieved though VlsE-mediated antigenic variation. It is mathematically predicted that a highly variable surface antigen prolongs bacterial infection sufficiently to exhaust the immune response directed toward invariant surface antigens. If the prediction is correct, it is expected that the antibody response to B. burgdorferi invariant antigens will become nonprotective as B. burgdorferi infection progresses. To test this assumption, changes in the protective efficacy of the immune response to B. burgdorferi surface antigens were monitored via a superinfection model over the course of 70 days. B. burgdorferi-infected mice were subjected to secondary challenge by heterologous B. burgdorferi at different time points postinfection (p.i.). When the infected mice were superinfected with a VlsE-deficient clone (ΔVlsE) at day 28 p.i., the active anti-B. burgdorferi immune response did not prevent ΔVlsE-induced spirochetemia. In contrast, most mice blocked culture-detectable spirochetemia induced by wild-type B. burgdorferi (WT), indicating that VlsE was likely the primary target of the antibody response. As the B. burgdorferi infection further progressed, however, reversed outcomes were observed. At day 70 p.i. the host immune response to non-VlsE antigens became sufficiently potent to clear spirochetemia induced by ΔVlsE and yet failed to prevent WT-induced spirochetemia. To test if any significant changes in the anti-B. burgdorferi antibody repertoire accounted for the observed outcomes, global profiles of antibody specificities were determined. However, comparison of mimotopes revealed no major difference between day 28 and day 70 antibody repertoires. Copyright © 2016 American Society for Microbiology.

  12. Follicular Helper T (Tfh) Cells Mediate IgE Antibody Response to Airborne Allergens

    Science.gov (United States)

    Kobayashi, Takao; Iijima, Koji; Dent, Alexander L.; Kita, Hirohito

    2016-01-01

    Background Type 2 helper T (Th2) cells have long been believed to play a pivotal role in allergic immune responses, including IgE antibody production and type 2 cytokine-mediated inflammation and pathology. A new T cell subset, T follicular helper cells (Tfh) cells, is specialized in supporting B cell maturation and antibody production. Objective To investigate the roles of Tfh cells in allergic immune responses. Methods Naïve mice were exposed to cytokines or natural allergens through the airways. Development of allergic immune responses was analyzed by collecting draining lymph nodes (LNs) and sera and by challenging the animals. Cytokine reporter mice and gene-deficient mice were used to dissect the immunologic mechanisms. Results We observed the development of IL-4-producing Tfh cells and Th2 cells in draining LNs following airway exposure to IL-1 family cytokines or natural allergens. Tfh cells and Th2 cells demonstrated unique phenotypes, tissue localization, and cytokine responses. Tfh cells supported the sustained production of IgE antibody in vivo in the absence of other T cell subsets or even when Th2 cell functions were severely compromised. Conversely, conditional deficiency of the master regulator Bcl6 in CD4+ T cells resulted in a marked reduction in Tfh cells and IgE antibody levels, but type 2 cytokine responses and eosinophilic inflammation in the airways remained unaffected. Conclusion Tfh cells play critical roles in the regulation of IgE antibody production. Allergic immune responses to airborne allergens likely involve two distinct subsets of IL-4-producing CD4+ T cells, namely Tfh cells and Th2 cells. PMID:27325434

  13. Follicular helper T cells mediate IgE antibody response to airborne allergens.

    Science.gov (United States)

    Kobayashi, Takao; Iijima, Koji; Dent, Alexander L; Kita, Hirohito

    2017-01-01

    T H 2 cells have long been believed to play a pivotal role in allergic immune responses, including IgE antibody production and type 2 cytokine-mediated inflammation and pathology. A new T-cell subset, follicular helper T (T FH ) cells, is specialized in supporting B-cell maturation and antibody production. We sought to investigate the roles of T FH cells in allergic immune responses. Naive mice were exposed to cytokines or natural allergens through the airways. Development of allergic immune responses was analyzed by collecting draining lymph nodes and sera and by challenging the animals. Cytokine reporter mice and gene-deficient mice were used to dissect the immunologic mechanisms. We observed the development of IL-4-producing T FH cells and T H 2 cells in draining lymph nodes after airway exposure to IL-1 family cytokines or natural allergens. T FH and T H 2 cells demonstrated unique phenotypes, tissue localization, and cytokine responses. T FH cells supported the sustained production of IgE antibody in vivo in the absence of other T-cell subsets or even when T H 2 cell functions were severely compromised. Conversely, conditional deficiency of the master regulator Bcl6 in CD4 + T cells resulted in a marked reduction in T FH cell numbers and IgE antibody levels, but type 2 cytokine responses and eosinophilic inflammation in the airways remained unaffected. T FH cells play critical roles in the regulation of IgE antibody production. Allergic immune responses to airborne allergens likely involve 2 distinct subsets of IL-4-producing CD4 + T cells, namely T FH and Th2 cells. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  14. Agonistic anti-CD40 antibody profoundly suppresses the immune response to infection with lymphocytic choriomeningitis virus

    DEFF Research Database (Denmark)

    Bartholdy, Christina; Kauffmann, Susanne Ørding; Christensen, Jan Pravsgaard

    2007-01-01

    -CD40 treatment of MHC class II-deficient mice infected with a moderate dose of LCMV resulted in severe suppression of the antiviral CD8 T cell response and uncontrolled virus spread, rather than improved CD8 T cell immune surveillance. In Ab-treated wild-type mice, the antiviral CD8 T cell response......Previous work has shown that agonistic Abs to CD40 (anti-CD40) can boost weak CD8 T cell responses as well as substitute for CD4 T cell function during chronic gammaherpes virus infection. Agonistic anti-CD40 treatment has, therefore, been suggested as a potential therapeutic strategy...... in immunocompromised patients. In this study, we investigated whether agonistic anti-CD40 could substitute for CD4 T cell help in generating a sustained CD8 T cell response and prevent viral recrudescence following infection with lymphocytic choriomeningitis virus (LCMV). Contrary to expectations, we found that anti...

  15. Squalene-containing licensed adjuvants enhance strain-specific antibody responses against the influenza hemagglutinin and induce subtype-specific antibodies against the neuraminidase.

    Science.gov (United States)

    Schmidt, Rebecca; Holznagel, Edgar; Neumann, Britta; Alex, Nina; Sawatsky, Bevan; Enkirch, Theresa; Pfeffermann, Kristin; Kruip, Carina; von Messling, Veronika; Wagner, Ralf

    2016-10-17

    While seasonal influenza vaccines are usually non-adjuvanted, H1N1pdm09 vaccines were formulated with different squalene-containing adjuvants, to enable the reduction of antigen content thus increasing the number of doses available. To comparatively assess the effects of these adjuvants on antibody responses against matched and mismatched strains, and to correlate antibody levels with protection from disease, ferrets were immunized with 2μg of commercial H1N1pdm09 vaccine antigen alone or formulated with different licensed adjuvants. The use of squalene-containing adjuvants increased neutralizing antibody responses around 100-fold, and resulted in a significantly reduced viral load after challenge with a matched strain. While all animals mounted strong total antibody responses against the homologous H1N1 hemagglutinin (HA) protein, which correlated with the respective neutralizing antibody titers, no reactivity with the divergent H3, H5, H7, and H9 proteins were detected. Only the adjuvanted vaccines also induced antibodies against the neuraminidase (NA) protein, which were able to also recognize NA proteins from other N1 carrying strains. These findings not only support the use of squalene-containing adjuvants in dose-sparing strategies but also support speculations that the induction of NA-specific responses associated with the use of these adjuvants may confer partial protection to heterologous strains carrying the same NA subtype. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Antibody response to Haemophilus influenzae type b capsular polysaccharide conjugated to tetanus toxoid in preterm infants

    DEFF Research Database (Denmark)

    Kristensen, Kim; Gyhrs, A; Lausen, B

    1996-01-01

    OBJECTIVE: To evaluate the antibody response to a Haemophilus influenzae type b capsular polysaccharide (HibCP) tetanus toxoid (TT) conjugate vaccine (HibCP-TT) in preterm infants. SUBJECTS: Thirty-five healthy preterm infants with gestational ages (GA) from 27 to 36 weeks and birth weights from...

  17. A life-style physical activity intervention and the antibody response to pneumococcal vaccination in women

    NARCIS (Netherlands)

    Long, J.E.; Ring, C.; Bosch, J.A.; Eves, F.; Drayson, M.T.; Calver, R.; Say, V.; Allen, D.; Burns, V.E.

    2013-01-01

    Objective: To assess whether a life-style physical activity intervention improved antibody response to a pneumococcal vaccination in sedentary middle-aged women. Methods: Eighty-nine sedentary women completed a 16-week exercise (physical activity consultation, pedometer, telephone/e-mail prompts; n

  18. Immunoglobulin M and G antibody responses to Plasmodium falciparum glutamate-rich protein

    DEFF Research Database (Denmark)

    Dziegiel, Morten Hanefeld; Rowe, P; Bennett, S

    1993-01-01

    The aims of the present study were to describe the age-related immunoglobulin M (IgM) and IgG response to part of a 220-kDa glutamate-rich protein (GLURP) from Plasmodium falciparum and to determine possible correlations of possession of these antibodies with malaria morbidity. IgM and IgG levels...

  19. Persistence of Serogroup C Antibody Responses Following Quadrivalent Meningococcal Conjugate Vaccination in United States Military Personnel

    Science.gov (United States)

    2014-05-14

    available at ScienceDirect Vaccine j our na l ho me page: www.elsev ier .com/ locate /vacc ine ersistence of serogroup C antibody responses following...22] Auckland C, Gray S, Borrow R, Andrews N, Goldblatt D, Ramsay M, et al. Clinical and immunologic risk factors for meningococcal C conjugate

  20. T cell responsiveness correlates differentially with antibody isotype levels in clinical and asymptomatic filariasis

    NARCIS (Netherlands)

    Yazdanbakhsh, M.; Paxton, W. A.; Kruize, Y. C.; Sartono, E.; Kurniawan, A.; van het Wout, A.; Selkirk, M. E.; Partono, F.; Maizels, R. M.

    1993-01-01

    To establish the relationships among T and B cell responses, active infection, and clinical manifestations in lymphatic filariasis, filarial-specific lymphocyte proliferation, IgG antibody isotypes, and IgE levels were determined in an exposed population: 31 asymptomatic amicrofilaremics, 43

  1. Selection for antibody response against sheep red blood cells and layer age affect egg quality

    NARCIS (Netherlands)

    Brand, van den H.; Parmentier, H.K.; Kemp, B.

    2004-01-01

    1. After 22 generations of divergent selection for antibody response against sheep red blood cells (SRBC), hatchability differed between the selected lines. Whether there is a relationship between hatchability and egg traits in these lines is not clear. 2. The aim of the present study was to

  2. A VAR2CSA:CSP conjugate capable of inducing dual specificity antibody responses

    DEFF Research Database (Denmark)

    Matondo, Sungwa; Thrane, Susan; Janitzek, Christoph Mikkel

    2017-01-01

    Catcher peptide. The covalent interaction between SpyTag/SpyCatcher enables the formation of DBL1x-DBL2x-ID2a:CSP conjugate vaccine. Immunogenicity and quality of antibody responses induced by the conjugate vaccine, as well as a control CSP-SpyCatcher vaccine, was tested in BALB/c mice.  Results: Serum samples...

  3. Meeting report: 4th ISIRV antiviral group conference: Novel antiviral therapies for influenza and other respiratory viruses.

    Science.gov (United States)

    McKimm-Breschkin, Jennifer L; Fry, Alicia M

    2016-05-01

    The International Society for Influenza and other Respiratory Virus Diseases (isirv) held its 4th Antiviral Group Conference at the University of Texas on 2-4 June, 2015. With emerging resistance to the drugs currently licensed for treatment and prophylaxis of influenza viruses, primarily the neuraminidase inhibitor oseltamivir phosphate (Tamiflu) and the M2 inhibitors amantadine and rimantadine, and the lack of effective interventions against other respiratory viruses, the 3-day programme focused on the discovery and development of inhibitors of several virus targets and key host cell factors involved in virus replication or mediating the inflammatory response. Virus targets included the influenza haemagglutinin, neuraminidase and M2 proteins, and both the respiratory syncytial virus and influenza polymerases and nucleoproteins. Therapies for rhinoviruses and MERS and SARS coronaviruses were also discussed. With the emerging development of monoclonal antibodies as therapeutics, the potential implications of antibody-dependent enhancement of disease were also addressed. Topics covered all aspects from structural and molecular biology to preclinical and clinical studies. The importance of suitable clinical trial endpoints and regulatory issues were also discussed from the perspectives of both industry and government. This meeting summary provides an overview, not only for the conference participants, but also for those interested in the current status of antivirals for respiratory viruses. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Systemic and Mucosal Antibody Responses to Soluble and Nanoparticle-Conjugated Antigens Administered Intranasally

    Directory of Open Access Journals (Sweden)

    Savannah E. Howe

    2016-10-01

    Full Text Available Nanoparticles (NPs are increasingly being used for drug delivery, as well as antigen carriers and immunostimulants for the purpose of developing vaccines. In this work, we examined how intranasal (i.n. priming followed by i.n. or subcutaneous (s.c. boosting immunization affects the humoral immune response to chicken ovalbumin (Ova and Ova conjugated to 20 nm NPs (NP-Ova. We show that i.n. priming with 20 mg of soluble Ova, a dose known to trigger oral tolerance when administered via gastric gavage, induced substantial systemic IgG1 and IgG2c, as well as mucosal antibodies. These responses were further boosted following a s.c. immunization with Ova and complete Freund’s adjuvant (Ova+CFA. In contrast, 100 µg of Ova delivered via NPs induced an IgG1-dominated systemic response, and primed the intestinal mucosa for secretion of IgA. Following a secondary s.c. or i.n. immunization with Ova+CFA or NP-Ova, systemic IgG1 titers significantly increased, and serum IgG2c and intestinal antibodies were induced in mice primed nasally with NP-Ova. Only Ova- and NP-Ova-primed mice that were s.c.-boosted exhibited substantial systemic and mucosal titers for up to 6 months after priming, whereas the antibodies of i.n.-boosted mice declined over time. Our results indicate that although the amount of Ova delivered by NPs was 1000-fold less than Ova delivered in soluble form, the antigen-specific antibody responses, both systemic and mucosal, are essentially identical by 6 months following the initial priming immunization. Additionally, both i.n.- and s.c.-boosting strategies for NP-Ova-primed mice were capable of inducing a polarized Th1/Th2 immune response, as well as intestinal antibodies; however, it is only by using a heterogeneous prime-boost strategy that long-lasting antibody responses were initiated. These results provide valuable insight for future mucosal vaccine development, as well as furthering our understanding of mucosal antibody responses.

  5. Correlation of pharmacodynamic activity, pharmacokinetics, and anti-product antibody responses to anti-IL-21R antibody therapeutics following IV administration to cynomolgus monkeys

    Directory of Open Access Journals (Sweden)

    Spaulding Vikki

    2010-04-01

    Full Text Available Abstract Background Anti-IL-21R antibodies are potential therapeutics for the treatment of autoimmune diseases. This study evaluated correlations between the pharmacodynamic (PD activity, pharmacokinetics, and anti-product antibody responses of human anti-IL-21R antibodies Ab-01 and Ab-02 following IV administration to cynomolgus monkeys. Methods The PD assay was based on the ability of recombinant human IL-21 (rhuIL-21 to induce expression of the IL-2RA gene in cynomolgus monkey whole blood samples ex vivo. Monkeys screened for responsiveness to rhuIL-21 stimulation using the PD assay, were given a single 10 mg/kg IV dosage of Ab-01, Ab-02, or a control antibody (3/group, and blood samples were evaluated for PD activity (inhibition of IL-2RA expression for up to 148 days. Anti-IL-21R antibody concentrations and anti-product antibody responses were measured in serum using immunoassays and flow cytometry. Results Following IV administration of Ab-01 and Ab-02 to cynomolgus monkeys, PD activity was observed as early as 5 minutes (first time point sampled. This PD activity had good correlation with the serum concentrations and anti-product antibody responses throughout the study. The mean terminal half-life (t1/2 was ~10.6 and 2.3 days for Ab-01 and Ab-02, respectively. PD activity was lost at ~5-13 weeks for Ab-01 and at ~2 weeks for Ab-02, when serum concentrations were relatively low. The estimated minimum concentrations needed to maintain PD activity were ~4-6 nM for Ab-01 and ~2.5 nM for Ab-02, and were consistent with the respective KD values for binding to human IL-21R. For Ab-01, there was noticeable inter-animal variability in t1/2 values (~6-14 days and the resulting PD profiles, which correlated with the onset of anti-product antibody formation. While all three Ab-01-dosed animals were positive for anti-Ab-01 antibodies, only one monkey (with the shortest t1/2 and the earliest loss of PD activity had evidence of neutralizing anti-Ab-01

  6. Lack of association between mannose binding lectin and antibody responses after acellular pertussis vaccinations.

    Directory of Open Access Journals (Sweden)

    Kirsi Gröndahl-Yli-Hannuksela

    Full Text Available BACKGROUND: Mannose-binding lectin (MBL is one of the key molecules in innate immunity and its role in human vaccine responses is poorly known. This study aimed to investigate the possible association of MBL polymorphisms with antibody production after primary and booster vaccinations with acellular pertussis vaccines in infants and adolescents. METHODOLOGY/PRINCIPAL FINDINGS: Five hundred and sixty eight subjects were included in this study. In the adolescent cohort 355 subjects received a dose of diphtheria and tetanus toxoids and acellular pertussis (dTpa vaccine ten years previously. Follow-up was performed at 3, 5 and 10 years. Infant cohort consisted of 213 subjects, who had received three primary doses of DTaP vaccine at 3, 5, and 12 months of age according to Finnish immunization program. Blood samples were collected before the vaccinations at 2,5 months of age and after the vaccinations at 13 months and 2 years of age. Concentrations of IgG antibodies to pertussis toxin, filamentous hemagglutinin, and pertactin and antibodies to diphtheria and tetanus toxoids were measured by standardized enzyme-linked immunosorbant assay. Single nucleotide polymorphisms of MBL2 gene exon1 (codons 52, 54, 57 were examined. MBL serum concentration was also measured from the adolescent cohort. No association was found with MBL2 exon 1 polymorphisms and antibody responses against vaccine antigens, after primary and booster dTpa vaccination. CONCLUSIONS: This study indicates that MBL polymorphisms do not affect the production and persistence of antibodies after acellular pertussis vaccination. Our finding also suggests that MBL might not be involved in modulating antibody responses to the vaccines made of purified bacterial proteins.

  7. Mapping Polyclonal HIV-1 Antibody Responses via Next-Generation Neutralization Fingerprinting.

    Directory of Open Access Journals (Sweden)

    Nicole A Doria-Rose

    2017-01-01

    Full Text Available Computational neutralization fingerprinting, NFP, is an efficient and accurate method for predicting the epitope specificities of polyclonal antibody responses to HIV-1 infection. Here, we present next-generation NFP algorithms that substantially improve prediction accuracy for individual donors and enable serologic analysis for entire cohorts. Specifically, we developed algorithms for: (a selection of optimized virus neutralization panels for NFP analysis, (b estimation of NFP prediction confidence for each serum sample, and (c identification of sera with potentially novel epitope specificities. At the individual donor level, the next-generation NFP algorithms particularly improved the ability to detect multiple epitope specificities in a sample, as confirmed both for computationally simulated polyclonal sera and for samples from HIV-infected donors. Specifically, the next-generation NFP algorithms detected multiple specificities in twice as many samples of simulated sera. Further, unlike the first-generation NFP, the new algorithms were able to detect both of the previously confirmed antibody specificities, VRC01-like and PG9-like, in donor CHAVI 0219. At the cohort level, analysis of ~150 broadly neutralizing HIV-infected donor samples suggested a potential connection between clade of infection and types of elicited epitope specificities. Most notably, while 10E8-like antibodies were observed in infections from different clades, an enrichment of such antibodies was predicted for clade B samples. Ultimately, such large-scale analyses of antibody responses to HIV-1 infection can help guide the design of epitope-specific vaccines that are tailored to take into account the prevalence of infecting clades within a specific geographic region. Overall, the next-generation NFP technology will be an important tool for the analysis of broadly neutralizing polyclonal antibody responses against HIV-1.

  8. Virologic, Clinical, and Immune Response Outcomes of Patients With Hepatitis C Virus-Associated Cryoglobulinemia Treated With Direct-Acting Antivirals.

    Science.gov (United States)

    Bonacci, Martín; Lens, Sabela; Londoño, María-Carlota; Mariño, Zoe; Cid, Maria C; Ramos-Casals, Manuel; Sánchez-Tapias, Jose María; Forns, Xavier; Hernández-Rodríguez, José

    2017-04-01

    Cryoglobulins (circulating immune complexes of polyclonal IgG, monoclonal IgM, and rheumatoid factor) are detected in the circulation of 40% to 60% of patients with chronic hepatitis C virus infection, and cryoglobulinemic vasculitis (CV) is observed in approximately 10% of patients. We aimed to assess the clinical and immune effects of direct-acting antiviral treatment. We performed a prospective study of 64 patients with HCV infection with circulating cryoglobulins receiving direct-acting antiviral therapy at a single center in Barcelona, Spain, from January 2014 through April 2016. Patients were classified as having CV (n = 35) or asymptomatic circulating cryoglobulins (ACC, n = 29). Clinical response was considered complete if a patient's Birmingham Vasculitis Activity Score (version 3) was 0, or if all affected organs improved 12 weeks after the end of therapy. A complete immunologic response (CIR) was defined as no detection of circulating cryoglobulins and normalized levels of complement and/or rheumatoid factor. Clinical manifestations of CV included purpura (65%), weakness (70%), arthralgia (31%), myalgia (20%), peripheral neuropathy (50%), and renal involvement (20%). At baseline, patients with CV had significantly higher levels of rheumatoid factor and lower levels of C4 complement than patients with ACC, whereas cryocrits were similar between groups (3.2% vs 2.6%). Overall, 60 patients (94%) had a sustained viral response 12 weeks after therapy. Among patients with CV, the median Birmingham Vasculitis Activity Score (version 3) decreased from 9 (range, 2-31) to 3 (range, 0-12) (P response. Immune-suppressive therapy was reduced for 4 of 13 patients and withdrawn for 6 of 13. Overall, 48% of patients achieved a CIR. A low baseline cryocrit level (immune activation, including circulating cryoglobulins, persisted in 52% of patients with CV or ACC, despite a sustained viral response 12 weeks after therapy. A longer follow-up period after viral

  9. Anti-α-galactosidase A antibody response to agalsidase beta treatment

    DEFF Research Database (Denmark)

    Wilcox, William R; Linthorst, Gabor E; Germain, Dominique P

    2012-01-01

    Agalsidase beta, a form of recombinant human α-galactosidase A (αGAL), is approved for use as enzyme replacement therapy (ERT) for Fabry disease. An immunogenic response against a therapeutic protein could potentially impact its efficacy or safety. The development of anti-αGAL IgG antibodies...... was evaluated in 571 men and 251 women from the Fabry Registry who were treated with agalsidase beta. Most men developed antibodies (416 of 571, 73%), whereas most women did not (31 of 251, 12%). Women were also significantly more likely to tolerize than men; whereas 18 of 31 women tolerized (58%, 95%CI: 52...

  10. Antibody response of five bird species after vaccination with a killed West Nile virus vaccine.

    Science.gov (United States)

    Okeson, Danelle M; Llizo, Shirley Yeo; Miller, Christine L; Glaser, Amy L

    2007-06-01

    West Nile virus has been associated with numerous bird mortalities in the United States since 1999. Five avian species at three zoological parks were selected to assess the antibody response to vaccination for West Nile virus: black-footed penguins (Spheniscus demersus), little blue penguins (Eudyptula minor), American flamingos (Phoenicopterus ruber), Chilean flamingos (Phoenicopterus chilensis), and Attwater's prairie chickens (Tympanuchus cupido attwateri). All birds were vaccinated intramuscularly at least twice with a commercially available inactivated whole virus vaccine (Innovator). Significant differences in antibody titer over time were detected for black-footed penguins and both flamingo species.

  11. The Complexity of Antibody Responses Elicited against the Respiratory Syncytial Virus Glycoproteins in Hospitalized Children Younger than 2 Years

    Directory of Open Access Journals (Sweden)

    Alfonsina Trento

    2017-11-01

    Full Text Available The influence of age and maternal antibodies on the antibody responses to human respiratory syncytial virus (hRSV glycoproteins in very young children has been a matter of controversy. Both, immaturity of the immune system at very early age and suppression of the host immune response by high level of maternal antibodies have been claimed to limit the host antibody response to virus infection and to jeopardize the use of hRSV vaccines under development in that age group. Hence, the antibody responses to the two major hRSV glycoproteins (F and G were evaluated in children younger than 2 years, hospitalized with laboratory confirmed hRSV bronchiolitis. A strong negative correlation was found between the titre of circulating ELISA antibodies directed against either prefusion or postfusion F in the acute phase, but not age, and their fold change at convalescence. These changes correlated also with the level of circulating neutralizing antibodies in sera. As reported in adults, most neutralizing antibodies in a subset of tested sera could not be depleted with postfusion F, suggesting that they were mostly directed against prefusion-specific epitopes. In contrast, a weak negative association was found for group-specific anti-G antibodies in the acute phase and their fold change at convalescence only after correcting for the antigenic group of the infecting virus. In addition, large discrepancies were observed in some individuals between the antibody responses specific for F and G glycoproteins. These results illustrate the complexity of the anti-hRSV antibody responses in children experiencing a primary severe infection and the influence of preexisting maternal antibodies on the host response, factors that should influence hRSV serological studies as well as vaccine development.

  12. Role of the Antigen Capture Pathway in the Induction of a Neutralizing Antibody Response to Anthrax Protective Antigen

    Directory of Open Access Journals (Sweden)

    Anita Verma

    2018-02-01

    Full Text Available Toxin neutralizing antibodies represent the major mode of protective immunity against a number of toxin-mediated bacterial diseases, including anthrax; however, the cellular mechanisms that lead to optimal neutralizing antibody responses remain ill defined. Here we show that the cellular binding pathway of anthrax protective antigen (PA, the binding component of anthrax toxin, determines the toxin neutralizing antibody response to this antigen. PA, which binds cellular receptors and efficiently enters antigen-presenting cells by receptor-mediated endocytosis, was found to elicit robust anti-PA IgG and toxin neutralizing antibody responses. In contrast, a receptor binding-deficient mutant of PA, which does not bind receptors and only inefficiently enters antigen-presenting cells by macropinocytosis, elicited very poor antibody responses. A chimeric protein consisting of the receptor binding-deficient PA mutant tethered to the binding subunit of cholera toxin, which efficiently enters cells using the cholera toxin receptor rather than the PA receptor, elicited an anti-PA IgG antibody response similar to that elicited by wild-type PA; however, the chimeric protein elicited a poor toxin neutralizing antibody response. Taken together, our results demonstrate that the antigen capture pathway can dictate the magnitudes of the total IgG and toxin neutralizing antibody responses to PA as well as the ratio of the two responses.

  13. Antibody response in cattle, sheep and rats to infection with. gamma. -irradiated metacercariae of Fasciola hepatica

    Energy Technology Data Exchange (ETDEWEB)

    Hughes, D.L.; Doy, T.G. (Agricultural Research Council, Compton (UK). Inst. for Research on Animal Diseases); Hanna, R.E.B. (Queen' s Univ., Belfast, Northern Ireland (UK))

    1982-05-01

    Cattle, sheep and rats were infected orally with ..gamma..-irradiated metacercariae of Fasciola hepatica, or with normal metacercariae. The antibody response was monitored in each host to metacercarial tegument (T0), juvenile tegument (T1), adult tegument (T2) and gut antigens. The response was examined at weekly intervals for cattle and sheep throughout 15 weeks of infection and four weeks after infection in rats, using an indirect fluorescent antibody labelling technique. It was found that the irradiated metacercariae engendered a normal humoral response to T0, T1 and gut antigens in all three hosts although the antibody levels were somewhat reduced due to early death or stunting of the flukes. T0 and T1 appeared to be antigenically similar. Antibodies against T2 appeared late in the animals infected with ..gamma..-irradiated metacercariae and the titres attained were considerably lower than in the controls. The T2 antigen stimulus in the animals given ..gamma..-irradiated metacercariae was probably provided by flukes which 'broke through' the developmental barrier imposed by irradiation and which were found alive at autopsy.

  14. Direct Probing of Germinal Center Responses Reveals Immunological Features and Bottlenecks for Neutralizing Antibody Responses to HIV Env Trimer.

    Science.gov (United States)

    Havenar-Daughton, Colin; Carnathan, Diane G; Torrents de la Peña, Alba; Pauthner, Matthias; Briney, Bryan; Reiss, Samantha M; Wood, Jennifer S; Kaushik, Kirti; van Gils, Marit J; Rosales, Sandy L; van der Woude, Patricia; Locci, Michela; Le, Khoa M; de Taeye, Steven W; Sok, Devin; Mohammed, Ata Ur Rasheed; Huang, Jessica; Gumber, Sanjeev; Garcia, AnaPatricia; Kasturi, Sudhir P; Pulendran, Bali; Moore, John P; Ahmed, Rafi; Seumois, Grégory; Burton, Dennis R; Sanders, Rogier W; Silvestri, Guido; Crotty, Shane

    2016-11-22

    Generating tier 2 HIV-neutralizing antibody (nAb) responses by immunization remains a challenging problem, and the immunological barriers to induction of such responses with Env immunogens remain unclear. Here, some rhesus monkeys developed autologous tier 2 nAbs upon HIV Env trimer immunization (SOSIP.v5.2) whereas others did not. This was not because HIV Env trimers were immunologically silent because all monkeys made similar ELISA-binding antibody responses; the key difference was nAb versus non-nAb responses. We explored the immunological barriers to HIV nAb responses by combining a suite of techniques, including longitudinal lymph node fine needle aspirates. Unexpectedly, nAb development best correlated with booster immunization GC B cell magnitude and Tfh characteristics of the Env-specific CD4 T cells. Notably, these factors distinguished between successful and unsuccessful antibody responses because GC B cell frequencies and stoichiometry to GC Tfh cells correlated with nAb development, but did not correlate with total Env Ab binding titers. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  15. The antibody response to well-defined malaria antigens after acute malaria in individuals living under continuous malaria transmission

    DEFF Research Database (Denmark)

    Petersen, E; Høgh, B; Dziegiel, M

    1992-01-01

    The IgG and IgM antibody responses to the C-terminal 783 amino acids of the P. falciparum glutamate-rich protein, GLURP489-1271, expressed as an E. coli fusion protein, the IgG response to a 18-mer synthetic peptide EDKNEKGQHEIVEVEEIL (GLURP899-916) representing the C-terminal repeats of GLURP...... the antigens, the responses were often short-lived. In adults, the antibody responses to the GLURP489-1271 fusion protein and the (EENV)6 peptide peaked after 2 weeks, and not all individuals responded to all antigens. The antibody response, even against large fragments of conserved antigens, is not uniformly...

  16. Opposite effects of total lymphoid irradiation on T cell-dependent and T cell-independent antibody responses

    Energy Technology Data Exchange (ETDEWEB)

    Tanay, A.; Strober, S.

    1984-02-01

    The effect of total lymphoid irradiation (TLI) on the primary antibody response to the dinitrophenylated heterologous protein, keyhole limpet hemocyanin (DNP-KLH), in complete Freund's adjuvant (CFA), and to the trinitrophenylated polysaccharide antigen, Brucella abortus (TNP-BA), was studied in BALB/c mice. The antibody response to both antigens was diminished in comparison with nonirradiated mice when antigens were injected within 3 days after TLI. When the mice were immunized 30 days after completion of TLI the antibody response to DNP-KLH in CFA was still diminished, but the antibody response to TNP-BA was enhanced 5- to 10-fold as compared with that of control animals. The opposite effect of TLI on the two antibody responses was also observed in a syngeneic primary adoptive transfer system.

  17. Antibody Response is More Likely to Pneumococcal Proteins Than to Polysaccharide After HIV-associated Invasive Pneumococcal Disease

    DEFF Research Database (Denmark)

    Kantsø, Bjørn; Green, Nicola; Goldblatt, David

    2015-01-01

    to at least 1 protein compared to 51% of non-IPD controls. HIV IPD cases responded to more proteins than non-IPD controls (8.6 ± 8.4 vs 4.2 ± 7.6 proteins; P = .01), and had a significantly higher probability of yielding an antibody response to the proteins PiaA, PsaA, and PcpA. Twenty-two percent of HIV......-infected individuals with IPD had a serotype-specific antibody response. Younger age at the time of IPD was the only predictor of a serotype-specific pneumococcal antibody response, whereas we did not identify predictors of a protein-specific antibody response. CONCLUSIONS: Antibody responses occurred more frequently...

  18. DEVELOPMENT OF ANTIVIRAL AGENTS

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. DEVELOPMENT OF ANTIVIRAL AGENTS. Chandipura virus can be regarded as a model system to design and develop antiviral agents. These agents could be small molecules or RNA/PNA aptamers or Antisense RNA to speicific gene sequence in the viral genome.

  19. Antibody responses of cervids (Cervus elaphus) following experimental Mycobacterium bovis infection and the implications for immunodiagnosis.

    Science.gov (United States)

    Harrington, Noel P; Surujballi, Om P; Prescott, John F; Duncan, J Robert; Waters, W Ray; Lyashchenko, Konstantin; Greenwald, Rena

    2008-11-01

    Captive and free-ranging wildlife animals are implicated in the maintenance and transmission of bovine tuberculosis and therefore pose a significant obstacle to eradication of the disease from domestic livestock. The current antemortem diagnostic method, the intradermal tuberculin skin test, is impractical for routine use with many wild animals. Antibody-based assays are particularly attractive because the animals are handled only once and immediate processing of the sample is not required. This report characterizes the antibody responses of red deer-elk hybrids (Cervus elaphus) against Mycobacterium bovis and subsequently evaluates the diagnostic performance of select antigens in a rapid-test format. Sequential serum samples were collected from 10 animals experimentally infected with M. bovis and 5 noninfected animals over a 7-month period postinfection (p.i.). Samples were evaluated by enzyme-linked immunosorbent assays, immunoblot analyses, and multiantigen print immunoassays for seroreactivity to mycobacterial antigens. Although all infected animals produced antibodies to M. bovis protein antigens, there was significant animal-to-animal variation in the kinetics and magnitudes of responses and the antigens recognized. The most frequently recognized antigens included MPB83, ESAT-6, CFP10, and MPB70. Responses to some antigens, such as MPB83, were consistently detected as early as 4 weeks after inoculation, whereas other antigens were detected only much later (>140 days p.i.). Antibody responses were boosted by injection of tuberculin for intradermal tuberculin skin testing. Comparison of single-antigen (fluorescence polarization assay) with multiantigen (CervidTB STAT-PAK) rapid tests demonstrated that a highly sensitive and specific serodiagnostic test for tuberculosis in cervids will require multiple and carefully selected seroreactive antigens covering a broad spectrum of antibody specificities.

  20. Prospective evaluation of antibody response to Streptococcus gallolyticus and risk of colorectal cancer.

    Science.gov (United States)

    Butt, Julia; Jenab, Mazda; Willhauck-Fleckenstein, Martina; Michel, Angelika; Pawlita, Michael; Kyrø, Cecilie; Tjønneland, Anne; Boutron-Ruault, Marie-Christine; Carbonnel, Franck; Severi, Gianluca; Kaaks, Rudolf; Kühn, Tilman; Boeing, Heiner; Trichopoulou, Antonia; la Vecchia, Carlo; Karakatsani, Anna; Panico, Salvatore; Tumino, Rosario; Agnoli, Claudia; Palli, Domenico; Sacerdote, Carlotta; Bueno-de-Mesquita, Bas; Weiderpass, Elisabete; Sánchez, Maria-José; Bonet Bonet, Catalina; Huerta, José María; Ardanaz, Eva; Bradbury, Kathryn; Gunter, Marc; Murphy, Neil; Freisling, Heinz; Riboli, Elio; Tsilidis, Kostas; Aune, Dagfinn; Waterboer, Tim; Hughes, David J

    2018-01-29

    The gut microbiome is increasingly implicated in colorectal cancer (CRC) development. A subgroup of patients diagnosed with CRC show high antibody responses to Streptococcus gallolyticus subspecies gallolyticus (SGG). However, it is unclear whether the association is also present pre-diagnostically. We assessed the association of antibody responses to SGG proteins in pre-diagnostic serum samples with CRC risk in a case-control study nested within a prospective cohort. Pre-diagnostic serum samples from 485 first incident CRC cases (mean time between blood draw and diagnosis 3.4 years) and 485 matched controls in the European Prospective Investigation into Nutrition and Cancer (EPIC) study were analyzed for antibody responses to 11 SGG proteins using multiplex serology. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable conditional logistic regression models. Antibody positivity for any of the 11 SGG proteins was significantly associated with CRC risk with 56% positive controls compared to 63% positive cases (OR: 1.36, 95% CI: 1.04-1.77). Positivity for two or more proteins of a previously identified SGG 6-marker panel with greater CRC-specificity was also observed among 9% of controls compared to 17% of CRC cases, corresponding to a significantly increased CRC risk (OR: 2.17, 95% CI: 1.44-3.27). In this prospective nested case-control study, we observed a positive association between antibody responses to SGG and CRC development in serum samples taken before evident disease onset. Further work is required to establish the possibly etiological significance of these observations and whether SGG serology may be applicable for CRC risk stratification. © 2018 UICC.

  1. Correlated effects of selection for immunity in White Leghorn chicken lines on natural antibodies and specific antibody responses to KLH and M. butyricum

    NARCIS (Netherlands)

    Minozzi, G.; Parmentier, H.K.; Mignon-Grasteau, S.; Nieuwland, M.G.B.; Bed'hom, B.; Gourichon, D.; Minvielle, F.; Pinard-van der Laan, M.H.

    2008-01-01

    Background - The effect of selection for three general immune response traits on primary antibody responses (Ab) to Mycobacterium butyricum or keyhole limpet hemocyanin (KLH) was studied in four experimental lines of White Leghorn chicken. Birds underwent 12 generations of selection for one of three

  2. The Matrix Protein of Nipah Virus Targets the E3-Ubiquitin Ligase TRIM6 to Inhibit the IKKε Kinase-Mediated Type-I IFN Antiviral Response.

    Directory of Open Access Journals (Sweden)

    Preeti Bharaj

    2016-09-01

    Full Text Available For efficient replication, viruses have developed mechanisms to evade innate immune responses, including the antiviral type-I interferon (IFN-I system. Nipah virus (NiV, a highly pathogenic member of the Paramyxoviridae family (genus Henipavirus, is known to encode for four P gene-derived viral proteins (P/C/W/V with IFN-I antagonist functions. Here we report that NiV matrix protein (NiV-M, which is important for virus assembly and budding, can also inhibit IFN-I responses. IFN-I production requires activation of multiple signaling components including the IκB kinase epsilon (IKKε. We previously showed that the E3-ubiquitin ligase TRIM6 catalyzes the synthesis of unanchored K48-linked polyubiquitin chains, which are not covalently attached to any protein, and activate IKKε for induction of IFN-I mediated antiviral responses. Using co-immunoprecipitation assays and confocal microscopy we show here that the NiV-M protein interacts with TRIM6 and promotes TRIM6 degradation. Consequently, NiV-M expression results in reduced levels of unanchored K48-linked polyubiquitin chains associated with IKKε leading to impaired IKKε oligomerization, IKKε autophosphorylation and reduced IFN-mediated responses. This IFN antagonist function of NiV-M requires a conserved lysine residue (K258 in the bipartite nuclear localization signal that is found in divergent henipaviruses. Consistent with this, the matrix proteins of Ghana, Hendra and Cedar viruses were also able to inhibit IFNβ induction. Live NiV infection, but not a recombinant NiV lacking the M protein, reduced the levels of endogenous TRIM6 protein expression. To our knowledge, matrix proteins of paramyxoviruses have never been reported to be involved in innate immune antagonism. We report here a novel mechanism of viral innate immune evasion by targeting TRIM6, IKKε and unanchored polyubiquitin chains. These findings expand the universe of viral IFN antagonism strategies and provide a new

  3. Genomic copy number variants: evidence for association with antibody response to anthrax vaccine adsorbed.

    Directory of Open Access Journals (Sweden)

    Michael I Falola

    Full Text Available Anthrax and its etiologic agent remain a biological threat. Anthrax vaccine is highly effective, but vaccine-induced IgG antibody responses vary widely following required doses of vaccinations. Such variation can be related to genetic factors, especially genomic copy number variants (CNVs that are known to be enriched among genes with immunologic function. We have tested this hypothesis in two study populations from a clinical trial of anthrax vaccination.We performed CNV-based genome-wide association analyses separately on 794 European Americans and 200 African-Americans. Antibodies to protective antigen were measured at week 8 (early response and week 30 (peak response using an enzyme-linked immunosorbent assay. We used DNA microarray data (Affymetrix 6.0 and two CNV detection algorithms, hidden markov model (PennCNV and circular binary segmentation (GeneSpring to determine CNVs in all individuals. Multivariable regression analyses were used to identify CNV-specific associations after adjusting for relevant non-genetic covariates.Within the 22 autosomal chromosomes, 2,943 non-overlapping CNV regions were detected by both algorithms. Genomic insertions containing HLA-DRB5, DRB1 and DQA1/DRA genes in the major histocompatibility complex (MHC region (chromosome 6p21.3 were moderately associated with elevated early antibody response (β = 0.14, p = 1.78×10(-3 among European Americans, and the strongest association was observed between peak antibody response and a segmental insertion on chromosome 1, containing NBPF4, NBPF5, STXMP3, CLCC1, and GPSM2 genes (β = 1.66, p = 6.06×10(-5. For African-Americans, segmental deletions spanning PRR20, PCDH17 and PCH68 genes on chromosome 13 were associated with elevated early antibody production (β = 0.18, p = 4.47×10(-5. Population-specific findings aside, one genomic insertion on chromosome 17 (containing NSF, ARL17 and LRRC37A genes was associated with elevated peak antibody

  4. Mycoplasma hyopneumoniae does not affect the interferon-related anti-viral response but predisposes the pig to a higher level of inflammation following swine influenza virus infection.

    Science.gov (United States)

    Deblanc, Céline; Delgado-Ortega, Mario; Gorin, Stéphane; Berri, Mustapha; Paboeuf, Frédéric; Berthon, Patricia; Herrler, Georg; Meurens, François; Simon, Gaëlle

    2016-10-01

    In pigs, influenza A viruses and Mycoplasma hyopneumoniae (Mhp) are major contributors to the porcine respiratory disease complex. Pre-infection with Mhp was previously shown experimentally to exacerbate the clinical outcomes of H1N1 infection during the first week after virus inoculation. In order to better understand the interactions between these pathogens, we aimed to assess very early responses (at 5, 24 and 48 h) after H1N1 infection in pigs pre-infected or not with Mhp. Clinical signs and macroscopic lung lesions were similar in both infected groups at early times post-H1N1 infection; and Mhp pre-infection affected neither the influenza virus replication nor the IFN-induced antiviral responses in the lung. However, it predisposed the animals to a higher inflammatory response to H1N1 infection, as revealed by the massive infiltration of neutrophils and macrophages into the lungs and the increased production of pro-inflammatory cytokines (IL-6, IL-1β and TNF-α). Thus, it seems it is this marked inflammatory state that would play a role in exacerbating the clinical signs subsequent to H1N1 infection.

  5. Humoral antibody response to glutaraldehyde-treated antigens of Dermatophilus congolensis.

    Science.gov (United States)

    Makinde, A A; Molokwu, J U; Ezeh, A O

    1986-04-01

    Glutaraldehyde-treated whole cell antigens (GA.WcA) of Dermatophilus congolensis induced in guinea pigs immunological memory in contrast to cell wall antigens treated similarly (GA.CwA). However, GA.WcA could not induce a secondary response in animals primed with untreated WcA while GA.CwA on the other hand did stimulate a secondary response in animals primed with untreated CwA. Primary antibody production was induced by both GA.CwA and untreated CwA to a similar level in their respective hosts but it was the secondary response that was found similar in response to GA.WcA and untreated WcA. However, both untreated WcA and CwA induced primary and secondary antibody production in their respective hosts though these responses were considerably higher in guinea pigs given untreated CwA. This study showed that both untreated and GA-treated antigens of D. congolensis are capable of stimulating antibody production in guinea pigs but they differ in their levels of stimulation.

  6. Antibody response to actinomyces antigen and dental caries experience: implications for caries susceptibility.

    Science.gov (United States)

    Levine, Martin; Owen, Willis L; Avery, Kevin T

    2005-06-01

    Fluoridated dentifrices reduce dental caries in subjects who perform effective oral hygiene. Actinomyces naeslundii increases in teeth-adherent microbial biofilms (plaques) in these subjects, and a well-characterized serum immunoglobulin G (IgG) antibody response (Actinomyces antibody [A-Ab]) is also increased. Other studies suggest that a serum IgG antibody response to streptococcal d-alanyl poly(glycerophosphate) (S-Ab) may indicate caries experience associated strongly with gingival health and exposure to fluoridated water. The aim of this study was to investigate relationships between A-Ab response, oral hygiene, S-Ab response, and caries experience. Measurements were made of A-Ab and S-Ab concentrations, caries experience (number of decayed, missing, and filled teeth [DMFT], number of teeth surfaces [DMFS], and number of decayed teeth needing treated [DT]), exposure to fluoridated water (Flu), mean clinical pocket depth (PD; in millimeters), and extent of plaque (PL) and gingival bleeding on probing (BOP). A-Ab concentration, the dependent variable in a multiple regression analysis, increased with S-Ab concentration and decreased with PL and DMFT adjusted for Flu (R(2) = 0.51, P caries in subjects performing effective oral hygiene using fluoridated dentifrices. Conversely, a low A-Ab response is suggestive of decreased A. naeslundii binding to saliva-coated apatite and greater caries experience, as reported by others.

  7. HIV-1 Cross-Reactive Primary Virus Neutralizing Antibody Response Elicited by Immunization in Nonhuman Primates.

    Science.gov (United States)

    Wang, Yimeng; O'Dell, Sijy; Turner, Hannah L; Chiang, Chi-I; Lei, Lin; Guenaga, Javier; Wilson, Richard; Martinez-Murillo, Paola; Doria-Rose, Nicole; Ward, Andrew B; Mascola, John R; Wyatt, Richard T; Karlsson Hedestam, Gunilla B; Li, Yuxing

    2017-11-01

    Elicitation of broadly neutralizing antibody (bNAb) responses is a major goal for the development of an HIV-1 vaccine. Current HIV-1 envelope glycoprotein (Env) vaccine candidates elicit predominantly tier 1 and/or autologous tier 2 virus neutralizing antibody (NAb) responses, as well as weak and/or sporadic cross-reactive tier 2 virus NAb responses with unknown specificity. To delineate the specificity of vaccine-elicited cross-reactive tier 2 virus NAb responses, we performed single memory B cell sorting from the peripheral blood of a rhesus macaque immunized with YU2gp140-F trimers in adjuvant, using JR-FL SOSIP.664, a native Env trimer mimetic, as a sorting probe to isolate monoclonal Abs (MAbs). We found striking genetic and functional convergence of the SOSIP-sorted Ig repertoire, with predominant VH4 or VH5 gene family usage and Env V3 specificity. Of these vaccine-elicited V3-specific MAbs, nearly 20% (6/33) displayed cross-reactive tier 2 virus neutralization, which recapitulated the serum neutralization capacity. Substantial similarities in binding specificity, neutralization breadth and potency, and sequence/structural homology were observed between selected macaque cross-reactive V3 NAbs elicited by vaccination and prototypic V3 NAbs derived from natural infections in humans, highlighting the convergence of this subset of primate V3-specific B cell repertories. Our study demonstrated that cross-reactive primary virus neutralizing B cell lineages could be elicited by vaccination as detected using a standardized panel of tier 2 viruses. Whether these lineages could be expanded to acquire increased breadth and potency of neutralization merits further investigation. IMPORTANCE Elicitation of antibody responses capable of neutralizing diverse HIV-1 primary virus isolates (designated broadly neutralizing antibodies [bNAbs]) remains a high priority for the vaccine field. bNAb responses were so far observed only in response to natural infection within a subset

  8. Anti-HIV Antibody Responses and the HIV Reservoir Size during Antiretroviral Therapy.

    Directory of Open Access Journals (Sweden)

    Sulggi A Lee

    Full Text Available A major challenge to HIV eradication strategies is the lack of an accurate measurement of the total burden of replication-competent HIV (the "reservoir". We assessed the association of anti-HIV antibody responses and the estimated size of the reservoir during antiretroviral therapy (ART.We evaluated anti-HIV antibody profiles using luciferase immunoprecipitation systems (LIPS assay in relation to several blood-based HIV reservoir measures: total and 2-LTR DNA (rtPCR or droplet digital PCR; integrated DNA (Alu PCR; unspliced RNA (rtPCR, multiply-spliced RNA (TILDA, residual plasma HIV RNA (single copy PCR, and replication-competent virus (outgrowth assay. We also assessed total HIV DNA and RNA in gut-associated lymphoid tissue (rtPCR. Spearman correlations and linear regressions were performed using log-transformed blood- or tissue-based reservoir measurements as predictors and log-transformed antibody levels as outcome variables.Among 51 chronically HIV-infected ART-suppressed participants (median age = 57, nadir CD4+ count = 196 cells/mm3, ART duration = 9 years, the most statistically significant associations were between antibody responses to integrase and HIV RNA in gut-associated lymphoid tissue (1.17 fold-increase per two-fold RNA increase, P = 0.004 and between antibody responses to matrix and integrated HIV DNA in resting CD4+ T cells (0.35 fold-decrease per two-fold DNA increase, P = 0.003. However, these associations were not statistically significant after a stringent Bonferroni-adjustment of P<0.00045. Multivariate models including age and duration of ART did not markedly alter results.Our findings suggest that anti-HIV antibody responses may reflect the size of the HIV reservoir during chronic treated HIV disease, possibly via antigen recognition in reservoir sites. Larger, prospective studies are needed to validate the utility of antibody levels as a measure of the total body burden of HIV during treatment.

  9. Vibrio cholerae O1 secretes an extracellular matrix in response to antibody-mediated agglutination.

    Directory of Open Access Journals (Sweden)

    Danielle E Baranova

    Full Text Available Vibrio cholerae O1 is one of two serogroups responsible for epidemic cholera, a severe watery diarrhea that occurs after the bacterium colonizes the human small intestine and secretes a potent ADP-ribosylating toxin. Immunity to cholera is associated with intestinal anti-lipopolysaccharide (LPS antibodies, which are known to inhibit V. cholerae motility and promote bacterial cell-cell crosslinking and aggregation. Here we report that V. cholerae O1 classical and El Tor biotypes produce an extracellular matrix (ECM when forcibly immobilized and agglutinated by ZAC-3 IgG, an intestinally-derived monoclonal antibody (MAb against the core/lipid A region of LPS. ECM secretion, as demonstrated by crystal violet staining and scanning electron microscopy, occurred within 30 minutes of antibody exposure and peaked by 3 hours. Non-motile mutants of V. cholerae did not secrete ECM following ZAC-3 IgG exposure, even though they were susceptible to agglutination. The ECM was enriched in O-specific polysaccharide (OSP but not Vibrio polysaccharide (VPS. Finally, we demonstrate that ECM production by V. cholerae in response to ZAC-3 IgG was associated with bacterial resistant to a secondary complement-mediated attack. In summary, we propose that V. cholerae O1, upon encountering anti-LPS antibodies in the intestinal lumen, secretes an ECM (or O-antigen capsule possibly as a strategy to shield itself from additional host immune factors and to exit an otherwise inhospitable host environment.

  10. Respons Antibodi Sekunder Terhadap Penyakit Tetelo pada Ayam Petelur Pascavaksinasi Ulangan dengan Vaksin Tetelo Aktif (NEWCASTLE DISEASESECONDARY ANTIBODY RESPONSE AFTER REVACCINATION IN LAYER WITH THE ACTIVE ND VACCINE

    Directory of Open Access Journals (Sweden)

    Andika Budi Kurnianto

    2016-11-01

    Full Text Available Revaccination is required in order to preventNewcastle Disease (ND reccurence inlayers chickens. Oneof vaccine for ND revaccination is freeze-died ND active vaccine containing e” 106,5EID50. Revaccinationisdone to trigger a faster secondary antibody responses in layers and can achieve protective antibody titersagainst ND that can be monitored by a hemagglutinationinhibition (HI. The aim of this study was todetermine the ND secondary antibody responses in layers after revaccination with ND active vaccine.Antibody titer of 20 layers chickens of 20 week old were determined before revaccinations (week 0 andafter revaccinations (week 1 until week 9. The first vaccination was conducted using ND-IB (NewcastleDisease-Infectious Bronchitis at the age of 2 days through eye drops and subcutaneous injection at the ageof 5 days using a dose of 1 ampoule.Vaccination is repeated at the age of 20 weeks at a dose of 1 ½ ampoule through drinking water. Blood samples were collected on the wing vein (venous cutane ulnar and left for 5-10 minutes at room temperature.Sera were then collected and stored at -20oC until use. HI antibody titerwas determined by micro titeration system. The HI mean titers were analyzed by Duncan test. The studyresults showed that antibody titer before revaccination was3,47 HI log 2 and the HI titers after revaccinationwere 4,02; 5,22; 6,52; 7,85; 8,4; 8,6; 7,7; 5,92; dan 3,87 HI log 2 respectivelly at weeks 1, 2, 3, 4, 5, 6, 7, 8, and9.The NDV revaccination with ND active vaccine significantly (P <0.01 increased in antibody titer inlayers starting from week 1 to week 6, but decreased following week 7 to week-9. It can be concluded thatrevaccinantion with ND active vaccine increases the antibody titers in layer chickens.

  11. Retinoic acid-inducible gene-I-like receptor (RLR)-mediated antiviral innate immune responses in the lower respiratory tract: Roles of TRAF3 and TRAF5.

    Science.gov (United States)

    Chiba, Yuki; Matsumiya, Tomoh; Satoh, Tsugumi; Hayakari, Ryo; Furudate, Ken; Xing, Fei; Yoshida, Hidemi; Tanji, Kunikazu; Mizukami, Hiroki; Imaizumi, Tadaatsu; Ito, Etsuro

    2015-11-13

    Upon viral infection, the cytoplasmic viral sensor retinoic acid-inducible gene-I (RIG-I) recognizes viral RNA to activate antiviral signaling to induce type I interferon (IFN). RIG-I-like receptors (RLRs) activate antiviral signaling in a tissue-specific manner. The molecular mechanism underlying antiviral signaling in the respiratory system remains unclear. We studied antiviral signaling in the lower respiratory tract (LRT), which is the site of many harmful viral infections. Epithelial cells of the LRT can be roughly divided into two groups: bronchial epithelial cells (BECs) and pulmonary alveolar epithelial cells (AECs). These two cell types exhibit different phenotypes; therefore, we hypothesized that these cells may play different roles in antiviral innate immunity. We found that BECs exhibited higher antiviral activity than AECs. TNF receptor-associated factor 3 (TRAF3) has been shown to be a crucial molecule in RLR signaling. The expression levels of TRAF3 and TRAF5, which have conserved domains that are nearly identical, in the LRT were examined. We found that the bronchus exhibited the highest expression levels of TRAF3 and TRAF5 in the LRT. These findings suggest the importance of the bronchus in antiviral innate immunity in the LRT and indicate that TRAF3 and TRAF5 may contribute to RLR signaling. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Serum antibody responses to periodontal microbiota in chronic and aggressive periodontitis: a postulate revisited.

    Science.gov (United States)

    Hwang, Andrew M; Stoupel, Janet; Celenti, Romanita; Demmer, Ryan T; Papapanou, Panos N

    2014-04-01

    The authors revisited the 1999 International Workshop postulate of robust serum antibody responses to infecting agents in localized aggressive periodontitis (LAgP) and weak responses in generalized aggressive periodontitis (GAgP). Antibody responses were further examined in localized and generalized chronic periodontitis (LCP and GCP). The study includes 119 patients (60 males and 59 females, aged 11 to 76 years), 18 with LAgP, 37 with GAgP, 37 with LCP, and 27 with GCP. Multiple subgingival plaque samples/patient (1,057 in total) were analyzed with respect to 11 bacterial species using checkerboard DNA-DNA hybridizations, and serum immunoglobulin (Ig)G levels were measured against the same bacteria using checkerboard immunoblotting. Further, infection ratios (antibody level over the average bacterial colonization by the homologous species) were computed for each patient. Comparisons of bacterial colonization, serum IgG levels, and infection ratios were made across the diagnostic categories using multivariable linear regression models adjusting for age and race/ethnicity. There were no statistically significant differences in serum IgG levels to Aggregatibacter actinomycetemcomitans among the four diagnostic categories. IgG levels to several species, including Porphyromonas gingivalis, Treponema denticola, and Campylobacter rectus, were highest in patients with GAgP and significantly different from LCP and GCP, but not from LAgP. Comparisons based on infection ratios showed no statistically significant differences for any species between GAgP and LAgP. This study provides evidence against the 1999 Workshop's postulate of weak serum antibody responses in patients with GAgP and shows that serum IgG responses in GAgP are comparable to those in LAgP, but higher than in GCP or LCP for several species.

  13. Immunological development in nestling American kestrels Falco sparverius: post-hatching ontogeny of the antibody response.

    Science.gov (United States)

    Smits, Judit E G; Bortolotti, Gary R

    2008-12-01

    Avian research involving examination of immune function or testing of immunocompetence in wild birds has been based upon information on Galliforms, (chicken and quail) even though they are precocial, whereas most wild species with which ecologists, biologists and toxicologists work are altricial; blind, naked and completely dependent at hatching. Here we begin to address this gap in knowledge, offering insight into the early, post-hatching, humoral immune response in an altricial bird, the American kestrel (Falco sparverius). Over two breeding seasons, nestling kestrels were immunized with a non-pathogenic antigen, dinitrophenol keyhole limpet hemocyanin (DNP-KLH), between 3 and 9 days post-hatching and boostered 6 days later. Background levels, primary and secondary immune responses were measured using an enzyme linked immunosorbent assay. The specificity of our laboratory produced rabbit, anti-kestrel antibody was determined using a double immunodiffusion assay. Results showed the rabbit antiserum to have specific anti-kestrel IgG activity. Birds as young as three days old could successfully mount an antibody response, the magnitude of which increased with age at first vaccination. Early immunization did not compromise growth rate, nor did it affect the maximum secondary response. Comparatively, adult kestrels immunized during the same season and following the same protocol, had antibody levels four times higher than those of the nestlings.

  14. Immune response to pneumococcal polysaccharides 4 and 14 in elderly and young adults. I Antibody concentrations, avidity and functional activity

    Directory of Open Access Journals (Sweden)

    Carlone George M

    2005-06-01

    Full Text Available Abstract Streptococcus pneumoniae is a serious worldwide pathogen and the focus of numerous vaccine development projects. Currently the most widely accepted surrogate marker for evaluating the efficacy of a given vaccine is to utilize ELISA. Measurement of antibody concentration by ELISA without reduction in cross-reactive antibodies causes an overestimation of antibody concentration and therefore protection, this is most notable in the aged, an at risk group for this infection. We compared the immune response to the pneumococcal polysaccharides (PPS 4 and 14 of 20 young to 20 elderly adults. Pre-and post-vaccination IgG antibody concentrations and antibody avidity against PPS4 and PPS14 were measured using two different enzyme-linked immunosorbant assay (ELISA absorption protocols. All sera were pre-absorbed with either cell-wall polysaccharide (CPS, or CPS and serotype 22F polysaccharide. Pre- and post-vaccination IgG antibody concentrations for serotype 4, but not 14, were significantly lowered with the additional absorption with serotype 22F polysaccharide in both age groups. Young and elderly demonstrated a significant increase from pre- to post-immunization antibody concentration, using either absorption method; and opsonophagocytic antibody titers in response to both PPS4 and PPS14. The correlation coefficients between ELISA and opsonophagocytic assays were improved by additional absorption with serotype 22F in response to serotype 4, but not serotype 14 in all age groups. Opsonophagocytic antibody titers in a sub-group of elderly (>77 years of age were significantly lower than the opsonophagocytic antibody concentrations in young adults. These results suggest the importance of eliminating cross-reactive antibodies from ELISA measurements by absorption of serum and an age-related impairment in the antibody response to pneumococcal polysaccharides.

  15. Insight into buffalo (Bubalus bubalis RIG1 and MDA5 receptors: a comparative study on dsRNA recognition and in-vitro antiviral response.

    Directory of Open Access Journals (Sweden)

    Manvender Singh

    Full Text Available RIG1 and MDA5 have emerged as important intracellular innate pattern recognition receptors that recognize viral RNA and mediate cellular signals controlling Type I interferon (IFN-I response. Buffalo RIG1 and MDA5 genes were investigated to understand the mechanism of receptor induced antiviral response. Sequence analysis revealed that RIG1 and MDA5 maintain a domain arrangement that is common in mammals. Critical binding site residues of the receptors are evolutionary conserved among mammals. Molecular dynamics simulations suggested that RIG1 and MDA5 follow a similar, if not identical, dsRNA binding pattern that has been previously reported in human. Moreover, binding free energy calculation revealed that MDA5 had a greater affinity towards dsRNA compared to RIG1. Constitutive expressions of RLR genes were ubiquitous in different tissues without being specific to immune organs. Poly I:C stimulation induced elevated expressions of IFN-β and IFN-stimulated genes (ISGs through interferon regulatory factors (IRFs mediated pathway in buffalo foetal fibroblast cells. The present study provides crucial insights into the structure and function of RIG1 and MDA5 receptors in buffalo.

  16. Age-dependent differences in cytokine and antibody responses after experimental RSV infection in a bovine model

    DEFF Research Database (Denmark)

    Grell, S.N.; Riber, Ulla; Tjørnehøj, Kirsten

    2005-01-01

    Respiratory syncytial virus (RSV) causes severe respiratory disease in both infants and calves. As in humans, bovine RSV (BRSV) infections are most severe in the first 6 months of life. In this study, experimental infection with BRSV was performed in calves aged 1-5, 9-16 or 32-37 weeks. Compared...... "inflammatory" but weak humoral antiviral response in very young animals suggests that enhanced inflammation contributes to disease during RSV infection during the early postnatal period....

  17. Enhancement of antiviral activity of collectin trimers through cross-linking and mutagenesis of the carbohydrate recognition domain

    DEFF Research Database (Denmark)

    White, Mitchell R; Boland, Patrick; Tecle, Tesfaldet

    2010-01-01

    . We have sought to find ways to increase the antiviral activity of collectin NCRDs. Cross-linking of the SP-D NCRD with nonblocking monoclonal antibodies (mAbs) markedly potentiates antiviral activity. In the present report, we demonstrate that F(ab')2 [but not F(ab')1] fragments of a cross-linking mAb...... collectins, we have constructed mutant versions of the human SP-D NCRD that have increased antiviral activity. These mutant NCRDs also had potentiated activity after cross-linking with F(ab')2 fragments or S protein complexes. Hence, the antiviral activity of NCRDs can be increased by 2 distinct...... have similar effects. Hence, cross-linking activity, but not the Fc domain of the mAb, is needed for increased antiviral activity. In contrast, the Fc domain of the mAb was important for increasing viral uptake or respiratory burst responses of human neutrophils. Our NCRD constructs contain an S...

  18. A Newly Emergent Turkey Arthritis Reovirus Shows Dominant Enteric Tropism and Induces Significantly Elevated Innate Antiviral and T Helper-1 Cytokine Responses.

    Directory of Open Access Journals (Sweden)

    Tamer A Sharafeldin

    Full Text Available Newly emergent turkey arthritis reoviruses (TARV were isolated from tendons of lame 15-week-old tom turkeys that occasionally had ruptured leg tendons. Experimentally, these TARVs induced remarkable tenosynovitis in gastrocnemius tendons of turkey poults. The current study aimed to characterize the location and the extent of virus replication as well as the cytokine response induced by TARV during the first two weeks of infection. One-week-old male turkeys were inoculated orally with TARV (O'Neil strain. Copy numbers of viral genes were estimated in intestines, internal organs and tendons at ½, 1, 2, 3, 4, 7, 14 days Post inoculation (dpi. Cytokine profile was measured in intestines, spleen and leg tendons at 0, 4, 7 and 14 dpi. Viral copy number peaked in jejunum, cecum and bursa of Fabricius at 4 dpi. Copy numbers increased dramatically in leg tendons at 7 and 14 dpi while minimal copies were detected in internal organs and blood during the same period. Virus was detected in cloacal swabs at 1-2 dpi, and peaked at 14 dpi indicating enterotropism of the virus and its early shedding in feces. Elevation of IFN-α and IFN-β was observed in intestines at 7 dpi as well as a prominent T helper-1 response (IFN-γ at 7 and 14 dpi. IFN-γ and IL-6 were elevated in gastrocnemius tendons at 14 dpi. Elevation of antiviral cytokines in intestines occurred at 7dpi when a significant decline of viral replication in intestines was observed. T helper-1 response in intestines and leg tendons was the dominant T-helper response. These results suggest the possible correlation between viral replication and cytokine response in early infection of TARV in turkeys. Our findings provide novel insights which help elucidate viral pathogenesis in turkey tendons infected with TARV.

  19. Protein Phosphatase, Mg2+/Mn2+-dependent 1A controls the innate antiviral and antibacterial response of macrophages during HIV-1 and Mycobacterium tuberculosis infection

    Science.gov (United States)

    Sun, Jim; Schaaf, Kaitlyn; Duverger, Alexandra; Wolschendorf, Frank; Speer, Alexander; Wagner, Frederic; Niederweis, Michael; Kutsch, Olaf

    2016-01-01

    Co-infection with HIV-1 and Mycobacterium tuberculosis (Mtb) is a major public health issue. While some research has described how each pathogen accelerates the course of infection of the other pathogen by compromising the immune system, very little is known about the molecular biology of HIV-1/Mtb co-infection at the host cell level. This is somewhat surprising, as both pathogens are known to replicate and persist in macrophages. We here identify Protein Phosphatase, Mg2+/Mn2+-dependent 1A (PPM1A) as a molecular link between Mtb infection and increased HIV-1 susceptibility of macrophages. We demonstrate that both Mtb and HIV-1 infection induce the expression of PPM1A in primary human monocyte/macrophages and THP-1 cells. Genetic manipulation studies revealed that increased PPMA1 expression rendered THP-1 cells highly susceptible to HIV-1 infection, while depletion of PPM1A rendered them relatively resistant to HIV-1 infection. At the same time, increased PPM1A expression abrogated the ability of THP-1 cells to respond to relevant bacterial stimuli with a proper cytokine/chemokine secretion response, blocked their chemotactic response and impaired their ability to phagocytose bacteria. These data suggest that PPM1A, which had previously been shown to play a role in the antiviral response to Herpes Simplex virus infection, also governs the antibacterial response of macrophages to bacteria, or at least to Mtb infection. PPM1A thus seems to play a central role in the innate immune response of macrophages, implying that host directed therapies targeting PPM1A could be highly beneficial, in particular for HIV/Mtb co-infected patients. PMID:27004401

  20. A Newly Emergent Turkey Arthritis Reovirus Shows Dominant Enteric Tropism and Induces Significantly Elevated Innate Antiviral and T Helper-1 Cytokine Responses.

    Science.gov (United States)

    Sharafeldin, Tamer A; Mor, Sunil K; Sobhy, Nader M; Xing, Zheng; Reed, Kent M; Goyal, Sagar M; Porter, Robert E

    2015-01-01

    Newly emergent turkey arthritis reoviruses (TARV) were isolated from tendons of lame 15-week-old tom turkeys that occasionally had ruptured leg tendons. Experimentally, these TARVs induced remarkable tenosynovitis in gastrocnemius tendons of turkey poults. The current study aimed to characterize the location and the extent of virus replication as well as the cytokine response induced by TARV during the first two weeks of infection. One-week-old male turkeys were inoculated orally with TARV (O'Neil strain). Copy numbers of viral genes were estimated in intestines, internal organs and tendons at ½, 1, 2, 3, 4, 7, 14 days Post inoculation (dpi). Cytokine profile was measured in intestines, spleen and leg tendons at 0, 4, 7 and 14 dpi. Viral copy number peaked in jejunum, cecum and bursa of Fabricius at 4 dpi. Copy numbers increased dramatically in leg tendons at 7 and 14 dpi while minimal copies were detected in internal organs and blood during the same period. Virus was detected in cloacal swabs at 1-2 dpi, and peaked at 14 dpi indicating enterotropism of the virus and its early shedding in feces. Elevation of IFN-α and IFN-β was observed in intestines at 7 dpi as well as a prominent T helper-1 response (IFN-γ) at 7 and 14 dpi. IFN-γ and IL-6 were elevated in gastrocnemius tendons at 14 dpi. Elevation of antiviral cytokines in intestines occurred at 7dpi when a significant decline of viral replication in intestines was observed. T helper-1 response in intestines and leg tendons was the dominant T-helper response. These results suggest the possible correlation between viral replication and cytokine response in early infection of TARV in turkeys. Our findings provide novel insights which help elucidate viral pathogenesis in turkey tendons infected with TARV.

  1. Research advances in determination of hepatitis B core antibody level

    Directory of Open Access Journals (Sweden)

    WANG Wei

    2016-07-01

    Full Text Available With the development and application of the double antigen sandwich method for quantification of hepatitis B core antibody (HBcAb in recent years, there is increasing knowledge of the ability of HBcAb to reflect the body′s anti-viral capability. This article introduces the commonly used measurement methods for HBcAb and the new trends in HBcAb measurement and summarizes the association of serum HBcAb level with viral antigen and the body′s immune response, as well as research advances in effective prediction of antiviral effect with baseline HBcAb measurement before antiviral therapy. It is also pointed out that the clinical application of HBcAb needs further investigation.

  2. Mapping the Human Memory B Cell and Serum Neutralizing Antibody Responses to Dengue Virus Serotype 4 Infection and Vaccination.

    Science.gov (United States)

    Nivarthi, Usha K; Kose, Nurgun; Sapparapu, Gopal; Widman, Douglas; Gallichotte, Emily; Pfaff, Jennifer M; Doranz, Benjamin J; Weiskopf, Daniela; Sette, Alessandro; Durbin, Anna P; Whitehead, Steve S; Baric, Ralph; Crowe, James E; de Silva, Aravinda M

    2017-03-01

    The four dengue virus (DENV) serotypes are mosquito-borne flaviviruses responsible for dengue fever and dengue hemorrhagic fever. People exposed to DENV develop antibodies (Abs) that strongly neutralize the serotype responsible for infection. Historically, infection with DENV serotype 4 (DENV4) has been less common and less studied than infections with the other three serotypes. However, DENV4 has been responsible for recent large and sustained epidemics in Asia and Latin America. The neutralizing antibody responses and the epitopes targeted against DENV4 have not been characterized in human infection. In this study, we mapped and characterized epitopes on DENV4 recognized by neutralizing antibodies in people previously exposed to DENV4 infections or to a live attenuated DENV4 vaccine. To study the fine specificity of DENV4 neutralizing human antibodies, B cells from two people exposed to DENV4 were immortalized and screened to identify DENV-specific clones. Two human monoclonal antibodies (MAbs) that neutralized DENV4 were isolated, and their epitopes were finely mapped using recombinant viruses and alanine scan mutation array techniques. Both antibodies bound to quaternary structure epitopes near the hinge region between envelope protein domain I (EDI) and EDII. In parallel, to characterize the serum neutralizing antibody responses, convalescence-phase serum samples from people previously exposed to primary DENV4 natural infections or a monovalent DENV4 vaccine were analyzed. Natural infection and vaccination also induced serum-neutralizing antibodies that targeted similar epitope domains at the EDI/II hinge region. These studies defined a target of neutralizing antigenic site on DENV4 targeted by human antibodies following natural infection or vaccination. IMPORTANCE The four serotypes of dengue virus are the causative agents of dengue fever and dengue hemorrhagic fever. People exposed to primary DENV infections develop long-term neutralizing antibody responses

  3. Mixed adjuvant formulations reveal a new combination that elicit antibody response comparable to Freund's adjuvants.

    Directory of Open Access Journals (Sweden)

    Rachel P J Lai

    Full Text Available Adjuvant formulations capable of inducing high titer and high affinity antibody responses would provide a major advance in the development of vaccines to viral infections such as HIV-1. Although oil-in-water emulsions, such as Freund's adjuvant (FCA/FIA, are known to be potent, their toxicity and reactogenicity make them unacceptable for human use. Here, we explored different adjuvants and compared their ability to elicit antibody responses to FCA/FIA. Recombinant soluble trimeric HIV-1 gp140 antigen was formulated in different adjuvants, including FCA/FIA, Carbopol-971P, Carbopol-974P and the licensed adjuvant MF59, or combinations of MF59 and Carbopol. The antigen-adjuvant formulation was administered in a prime-boost regimen into rabbits, and elicitation of antigen binding and neutralizing antibodies (nAbs was evaluated. When used individually, only FCA/FIA elicited significantly higher titer of nAbs than the control group (gp140 in PBS (p<0.05. Sequential prime-boost immunizations with different adjuvants did not offer improvements over the use of FCA/FIA or MF59. Remarkably however, the concurrent use of the combination of Carbopol-971P and MF59 induced potent adjuvant activity with significantly higher titer nAbs than FCA/FIA (p<0.05. This combination was not associated with any obvious local or systemic adverse effects. Antibody competition indicated that the majority of the neutralizing activities were directed to the CD4 binding site (CD4bs. Increased antibody titers to the gp41 membrane proximal external region (MPER and gp120 V3 were detected when the more potent adjuvants were used. These data reveal that the combination of Carbopol-971P and MF59 is unusually potent for eliciting nAbs to a variety of HIV-1 nAb epitopes.

  4. Steroid-Responsive Epilepsia Partialis Continua with Anti-Thyroid Antibodies: A Spectrum of Hashimoto's Encephalopathy

    OpenAIRE

    Hiroki Masuda; Masahiro Mori; Shoichi Ito; Toshiyuki Yagishita; Satoshi Kuwabara

    2014-01-01

    Background: When a neuropsychiatric symptom due to encephalopathy develops in a patient with anti-thyroid antibodies, especially when the symptom is steroid-responsive, Hashimoto's encephalopathy (HE) needs to be included in the differential diagnosis of the patient. Although HE is an elusive disease, it is thought to cause various clinical presentations including seizures, myoclonus, and epilepsia partialis continua (EPC). Case Report: We present the case of a 33-year-old Japanese woman who ...

  5. Humoral antibody response after receipt of inactivated seasonal influenza vaccinations one year apart in children

    OpenAIRE

    Fang, VJ; Ip, DKM; Ng, S; Chiu, SS; Cowling, BJ; Leung, GM; Peiris, JSM

    2012-01-01

    Background: Annual vaccination against seasonal influenza viruses is recommended for school-age children in some countries. There are limited data on the immunogenicity and efficacy of repeated influenza vaccinations. Methods: In a randomized controlled trial, we administered seasonal trivalent inactivated influenza vaccine (TIV) or placebo to 64 children 6-15 years of age in two consecutive years and explored their humoral antibody responses. Results: Receipt of TIV in the first year was ass...

  6. Neutralizing antibody response in the patients with hand, foot and mouth disease to enterovirus 71 and its clinical implications

    Directory of Open Access Journals (Sweden)

    Zhu Liye

    2011-06-01

    Full Text Available Abstract Enterovirus 71 (EV71 has emerged as a significant pathogen causing large outbreaks in China for the past 3 years. Developing an EV71 vaccine is urgently needed to stop the spread of the disease; however, the adaptive immune response of humans to EV71 infection remains unclear. We examined the neutralizing antibody titers in HFMD patients and compared them to those of asymptomatic healthy children and young adults. We found that 80% of HFMD patients became positive for neutralizing antibodies against EV71 (GMT = 24.3 one day after the onset of illness. The antibody titers in the patients peaked two days (GMT = 79.5 after the illness appeared and were comparable to the level of adults (GMT = 45.2. Noticeably, the antibody response was not correlated with disease severity, suggesting that cellular immune response, besides neutralizing antibodies, could play critical role in controlling the outcome of EV71 infection in humans.

  7. Antibody response in cattle after vaccination with inactivated and attenuated rabies vaccines

    Directory of Open Access Journals (Sweden)

    RODRIGUES da SILVA Andréa de Cássia

    2000-01-01

    Full Text Available Despite the absence of current official reports showing the number of cattle infected by rabies, it is estimated that nearly 30,000 bovines are lost each year in Brazil. In order to minimize the important economic losses, control of the disease is achieved by eliminating bat colonies and by herd vaccination. In this study, we compare the antibody response in cattle elicited by vaccination with an attenuated ERA vaccine (AEvac and an inactivated-adjuvanted PV (IPVvac vaccine. The antibody titers were appraised by cell-culture neutralization test and ELISA, and the percentage of seropositivity was ascertained for a period of 180 days. IPVvac elicited complete seropositivity rates from day 30 to day 150, and even on day 180, 87% of the sera showed virus-neutralizing antibody titers (VNA higher than 0.5IU/ml. There were no significant differences between the VNA titers and seropositivity rates obtained with IPVvac in the two methods tested. AEvac, however, elicited significantly lower titers than those observed in the group receiving inactivated vaccine. In addition, the profiles of antirabies IgG antibodies, evaluated by ELISA, and VNA, appraised by cell-culture neutralization test, were slightly different, when both vaccines were compared.

  8. Impaired antibody response causes persistence of prototypic T cell-contained virus.

    Directory of Open Access Journals (Sweden)

    Andreas Bergthaler

    2009-04-01

    Full Text Available CD8 T cells are recognized key players in control of persistent virus infections, but increasing evidence suggests that assistance from other immune mediators is also needed. Here, we investigated whether specific antibody responses contribute to control of lymphocytic choriomeningitis virus (LCMV, a prototypic mouse model of systemic persistent infection. Mice expressing transgenic B cell receptors of LCMV-unrelated specificity, and mice unable to produce soluble immunoglobulin M (IgM exhibited protracted viremia or failed to resolve LCMV. Virus control depended on immunoglobulin class switch, but neither on complement cascades nor on Fc receptor gamma chain or Fc gamma receptor IIB. Cessation of viremia concurred with the emergence of viral envelope-specific antibodies, rather than with neutralizing serum activity, and even early nonneutralizing IgM impeded viral persistence. This important role for virus-specific antibodies may be similarly underappreciated in other primarily T cell-controlled infections such as HIV and hepatitis C virus, and we suggest this contribution of antibodies be given consideration in future strategies for vaccination and immunotherapy.

  9. Steroid-Responsive Epilepsia Partialis Continua with Anti-Thyroid Antibodies: A Spectrum of Hashimoto's Encephalopathy?

    Science.gov (United States)

    Masuda, Hiroki; Mori, Masahiro; Ito, Shoichi; Yagishita, Toshiyuki; Kuwabara, Satoshi

    2014-05-01

    When a neuropsychiatric symptom due to encephalopathy develops in a patient with anti-thyroid antibodies, especially when the symptom is steroid-responsive, Hashimoto's encephalopathy (HE) needs to be included in the differential diagnosis of the patient. Although HE is an elusive disease, it is thought to cause various clinical presentations including seizures, myoclonus, and epilepsia partialis continua (EPC). We present the case of a 33-year-old Japanese woman who acutely developed EPC in the right hand as an isolated manifestation. A thyroid ultrasound showed an enlarged hypoechogenic gland, and a thyroid status assessment showed euthyroid with high titers of thyroid antibodies. A brain MRI revealed a nodular lesion in the left precentral gyrus. Corticosteroid treatment resulted in a cessation of the symptom. A precentral nodular lesion can be responsible for steroid-responsive EPC in a patient with anti-thyroid antibodies and may be caused by HE. The serial MRI findings of our case suggest the presence of primary demyelination, with ischemia possibly due to vasculitis around the demyelinating lesion.

  10. Steroid-Responsive Epilepsia Partialis Continua with Anti-Thyroid Antibodies: A Spectrum of Hashimoto's Encephalopathy

    Directory of Open Access Journals (Sweden)

    Hiroki Masuda

    2014-05-01

    Full Text Available Background: When a neuropsychiatric symptom due to encephalopathy develops in a patient with anti-thyroid antibodies, especially when the symptom is steroid-responsive, Hashimoto's encephalopathy (HE needs to be included in the differential diagnosis of the patient. Although HE is an elusive disease, it is thought to cause various clinical presentations including seizures, myoclonus, and epilepsia partialis continua (EPC. Case Report: We present the case of a 33-year-old Japanese woman who acutely developed EPC in the right hand as an isolated manifestation. A thyroid ultrasound showed an enlarged hypoechogenic gland, and a thyroid status assessment showed euthyroid with high titers of thyroid antibodies. A brain MRI revealed a nodular lesion in the left precentral gyrus. Corticosteroid treatment resulted in a cessation of the symptom. Conclusions: A precentral nodular lesion can be responsible for steroid-responsive EPC in a patient with anti-thyroid antibodies and may be caused by HE. The serial MRI findings of our case suggest the presence of primary demyelination, with ischemia possibly due to vasculitis around the demyelinating lesion.

  11. Observed parent-child relationship quality predicts antibody response to vaccination in children.

    Science.gov (United States)

    O'Connor, Thomas G; Wang, Hongyue; Moynihan, Jan A; Wyman, Peter A; Carnahan, Jennifer; Lofthus, Gerry; Quataert, Sally A; Bowman, Melissa; Burke, Anne S; Caserta, Mary T

    2015-08-01

    Quality of the parent-child relationship is a robust predictor of behavioral and emotional health for children and adolescents; the application to physical health is less clear. We investigated the links between observed parent-child relationship quality in an interaction task and antibody response to meningococcal conjugate vaccine in a longitudinal study of 164 ambulatory 10-11 year-old children; additional analyses examine associations with cortisol reactivity, BMI, and somatic illness. Observed Negative/Conflict behavior in the interaction task predicted a less robust antibody response to meningococcal serotype C vaccine in the child over a 6 month-period, after controlling for socio-economic and other covariates. Observer rated interaction conflict also predicted increased cortisol reactivity following the interaction task and higher BMI, but these factors did not account for the link between relationship quality and antibody response. The results begin to document the degree to which a major source of child stress exposure, parent-child relationship conflict, is associated with altered immune system development in children, and may constitute an important public health consideration. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Steroid-Responsive Epilepsia Partialis Continua with Anti-Thyroid Antibodies: A Spectrum of Hashimoto's Encephalopathy?

    Science.gov (United States)

    Masuda, Hiroki; Mori, Masahiro; Ito, Shoichi; Yagishita, Toshiyuki; Kuwabara, Satoshi

    2014-01-01

    Background When a neuropsychiatric symptom due to encephalopathy develops in a patient with anti-thyroid antibodies, especially when the symptom is steroid-responsive, Hashimoto's encephalopathy (HE) needs to be included in the differential diagnosis of the patient. Although HE is an elusive disease, it is thought to cause various clinical presentations including seizures, myoclonus, and epilepsia partialis continua (EPC). Case Report We present the case of a 33-year-old Japanese woman who acutely developed EPC in the right hand as an isolated manifestation. A thyroid ultrasound showed an enlarged hypoechogenic gland, and a thyroid status assessment showed euthyroid with high titers of thyroid antibodies. A brain MRI revealed a nodular lesion in the left precentral gyrus. Corticosteroid treatment resulted in a cessation of the symptom. Conclusions A precentral nodular lesion can be responsible for steroid-responsive EPC in a patient with anti-thyroid antibodies and may be caused by HE. The serial MRI findings of our case suggest the presence of primary demyelination, with ischemia possibly due to vasculitis around the demyelinating lesion. PMID:24932178

  13. Antibody responses to Sarcoptes scabiei apolipoprotein in a porcine model: relevance to immunodiagnosis of recent infection.

    Science.gov (United States)

    Rampton, Melanie; Walton, Shelley F; Holt, Deborah C; Pasay, Cielo; Kelly, Andrew; Currie, Bart J; McCarthy, James S; Mounsey, Kate E

    2013-01-01

    No commercial immunodiagnostic tests for human scabies are currently available, and existing animal tests are not sufficiently sensitive. The recombinant Sarcoptes scabiei apolipoprotein antigen Sar s 14.3 is a promising immunodiagnostic, eliciting high levels of IgE and IgG in infected people. Limited data are available regarding the temporal development of antibodies to Sar s 14.3, an issue of relevance in terms of immunodiagnosis. We utilised a porcine model to prospectively compare specific antibody responses to a primary infestation by ELISA, to Sar s 14.3 and to S. scabiei whole mite antigen extract (WMA). Differences in the antibody profile between antigens were apparent, with Sar s 14.3 responses detected earlier, and declining significantly after peak infestation compared to WMA. Both antigens resulted in >90% diagnostic sensitivity from weeks 8-16 post infestation. These data provide important information on the temporal development of humoral immune responses in scabies and further supports the development of recombinant antigen based immunodiagnostic tests for recent scabies infestations.

  14. Antibody responses to Sarcoptes scabiei apolipoprotein in a porcine model: relevance to immunodiagnosis of recent infection.

    Directory of Open Access Journals (Sweden)

    Melanie Rampton

    Full Text Available No commercial immunodiagnostic tests for human scabies are currently available, and existing animal tests are not sufficiently sensitive. The recombinant Sarcoptes scabiei apolipoprotein antigen Sar s 14.3 is a promising immunodiagnostic, eliciting high levels of IgE and IgG in infected people. Limited data are available regarding the temporal development of antibodies to Sar s 14.3, an issue of relevance in terms of immunodiagnosis. We utilised a porcine model to prospectively compare specific antibody responses to a primary infestation by ELISA, to Sar s 14.3 and to S. scabiei whole mite antigen extract (WMA. Differences in the antibody profile between antigens were apparent, with Sar s 14.3 responses detected earlier, and declining significantly after peak infestation compared to WMA. Both antigens resulted in >90% diagnostic sensitivity from weeks 8-16 post infestation. These data provide important information on the temporal development of humoral immune responses in scabies and further supports the development of recombinant antigen based immunodiagnostic tests for recent scabies infestations.

  15. Inhibition of viral replication reduces regulatory T cells and enhances the antiviral immune response in chronic hepatitis B.

    Science.gov (United States)

    Stoop, Jeroen N; van der Molen, Renate G; Kuipers, Ernst J; Kusters, Johannes G; Janssen, Harry L A

    2007-04-25

    Regulatory T cells (Treg) play a key role in the impaired immune response that is typical for a chronic Hepatitis B virus (HBV) infection. To gain more insight in the mechanism that is responsible for this impaired immune response, the effect of viral load reduction resulting from treatment with the nucleotide analogue adefovir dipivoxil on the percentages of Treg and HBV-specific T-cell responses was analyzed. Peripheral blood mononuclear cells (PBMC) of 12 patients were collected at baseline and during treatment. In parallel to the decline in viral load, we found a decline in circulating Treg, combined with an increase in HBV core antigen-specific IFN-gamma production and proliferation. The production of IL10 did not decrease during therapy. In conclusion, adefovir induced viral load reduction results in a decline of circulating Treg together with a partial recovery of the immune response.

  16. Inhibition of viral replication reduces regulatory T cells and enhances the antiviral immune response in chronic hepatitis B

    International Nuclear Information System (INIS)

    Stoop, Jeroen N.; Molen, Renate G. van der; Kuipers, Ernst J.; Kusters, Johannes G.; Janssen, Harry L.A.

    2007-01-01

    Regulatory T cells (Treg) play a key role in the impaired immune response that is typical for a chronic Hepatitis B virus (HBV) infection. To gain more insight in the mechanism that is responsible for this impaired immune response, the effect of viral load reduction resulting from treatment with the nucleotide analogue adefovir dipivoxil on the percentages of Treg and HBV-specific T-cell responses was analyzed. Peripheral blood mononuclear cells (PBMC) of 12 patients were collected at baseline and during treatment. In parallel to the decline in viral load, we found a decline in circulating Treg, combined with an increase in HBV core antigen-specific IFN-γ production and proliferation. The production of IL10 did not decrease during therapy. In conclusion, adefovir induced viral load reduction results in a decline of circulating Treg together with a partial recovery of the immune response

  17. Systems biology: A tool for charting the antiviral landscape.

    Science.gov (United States)

    Bowen, James R; Ferris, Martin T; Suthar, Mehul S

    2016-06-15

    The host antiviral programs that are initiated following viral infection form a dynamic and complex web of responses that we have collectively termed as "the antiviral landscape". Conventional approaches to studying antiviral responses have primarily used reductionist systems to assess the function of a single or a limited subset of molecules. Systems biology is a holistic approach that considers the entire system as a whole, rather than individual components or molecules. Systems biology based approaches facilitate an unbiased and comprehensive analysis of the antiviral landscape, while allowing for the discovery of emergent properties that are missed by conventional approaches. The antiviral landscape can be viewed as a hierarchy of complexity, beginning at the whole organism level and progressing downward to isolated tissues, populations of cells, and single cells. In this review, we will discuss how systems biology has been applied to better understand the antiviral landscape at each of these layers. At the organismal level, the Collaborative Cross is an invaluable genetic resource for assessing how genetic diversity influences the antiviral response. Whole tissue and isolated bulk cell transcriptomics serves as a critical tool for the comprehensive analysis of antiviral responses at both the tissue and cellular levels of complexity. Finally, new techniques in single cell analysis are emerging tools that will revolutionize our understanding of how individual cells within a bulk infected cell population contribute to the overall antiviral landscape. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Antibody responses against epitopes on the F protein of bovine respiratory syncytial virus differ in infected or vaccinated cattle

    NARCIS (Netherlands)

    Schrijver, R.S.; Hensen, E.J.; Langedijk, J.P.M.; Daus, F.; Middel, W.G.J.; Kramps, J.A.; Oirschot, van J.T.

    1997-01-01

    The fusion protein F of bovine respiratory syncytial virus (BRSV) is an important target for humoral and cellular immune responses, and antibodies against the F protein have been associated with protection. However, the F protein can induce antibodies with different biological activity, possibly

  19. An innate antiviral pathway acting before interferons at epithelial surfaces

    DEFF Research Database (Denmark)

    Iversen, Marie B; Reinert, Line S; Thomsen, Martin K

    2016-01-01

    we identify an innate antiviral pathway that works at epithelial surfaces before the IFNs. The pathway is activated independently of known innate sensors of viral infections through a mechanism dependent on viral O-linked glycans, which induce CXCR3 chemokines and stimulate antiviral activity...... in a manner dependent on neutrophils. This study therefore identifies a previously unknown layer of antiviral defense that exerts its action on epithelial surfaces before the classical IFN response is operative....

  20. A life-style physical activity intervention and the antibody response to pneumococcal vaccination in women.

    Science.gov (United States)

    Long, Joanna E; Ring, Chris; Bosch, Jos A; Eves, Francis; Drayson, Mark T; Calver, Rebecca; Say, Vanessa; Allen, Daniel; Burns, Victoria E

    2013-10-01

    To assess whether a life-style physical activity intervention improved antibody response to a pneumococcal vaccination in sedentary middle-aged women. Eighty-nine sedentary women completed a 16-week exercise (physical activity consultation, pedometer, telephone/e-mail prompts; n = 44) or control (advisory leaflet; n = 45) intervention. Pneumococcal vaccination was administered at 12 weeks, and antibody titers (11 of the 23 contained in the pneumococcal vaccine) were determined before vaccination and 4 weeks and 6 months later. Physical activity, aerobic fitness, body composition, and psychological factors were measured before and after the intervention. The intervention group displayed a greater increase in walking behavior (from mean [standard deviation] = 82.16 [90.90] to 251.87 [202.13]) compared with the control condition (111.67 [94.64] to 165.16 [117.22]; time by group interaction: F(1,68) = 11.25, p = .001, η(2) = 0.14). Quality of life also improved in the intervention group (from 19.37 [3.22] to 16.70 [4.29]) compared with the control condition (19.97 [4.22] to 19.48 [5.37]; time by group interaction: F(1,66) = 4.44, p = .039, η(2) = 0.06). However, no significant effects of the intervention on antibody response were found (time by group η(2) for each of the 11 pneumococcal strains ranged from 0.001 to 0.018; p values all >.264). Participation in a life-style physical activity intervention increased subjective and objective physical activity levels and quality of life but did not affect antibody response to pneumococcal vaccination.

  1. Predictors Associated with Increase in Skeletal Muscle Mass after Sustained Virological Response in Chronic Hepatitis C Treated with Direct Acting Antivirals

    Directory of Open Access Journals (Sweden)

    Kazunori Yoh

    2017-10-01

    Full Text Available Aims: We aimed to examine changes in skeletal muscle mass in chronic hepatitis C (CHC patients undergoing interferon (IFN-free direct acting antivirals (DAAs therapy who achieved sustained virological response (SVR. Patients and methods: A total of 69 CHC patients treated with DAAs were analyzed. We compared the changes in skeletal muscle index (SMI using bio-impedance analysis at baseline and SMI at SVR. SMI was calculated as the sum of skeletal muscle mass in upper and lower extremities divided by height squared (cm2/m2. Further, we identified pretreatment parameters contributing to the increased SMI at SVR. Results: SMI in males at baseline ranged from 6.73 to 9.08 cm2/m2 (median, 7.65 cm2/m2, while that in females ranged from 4.45 to 7.27 cm2/m2 (median, 5.81 cm2/m2. At SVR, 36 patients (52.2% had increased SMI as compared with baseline. In the univariate analysis, age (p = 0.0392, hyaluronic acid (p = 0.0143, and branched-chain amino acid to tyrosine ratio (BTR (p = 0.0024 were significant pretreatment factors linked to increased SMI at SVR. In the multivariate analysis, only BTR was an independent predictor linked to the increased SMI at SVR (p = 0.0488. Conclusion: Pretreatment BTR level can be helpful for predicting increased SMI after SVR in CHC patients undergoing IFN-free DAAs therapy.

  2. Impact of sustained virological response to chronic hepatitic C antiviral therapy on new onset diabetes mellitus type 2 after controlling for metabolic syndrome.

    Science.gov (United States)

    Pandya, Prashant; Pant, Chaitanya; Taylor, Ryan; Oni, Olurinde

    2017-04-01

    The high cost associated with antiviral treatment for chronic hepatitis C virus (HCV) infection mandates further investigation in the context of preventing complications such as type 2 diabetes mellitus (DM2). We determined the cumulative incidence of DM2 in subjects with chronic HCV infection who received concomitant pegylated interferon (Peg-IFN) and ribavirin. We conducted a retrospective analysis of data obtained from Veterans Administrations Informatics and Computing Infrastructure (VINCI) to identify an adult cohort of patients without diabetes with chronic HCV infection who received Peg-IFN-based therapy between October 2001 and December 2011. Patients with history of HIV, hepatitis B infection, hepatocellular cancer (HCC), non-HCC cancers, and history of transplantation were excluded. Sustained virological response (SVR) was defined as negative HCV RNA 3 months after completion of therapy. Using Cox proportional hazards regression for multivariable analysis, we determined that patients who achieved SVR were at a significantly less risk of developing DM2. Adjusted survival rates showed that the responders' group was significantly less likely to develop DM2 over time (HR 0.60, CI 0.48 to 0.74, pcontrolling for correlates of metabolic syndrome. Copyright © 2017 American Federation for Medical Research.

  3. The E3 Ubiquitin Ligase TRIM40 Attenuates Antiviral Immune Responses by Targeting MDA5 and RIG-I

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    Chunyuan Zhao

    2017-11-01

    Full Text Available Retinoic acid-inducible gene-I (RIG-I-like receptors (RLRs, including melanoma differentiation-associated gene 5 (MDA5 and RIG-I, are crucial for host recognition of non-self RNAs, especially viral RNA. Thus, the expression and activation of RLRs play fundamental roles in eliminating the invading RNA viruses and maintaining immune homeostasis. However, how RLR expression is tightly regulated remains to be further investigated. In this study, we identified a major histocompatibility complex (MHC-encoded gene, tripartite interaction motif 40 (TRIM40, as a suppressor of RLR signaling by directly targeting MDA5 and RIG-I. TRIM40 binds to MDA5 and RIG-I and promotes their K27- and K48-linked polyubiquitination via its E3 ligase activity, leading to their proteasomal degradation. TRIM40 deficiency enhances RLR-triggered signaling. Consequently, TRIM40 deficiency greatly enhances antiviral immune responses and decreases viral replication in vivo. Thus, we demonstrate that TRIM40 limits RLR-triggered innate activation, suggesting TRIM40 as a potential therapeutic target for the control of viral infection.

  4. The IgM Response to Modified LDL in Experimental Atherosclerosis Hypochlorite-modified LDL IgM Antibodies versus Classical Natural T15 IgM Antibodies

    NARCIS (Netherlands)

    van Leeuwen, Marcella; Damoiseaux, Jan; Duijvestijn, Adriaan; Heeringa, Peter; Gijbels, Marion; de Winther, Menno; Tervaert, Jan Willem Cohen; Shoenfeld, Y; Gershwin, ME

    2009-01-01

    Introduction: It is hypothesized that IgM antibodies to oxidized LDL are anti-atherogenic. Myeloperoxidase from plaque-infiltrating neutrophils catalyzes the production of hypochlorite (HOCl), which oxidizes LDL. Here we study the IgM response to HOCl-modified LDL in comparison to titers of T15

  5. Early and enhanced antitoxin responses elicited with complexes of tetanus toxoid and specific mouse and human antibodies

    International Nuclear Information System (INIS)

    Stoner, R.D.; Terres, G.; Hess, M.W.

    1975-01-01

    Primary tetanus antitoxin responses were early and enhanced in mice when tetanus toxoid was administered in complex with specific isologous antitoxin or specific mouse γ-globulin. Antitoxin responses were enhanced when fluid tetanus toxoid was complexed in vitro in antigen-to-antibody ratios of equivalence or antigen excess; responses to complexed toxoid in antibody excess were comparatively repressed. Primary responses were greatly inhibited in mice immunized with the same amount of toxoid complexed at equivalence or in antibody excess with specific human γ-globulin. Although primary responses were totally repressed, a primed state developed; a second injection of fluid toxoid within a few days produced excellent antitoxin responses. Separate injections of antigen and antibody at different sites produced an excellent in vivo primed state for early and high responses. Antibody production after stimulation with complexed toxoid was also enhanced in mice irradiated with 400 rads, a dose that ordinarily completely suppresses primary responses with fluid toxoid alone. These data provide evidence for the efficacy of antigen-antibody complexes in early and active immunization. (U.S.)

  6. A novel unsupervised method to identify genes important in the anti-viral response: application to interferon/ribavirin in hepatitis C patients.

    Directory of Open Access Journals (Sweden)

    Leonid I Brodsky

    2007-07-01

    Full Text Available Treating hepatitis C with interferon/ribavirin results in a varied response in terms of decrease in viral titer and ultimate outcome. Marked responders have a sharp decline in viral titer within a few days of treatment initiation, whereas in other patients there is no effect on the virus (poor responders. Previous studies have shown that combination therapy modifies expression of hundreds of genes in vitro and in vivo. However, identifying which, if any, of these genes have a role in viral clearance remains challenging.The goal of this paper is to link viral levels with gene expression and thereby identify genes that may be responsible for early decrease in viral titer.Microarrays were performed on RNA isolated from PBMC of patients undergoing interferon/ribavirin therapy. Samples were collected at pre-treatment (day 0, and 1, 2, 7, 14 and 28 days after initiating treatment. A novel method was applied to identify genes that are linked to a decrease in viral titer during interferon/ribavirin treatment. The method uses the relationship between inter-patient gene expression based proximities and inter-patient viral titer based proximities to define the association between microarray gene expression measurements of each gene and viral-titer measurements.We detected 36 unique genes whose expressions provide a clustering of patients that resembles viral titer based clustering of patients. These genes include IRF7, MX1, OASL and OAS2, viperin and many ISG's of unknown function.The genes identified by this method appear to play a major role in the reduction of hepatitis C virus during the early phase of treatment. The method has broad utility and can be used to analyze response to any group of factors influencing biological outcome such as antiviral drugs or anti-cancer agents where microarray data are available.

  7. Wildtype p53-specific Antibody and T-Cell Responses in Cancer Patients

    DEFF Research Database (Denmark)

    Pedersen, Anders Elm; Stryhn, Anette; Justesen, Sune

    2011-01-01

    Mutation in the p53 gene based on single amino acid substitutions is a frequent event in human cancer. Accumulated mutant p53 protein is released to antigen presenting cells of the immune system and anti-p53 immune responses even against wt p53 is induced and observed in a number of human cancer...... patients. Detection of antibodies against wt p53 protein has been used as a diagnostic and prognostic marker and discovery of new T-cell epitopes has enabled design of cancer vaccination protocols with promising results. Here, we identified wt p53-specific antibodies in various cancer patients......(264-272) in breast cancer patients and against HLA-A*01:01 binding peptide wt p53(226-234) and HLA-B*07:02 binding peptide wt p53(74-82) in renal cell cancer and breast cancer patients, respectively. Finally, we analyzed antibody and T-cell responses against wt p53 15-mer peptides in patients with metastatic renal...

  8. LOCAL ANTIBODY AND CELLULAR IMMUNE RESPONSES TO INFLUENZA INFECTION AND VACCINATION

    Directory of Open Access Journals (Sweden)

    G. D. Petukhova

    2006-01-01

    Full Text Available Abstract. Local immune responses of mucous membranes of an organism are the first and most significant barriers preventing many virus infections, including influenza. The barrier against influenza infection is the mucosalassociated lymphoid tissue of the upper airways. It is considered, that nasopharyngeal-associated lymphoid tissue (NALT in rodents is an equivalent of lymphoid tissue in human Waldeyer’s ring. Present work is the first attempt to analyze and compare the development of cellular and antibody immune responses in NALT in a mouse model of experimental influenza infection using a pathogenic influenza A (H1N1 virus and an attenuated reassorted (2/6 genetic formula live influenza A (H1N1 vaccine.It was shown, that the vaccine strain inherits the ability to induce high-grade local antibody responses like as the virulent parental strain. However, the vaccine strain is inferior to virulent parental strain in capacity to stimulate production of circulating antibodies. Both parental and Р 2/6 strains are equally able to induce lymphoproliferative immune response in NALT lymphocytes. The attenuated reassortant virus is able to stimulate proliferation of Th (CD4+, B-cells (CD19+ and CTL (CD8+ in NALT. As shown by the cytokine activity testing (IFN-γ, IL-6, the attenuated reassortant virus activates both Th1- and Th2-lymphocytes in NALT.This data suggest that intranasal immunization with live attenuated reassortant viruses (genetic formula 2/6 results into active and balanced stimulation of both Th1-and Th2-immune responses at the primary site of infection (NALT.

  9. Antibody response in naïve and sensitised goats infested by Sarcoptes scabiei

    Directory of Open Access Journals (Sweden)

    Simson Tarigan

    2004-12-01

    Full Text Available The purpose of this study was to characterize the IgG and IgE antibody responses in goats infested repeatedly with Sarcoptes scabiei. Ten goats purchased from scabies-free farms were infested with 2000 live mites on the auricles. Fifty days after the initial infestation, the goats were treated with ivermectin. After being completely recovered, the goats were reinfested then treated again at 50 days post infestation. Blood samples were collected at the time of the first infestation, then every 10 days afterwards for 270 days. Seroconversion for IgG took place after 30 days following the first infestation, whereas the maximum level of the specific IgG antibodies occurred after 50 days. Immunoblot analysis identified a number of antigens (Mr 180, 135, 43 and 38 KDa that recognised by the IgG at 10 days and continuously recognised throughout the course of the multiple infestations. Being consistently recognised, those antigens should be essential in the development immunological diagnostic tests for scabies. The levels of scabies-specific IgE antibodies increased slowly during the first infestation and rapidly dropped following treatment of the animals with ivermectin. In the second and third infestations, however, the reaginic antibodies rose rapidly and with a grater level. On immunoblot analysis, at least 10 antigens (Mr 130, 72, 64, 58, 48, 44, 41, 39, 27 and 25 KDa were observed to be recognised by the IgE present in the sera from scabies-infested animals. Since IgE response is considered to play a major role in the immune protection, those allergens, therefore, could be used as the main component of an anti-scabies vaccine.

  10. Specificity of Subcapsular Antibody Responses in Ethiopian Patients following Disease Caused by Serogroup A Meningococci▿

    Science.gov (United States)

    Norheim, Gunnstein; Aseffa, Abraham; Yassin, Mohammed Ahmed; Mengistu, Getahun; Kassu, Afework; Fikremariam, Dereje; Tamire, Wegene; Merid, Yared; Høiby, E. Arne; Caugant, Dominique A.; Fritzsønn, Elisabeth; Tangen, Torill; Melak, Berhanu; Berhanu, Degu; Harboe, Morten; Kolberg, Jan; Rosenqvist, Einar

    2008-01-01

    Dissecting the specificities of human antibody responses following disease caused by serogroup A meningococci may be important for the development of improved vaccines. We performed a study of Ethiopian patients during outbreaks in 2002 and 2003. Sera were obtained from 71 patients with meningitis caused by bacteria of sequence type 7, as confirmed by PCR or culture, and from 113 Ethiopian controls. Antibody specificities were analyzed by immunoblotting (IB) against outer membrane antigen extracts of a reference strain and of the patients' own isolates and by enzyme-linked immunosorbent assay for immunoglobulin G (IgG) levels against lipooligosaccharide (LOS) L11 and the proteins NadA and NspA. IB revealed that the main antigens targeted were the proteins PorA, PorB, RmpM, and Opa/OpcA, as well as LOS. MenA disease induced significant increases in IgG against LOS L11 and NadA. The IgG levels against LOS remained elevated following disease, whereas the IgG anti-NadA levels returned to acute-phase levels in the late convalescent phase. Among adults, the anti-LOS IgG levels were similar in acute-phase patient sera as in control sera, whereas anti-NadA IgG levels were significantly higher in acute-phase sera than in controls. The IgG antibody levels against LOS and NadA correlated moderately but significantly with serum bactericidal activity against MenA strains. Future studies on immune response during MenA disease should take into account the high levels of anti-MenA polysaccharide IgG commonly found in the population and seek to clarify the role of antibodies against subcapsular antigens in protection against MenA disease. PMID:18337382

  11. Association between polycystic ovary syndrome, oral microbiota and systemic antibody responses.

    Science.gov (United States)

    Akcalı, Aliye; Bostanci, Nagihan; Özçaka, Özgün; Öztürk-Ceyhan, Banu; Gümüş, Pınar; Buduneli, Nurcan; Belibasakis, Georgios N

    2014-01-01

    Polycystic ovary syndrome (PCOS) is a hormonal disorder of women that not only is the leading cause of infertility but also shows a reciprocal link with oral health. This study aimed to investigate the hypothesis that the levels of putative periodontal pathogens in saliva and their antibody response in serum are elevated in PCOS, compared to systemic health. A total of 125 women were included in four groups; 45 women with PCOS and healthy periodontium, 35 women with PCOS and gingivitis, 25 systemically and periodontally healthy women, 20 systemically healthy women with gingivitis. Salivary levels of seven putative periodontal pathogens were analyzed by quantitative real-time polymerase chain reaction and serum antibody levels were analyzed by ELISA. In women with PCOS, salivary Porphyromonas gingivalis, Fusobacterium nucleatum, Streptococcus oralis and Tannerella forsythia levels were higher than matched systemically healthy women, particularly in the case of gingivitis. Aggregatibacter actinomycetemcomitans and Treponema denticola levels were similar among study groups. The presence of PCOS also enhanced P. gingivalis, Prevotella intermedia and S. oralis serum antibody levels, when gingivitis was also present. Gingival inflammation correlated positively with levels of the studied taxa in saliva, particularly in PCOS. The presence of P. gingivalis and F. nucleatum in saliva also exhibited a strong positive correlation with the corresponding serum antibody levels. In conclusion, as an underlying systemic endocrine condition, PCOS may quantitatively affect the composition of oral microbiota and the raised systemic response to selective members of this microbial community, exerting a confounding role in resultant gingival inflammation and periodontal health. The most consistent effect appeared to be exerted on P. gingivalis.

  12. Association between polycystic ovary syndrome, oral microbiota and systemic antibody responses.

    Directory of Open Access Journals (Sweden)

    Aliye Akcalı

    Full Text Available Polycystic ovary syndrome (PCOS is a hormonal disorder of women that not only is the leading cause of infertility but also shows a reciprocal link with oral health. This study aimed to investigate the hypothesis that the levels of putative periodontal pathogens in saliva and their antibody response in serum are elevated in PCOS, compared to systemic health. A total of 125 women were included in four groups; 45 women with PCOS and healthy periodontium, 35 women with PCOS and gingivitis, 25 systemically and periodontally healthy women, 20 systemically healthy women with gingivitis. Salivary levels of seven putative periodontal pathogens were analyzed by quantitative real-time polymerase chain reaction and serum antibody levels were analyzed by ELISA. In women with PCOS, salivary Porphyromonas gingivalis, Fusobacterium nucleatum, Streptococcus oralis and Tannerella forsythia levels were higher than matched systemically healthy women, particularly in the case of gingivitis. Aggregatibacter actinomycetemcomitans and Treponema denticola levels were similar among study groups. The presence of PCOS also enhanced P. gingivalis, Prevotella intermedia and S. oralis serum antibody levels, when gingivitis was also present. Gingival inflammation correlated positively with levels of the studied taxa in saliva, particularly in PCOS. The presence of P. gingivalis and F. nucleatum in saliva also exhibited a strong positive correlation with the corresponding serum antibody levels. In conclusion, as an underlying systemic endocrine condition, PCOS may quantitatively affect the composition of oral microbiota and the raised systemic response to selective members of this microbial community, exerting a confounding role in resultant gingival inflammation and periodontal health. The most consistent effect appeared to be exerted on P. gingivalis.

  13. Neutralizing antibodies obtained in a persistent immune response are effective against deleterious effects induced by the Thalassophryne nattereri fish venom.

    Science.gov (United States)

    Piran-Soares, Ana Amélia; Komegae, Evilin Naname; Souza, Valdênia Maria Oliveira; Fonseca, Luiz Alberto; Lima, Carla; Lopes-Ferreira, Mônica

    2007-06-01

    Thalassophryne nattereri envenoming represents a great cost to North and Northeast Brazilian communities in terms of public healths, leisure and tourism. Victims rapidally develop symptoms as pain, local swelling, erythema followed by intense necrosis that persist for long days. The aim of this work was tested the immune competence of neutralizing antibodies in pre-immunized mice against principal toxic activities induced by venom. During the primary antibody response in mice, an elevation of IgG antibody levels was only observed on day 28. After boosting, high antibody levels were detected between days 49 and 70, with a 12-fold increase in IgG level over control values at day 49. We confirmed the in vitro neutralizing capacity of T. nattereri anti-venom against toxic effects and thereafter we show that neutralizing antibodies obtained in a persistent immune response are more effective, inclusive against edematous reaction. After boosting during the secondary response mice with high antibody levels do not present any alterations in venule or arteriole after topical application of venom on cremaster muscle. In addition, CK activity diminished in these mice with high neutralizing antibody levels corroborating the attenuation of the myonecrotic effect by venom. In addition, we determined the presence of high IgG antibodies levels in patients 6 months after injury by T. nattereri. In conclusion, the presence of neutralizing antibodies against to T. nattereri venom in the serum of pre-immunized mice could change the outcome of lesion at site of posterior envenoming. Antigen-specific antibodies of high affinity in consequence to specific immune response, dependent of T lymphocyte activation, could minimize the symptoms of intense and immediate inflammatory reaction caused by T. nattereri venom. These finding prompt us to the possibility of development of immune therapeutic strategies using specific anti-venom as an efficient intervention for protecting human victims.

  14. Molecular dissection of the human antibody response to the structural repeat epitope of Plasmodium falciparum sporozoite from a protected donor

    Directory of Open Access Journals (Sweden)

    Rogers William O

    2004-07-01

    Full Text Available Abstract Background The circumsporozoite surface protein is the primary target of human antibodies against Plasmodium falciparum sporozoites, these antibodies are predominantly directed to the major repetitive epitope (Asn-Pro-Asn-Alan, (NPNAn. In individuals immunized by the bites of irradiated Anopheles mosquitoes carrying P. falciparum sporozoites in their salivary glands, the anti-repeat response dominates and is thought by many to play a role in protective immunity. Methods The antibody repertoire from a protected individual immunized by the bites of irradiated P. falciparum infected Anopheles stephensi was recapitulated in a phage display library. Following affinity based selection against (NPNA3 antibody fragments that recognized the PfCSP repeat epitope were rescued. Results Analysis of selected antibody fragments implied the response was restricted to a single antibody fragment consisting of VH3 and VκI families for heavy and light chain respectively with moderate affinity for the ligand. Conclusion The dissection of the protective antibody response against the repeat epitope revealed that the response was apparently restricted to a single VH/VL pairing (PfNPNA-1. The affinity for the ligand was in the μM range. If anti-repeat antibodies are involved in the protective immunity elicited by exposure to radiation attenuated P. falciparum sporozoites, then high circulating levels of antibodies against the repeat region may be more important than intrinsic high affinity for protection. The ability to attain and sustain high levels of anti-(NPNAn will be one of the key determinants of efficacy for a vaccine that relies upon anti-PfCSP repeat antibodies as the primary mechanism of protective immunity against P. falciparum.

  15. Antibody responses to allergen Lol pIV are suppressed following adoptive transfer of B lymphocytes from the internal image anti-idiotypic antibody-treated mice.

    Science.gov (United States)

    Zhou, E M; Kisil, F T

    1995-10-01

    An internal image anti-idiotypic antibody, designated B1/1, was generated against an idiotope (Id91) of the monoclonal antibody (mAb91) specific for Lol pIV. The administration of B1/1 in PBS, at doses ranging from 100 ng to 100 micrograms/mouse, to syngeneic Balb/c mice resulted in the suppression of the formation of anti-Lol pIV antibodies that possessed the Id91. Spleen cells obtained from the mice 2 weeks after the treatment with B1/1 (25 micrograms/mouse) were adoptively transferred intravenously into the syngeneic recipients which were challenged intraperitoneally with Lol pIV in alum 2 hr after the transfer. The recipients were boosted with Lol pIV 14 days later. It was demonstrated that the transfer of splenic B cells (but not of T cells) from B1/1-treated donors induced a significant suppression of not only the level of IgE and IgG antibodies to Lol pIV, but also the level of antibodies possessing the Id91. Treatment of the B cells with mAb91 plus complement abrogated their ability to transfer the suppression. This study indicates that the treatment with the anti-Id B1/1 generated B cells that were characterized, serologically, as possessing the anti-Id-like antibodies on their surface and were responsible for transferring the suppression of the formation of antibodies to allergen Lol pIV and the expression of Id91.

  16. Inhibition of Human Immunodeficiency Virus Type 1 Tat-trans-Activation-Responsive Region Interaction by an Antiviral Quinolone Derivative

    Science.gov (United States)

    Richter, Sara; Parolin, Cristina; Gatto, Barbara; Del Vecchio, Claudia; Brocca-Cofano, Egidio; Fravolini, Arnaldo; Palù, Giorgio; Palumbo, Manlio

    2004-01-01

    WM5, a 6-aminoquinolone derivative, binds with high affinity to the bulge of the trans-activation-responsive region (TAR), whereas it displays low binding affinity for the loop and stem regions of TAR and for random RNA and DNA sequences. Furthermore, WM5 disrupts the natural protein-nucleic acid complex with a 50% inhibitory concentration in the low micromolar range in both in vitro and in vivo assays. PMID:15105155

  17. Role of CD40 ligand and CD28 in induction and maintenance of antiviral CD8+ effector T cell responses

    DEFF Research Database (Denmark)

    Andreasen, Susanne; Christensen, Jeanette Erbo; Marker, O

    2000-01-01

    and extensively, whereas vesicular stomatitis virus (VSV) spreads poorly. We found that the primary response of CD40L-/- mice toward VSV is significantly impaired; proliferation of both CD4+ and CD8+ cells is reduced 2- to 3-fold, few CD8+ cells acquire an activated phenotype, and little functional activity...... is induced. Very similar results were obtained in VSV-infected, CD28-deficient mice. In contrast, neither CD40L nor CD28 was required for induction of a primary CD8+ response toward LCMV. Surprisingly, lack of CD4+ T cells had no impact on the primary immune response toward any of the viruses, even though...... the CD40 ligand dependence demonstrated for VSV would be expected to be associated with CD4 dependence. Upon coinfection of VSV-infected mice with LCMV, the requirement for CD40 ligand (but not CD28) could be partially bypassed, as evidenced by a 3-fold increase in the frequency of VSV-specific CD8+ T...

  18. Long-Term Antibody and Immune Memory Response Induced by Pulmonary Delivery of the Influenza Iscomatrix Vaccine

    OpenAIRE

    Vujanic, Ana; Snibson, Kenneth J.; Wee, Janet L. K.; Edwards, Stirling J.; Pearse, Martin J.; Scheerlinck, Jean-Pierre Y.; Sutton, Philip

    2012-01-01

    Pulmonary delivery of an influenza Iscomatrix adjuvant vaccine induces a strong systemic and mucosal antibody response. Since an influenza vaccine needs to induce immunological memory that lasts at least 1 year for utility in humans, we examined the longevity of the immune response induced by such a pulmonary vaccination, with and without antigen challenge. Sheep were vaccinated in the deep lung with an influenza Iscomatrix vaccine, and serum and lung antibody levels were quantified for up to...

  19. Mitochondrial antiviral signaling protein plays a major role in induction of the fish innate immune response against RNA and DNA viruses.

    Science.gov (United States)

    Biacchesi, Stéphane; LeBerre, Monique; Lamoureux, Annie; Louise, Yoann; Lauret, Emilie; Boudinot, Pierre; Brémont, Michel

    2009-08-01

    Viral infection triggers host innate immune responses through cellular sensor molecules which activate multiple signaling cascades that induce the production of interferons (IFN) and other cytokines. The recent identification of mammalian cytoplasmic viral RNA sensors, such as retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and their mitochondrial adaptor, the mitochondrial antiviral signaling protein (MAVS), also called IPS-1, VISA, and Cardif, highlights the significance of these molecules in the induction of IFN. Teleost fish also possess a strong IFN system, but nothing is known concerning the RLRs and their downstream adaptor. In this study, we cloned MAVS cDNAs from several fish species (including salmon and zebrafish) and showed that they were orthologs of mammalian MAVS. We demonstrated that overexpression of these mitochondrial proteins in fish cells led to a constitutive induction of IFN and IFN-stimulated genes (ISGs). MAVS-overexpressing cells were almost fully protected against RNA virus infection, with a strong inhibition of both DNA and RNA virus replication (1,000- and 10,000-fold decreases, respectively). Analyses of MAVS deletion mutants showed that both the N-terminal CARD-like and C-terminal transmembrane domains, but not the central proline-rich region, were indispensable for MAVS signaling function. In addition, we cloned the cDNAs encoding a RIG-I-like molecule from salmonid and cyprinid cell lines. Like the case with MAVS, overexpression of RIG-I CARDs in fish cells led to a strong induction of both IFN and ISGs, conferring on fish cells full protection against RNA virus infection. This report provides the first demonstration that teleost fish possess a functional RLR pathway in which MAVS may play a central role in the induction of the innate immune response.

  20. CpG oligodeoxynucleotide-specific goose TLR21 initiates an anti-viral immune response against NGVEV but not AIV strain H9N2 infection.

    Science.gov (United States)

    Qi, Yulin; Yan, Bing; Chen, Shun; Chen, Hongjun; Wang, Mingshu; Jia, Renyong; Zhu, Dekang; Liu, Mafeng; Liu, Fei; Yang, Qiao; Sun, Kunfeng; Wu, Ying; Chen, Xiaoyue; Jing, Bo; Cheng, Anchun

    2016-03-01

    Toll-like receptors (TLRs) recognize components of pathogens and mediate the host innate immune response. TLR21 is a TLR that specifically recognizes exogenous double-stranded DNA and rapidly signals to downstream innate immune factors. This study reports the cDNA of goose TLR21 and identifies its immune characteristics. The goose TLR21 is 3161 base pairs and encodes a 975 amino acid protein. As predicted, the goose transmembrane protein TLR21 has a signal peptide, leucine-rich repeat regions, a transmembrane domain, and a Toll/interleukin-1 receptor domain. Multiple sequence alignments and phylogenetic analyses showed that goose TLR21 has homology to chicken TLR21. The tissue distribution of TLR21 suggested that it has high transcript levels in immune-associated tissues, especially in the bursa of Fabricius, the Hadrian gland, and the thymus. After challenge with agonist ODN2006 and new type gosling viral enteritis virus (NGVEV), significant induction of TLR21 production, pro-inflammatory cytokines IL-1β and IL-6, and interferons were observed in peripheral blood mononuclear cells. Both synthetic DNA (ODN2006) and viral DNA (NGVEV) can be recognized by goose TLR21, which leads to a rapid up-regulation of pro-inflammatory cytokines and anti-viral molecules. In vivo, avian influenza A virus H9N2 and NGVEV were used to infect goslings, which was followed by a significant up-regulation of TLR21 mRNA transcripts in multiple tissues of NGVEV-infected geese. In general, goose TLR21 plays an important role in binding invading pathogenic DNA viruses, which subsequently triggers an innate immune response; furthermore, it acts as a functional homologue of mammalian TLR9, as TLR21 recognizes a mammalian TLR9 agonist. Copyright © 2015 Elsevier GmbH. All rights reserved.

  1. BAFF mediates splenic B cell response and antibody production in experimental Chagas disease.

    Directory of Open Access Journals (Sweden)

    Daniela A Bermejo

    Full Text Available BACKGROUND: B cells and antibodies are involved not only in controlling the spread of blood circulating Trypanosoma cruzi, but also in the autoreactive manifestations observed in Chagas disease. Acute infection results in polyclonal B cell activation associated with hypergammaglobulinemia, delayed specific humoral immunity and high levels of non-parasite specific antibodies. Since TNF superfamily B lymphocyte Stimulator (BAFF mediates polyclonal B cell response in vitro triggered by T. cruzi antigens, and BAFF-Tg mice show similar signs to T. cruzi infected mice, we hypothesized that BAFF can mediate polyclonal B cell response in experimental Chagas disease. METHODOLOGY/PRINCIPAL FINDINGS: BAFF is produced early and persists throughout the infection. To analyze BAFF role in experimental Chagas disease, Balb/c infected mice were injected with BR3:Fc, a soluble receptor of BAFF, to block BAFF activity. By BAFF blockade we observed that this cytokine mediates the mature B cell response and the production of non-parasite specific IgM and IgG. BAFF also influences the development of antinuclear IgG and parasite-specific IgM response, not affecting T. cruzi-specific IgG and parasitemia. Interestingly, BAFF inhibition favors the parasitism in heart. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate, for the first time, an active role for BAFF in shaping the mature B cell repertoire in a parasite infection.

  2. Immunity to Brugia pahangi in athymic nude and normal mice: eosinophilia, antibody and hypersensitivity responses.

    Science.gov (United States)

    Vickery, A C; Vincent, A L

    1984-11-01

    Congenitally athymic nude (nu/nu) mice, immunologically reconstituted by thymus grafting before inoculation with infective larvae, and mice heterozygous for the nu gene (nu/+), mounted potent protective humoral and cellular immune responses to Brugia pahangi. Although responses were not identical, both groups of mice produced IgM, IgG and IgE antibodies specific for adult worm antigen (S-Ag) present in a crude aqueous extract, made immediate and delayed hypersensitivity footpad swelling responses when challenged with S-Ag and eliminated their infection in the early larval stages. Heterozygotes also exhibited a marked eosinophilia which peaked coincident with larval killing. In contrast, thymus grafting of patent nudes had no effect upon microfilaraemias or adult worm burdens and did not completely protect against a challenge larval inoculum although antibodies specific for S-Ag were produced. With the occasional exceptions of moderate immediate footpad swelling and very low titres of IgM specific for S-Ag, no specific immune responses to B. pahangi were found in ungrafted nude mice which allowed full development of adult worms and supported patent infections.

  3. Differential lymphocyte and antibody responses in deer mice infected with Sin Nombre hantavirus or Andes hantavirus.

    Science.gov (United States)

    Schountz, Tony; Quackenbush, Sandra; Rovnak, Joel; Haddock, Elaine; Black, William C; Feldmann, Heinz; Prescott, Joseph

    2014-08-01

    Hantavirus cardiopulmonary syndrome (HCPS) is a rodent-borne disease with a high case-fatality rate that is caused by several New World hantaviruses. Each pathogenic hantavirus is naturally hosted by a principal rodent species without conspicuous disease and infection is persistent, perhaps for life. Deer mice (Peromyscus maniculatus) are the natural reservoirs of Sin Nombre virus (SNV), the etiologic agent of most HCPS cases in North America. Deer mice remain infected despite a helper T cell response that leads to high-titer neutralizing antibodies. Deer mice are also susceptible to Andes hantavirus (ANDV), which causes most HCPS cases in South America; however, deer mice clear ANDV. We infected deer mice with SNV or ANDV to identify differences in host responses that might account for this differential outcome. SNV RNA levels were higher in the lungs but not different in the heart, spleen, or kidneys. Most ANDV-infected deer mice had seroconverted 14 days after inoculation, but none of the SNV-infected deer mice had. Examination of lymph node cell antigen recall responses identified elevated immune gene expression in deer mice infected with ANDV and suggested maturation toward a Th2 or T follicular helper phenotype in some ANDV-infected deer mice, including activation of the interleukin 4 (IL-4) pathway in T cells and B cells. These data suggest that the rate of maturation of the immune response is substantially higher and of greater magnitude during ANDV infection, and these differences may account for clearance of ANDV and persistence of SNV. Hantaviruses persistently infect their reservoir rodent hosts without pathology. It is unknown how these viruses evade sterilizing immune responses in the reservoirs. We have determined that infection of the deer mouse with its homologous hantavirus, Sin Nombre virus, results in low levels of immune gene expression in antigen-stimulated lymph node cells and a poor antibody response. However, infection of deer mice with a

  4. Immunoglobulin M and G antibody responses to Plasmodium falciparum glutamate-rich protein

    DEFF Research Database (Denmark)

    Dziegiel, M; Rowe, P; Bennett, S

    1993-01-01

    The aims of the present study were to describe the age-related immunoglobulin M (IgM) and IgG response to part of a 220-kDa glutamate-rich protein (GLURP) from Plasmodium falciparum and to determine possible correlations of possession of these antibodies with malaria morbidity. IgM and IgG levels...... in May and in October. Seropositivity rates increased with age to a maximum of 77% for IgM and 95% for IgG in adults. High prevalences of seropositivity were associated with certain human leukocyte antigen class II alleles (DRw8, DR9, DR7, DR4, DQw7, and DQw2) or haplotypes. The relationship between anti......-GLURP489-1271 antibodies and clinical immunity is not clear; asymptomatically infected children aged 5 to 8 years had significantly higher levels of IgG than clinically ill children of the same age, suggesting that antibodies to the carboxy-terminal part of the GLURP may contribute to immunity to P...

  5. Guinea pig complement potently measures vibriocidal activity of human antibodies in response to cholera vaccines.

    Science.gov (United States)

    Kim, Kyoung Whun; Jeong, Soyoung; Ahn, Ki Bum; Yang, Jae Seung; Yun, Cheol-Heui; Han, Seung Hyun

    2017-12-01

    The vibriocidal assay using guinea pig complement is widely used for the evaluation of immune responses to cholera vaccines in human clinical trials. However, it is unclear why guinea pig complement has been used over human complement in the measurement of vibriocidal activity of human sera and there have not been comparison studies for the use of guinea pig complement over those from other species. Therefore, we comparatively investigated the effects of complements derived from human, guinea pig, rabbit, and sheep on vibriocidal activity. Complements from guinea pig, rabbit, and human showed concentration-dependent vibriocidal activity in the presence of quality control serum antibodies. Of these complements, guinea pig complement was the most sensitive and effective over a wide concentration range. When the vibriocidal activity of complements was measured in the absence of serum antibodies, human, sheep, and guinea pig complements showed vibriocidal activity up to 40-fold, 20-fold, and 1-fold dilution, respectively. For human pre- and post-vaccination sera, the most potent vibriocidal activity was observed when guinea pig complement was used. In addition, the highest fold-increases between pre- and post- vaccinated sera were obtained with guinea pig complement. Furthermore, human complement contained a higher amount of V. cholerae- and its lipopolysaccharide-specific antibodies than guinea pig complement. Collectively, these results suggest that guinea pig complements are suitable for vibriocidal assays due to their high sensitivity and effectiveness to human sera.

  6. Synthetic Three-Component HIV-1 V3 Glycopeptide Immunogens Induce Glycan-Dependent Antibody Responses.

    Science.gov (United States)

    Cai, Hui; Orwenyo, Jared; Giddens, John P; Yang, Qiang; Zhang, Roushu; LaBranche, Celia C; Montefiori, David C; Wang, Lai-Xi

    2017-12-21

    Eliciting broadly neutralizing antibody (bNAb) responses against HIV-1 is a major goal for a prophylactic HIV-1 vaccine. One approach is to design immunogens based on known broadly neutralizing epitopes. Here we report the design and synthesis of an HIV-1 glycopeptide immunogen derived from the V3 domain. We performed glycopeptide epitope mapping to determine the minimal glycopeptide sequence as the epitope of V3-glycan-specific bNAbs PGT128 and 10-1074. We further constructed a self-adjuvant three-component immunogen that consists of a 33-mer V3 glycopeptide epitope, a universal T helper epitope P30, and a lipopeptide (Pam 3 CSK 4 ) that serves as a ligand of Toll-like receptor 2. Rabbit immunization revealed that the synthetic self-adjuvant glycopeptide could elicit substantial glycan-dependent antibodies that exhibited broader recognition of HIV-1 gp120s than the non-glycosylated V3 peptide. These results suggest that the self-adjuvant synthetic glycopeptides can serve as an important component to elicit glycan-specific antibodies in HIV vaccine design. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Intrasubtype B HIV-1 Superinfection Correlates with Delayed Neutralizing Antibody Response

    Science.gov (United States)

    Landais, Elise; Caballero, Gemma; Phung, Pham; Kosakovsky Pond, Sergei L.; Poignard, Pascal; Richman, Douglas D.; Little, Susan J.; Smith, Davey M.

    2017-01-01

    ABSTRACT Understanding whether the neutralizing antibody (NAb) response impacts HIV-1 superinfection and how superinfection subsequently modulates the NAb response can help clarify correlates of protection from HIV exposures and better delineate pathways of NAb development. We examined associations between the development of NAb and the occurrence of superinfection in a well-characterized, antiretroviral therapy (ART)-naive, primary infection cohort of men who have sex with men. Deep sequencing was applied to blood plasma samples from the cohort to detect cases of superinfection. We compared the NAb activity against autologous and heterologous viruses between 10 participants with intrasubtype B superinfection and 19 monoinfected controls, matched to duration of infection and risk behavior. Three to 6 months after primary infection, individuals who would later become superinfected had significantly weaker NAb activity against tier 1 subtype B viruses (P = 0.003 for SF-162 and P = 0.017 for NL4-3) and marginally against autologous virus (P = 0.054). Lower presuperinfection NAb responses correlated with weaker gp120 binding and lower plasma total IgG titers. Soon after superinfection, the NAb response remained lower, but between 2 and 3 years after primary infection, NAb levels strengthened and reached those of controls. Superinfecting viruses were typically not susceptible to neutralization by presuperinfection plasma. These observations suggest that recently infected individuals with a delayed NAb response against primary infecting and tier 1 subtype B viruses are more susceptible to superinfection. IMPORTANCE Our findings suggest that within the first year after HIV infection, a relatively weak neutralizing antibody response against primary and subtype-specific neutralization-sensitive viruses increases susceptibility to superinfection in the face of repeated exposures. As natural infection progresses, the immune response strengthens significantly in some

  8. The Human Cytomegalovirus Major Immediate-Early Proteins as Antagonists of Intrinsic and Innate Antiviral Host Responses

    Directory of Open Access Journals (Sweden)

    Michael Nevels

    2009-11-01

    Full Text Available The major immediate-early (IE gene of human cytomegalovirus (CMV is believed to have a decisive role in acute infection and its activity is an important indicator of viral reactivation from latency. Although a variety of gene products are expressed from this region, the 72-kDa IE1 and the 86-kDa IE2 nuclear phosphoproteins are the most abundant and important. Both proteins have long been recognized as promiscuous transcriptional regulators. More recently, a critical role of the IE1 and IE2 proteins in counteracting nonadaptive host cell defense mechanisms has been revealed. In this review we will briefly summarize the available literature on IE1- and IE2-dependent mechanisms contributing to CMV evasion from intrinsic and innate immune responses.

  9. Optimal Sequential Immunization Can Focus Antibody Responses against Diversity Loss and Distraction.

    Science.gov (United States)

    Wang, Shenshen

    2017-01-01

    Affinity maturation is a Darwinian process in which B lymphocytes evolve potent antibodies to encountered antigens and generate immune memory. Highly mutable complex pathogens present an immense antigenic diversity that continues to challenge natural immunity and vaccine design. Induction of broadly neutralizing antibodies (bnAbs) against this diversity by vaccination likely requires multiple exposures to distinct but related antigen variants, and yet how affinity maturation advances under such complex stimulation remains poorly understood. To fill the gap, we present an in silico model of affinity maturation to examine two realistic new aspects pertinent to vaccine development: loss in B cell diversity across successive immunization periods against different variants, and the presence of distracting epitopes that entropically disfavor the evolution of bnAbs. We find these new factors, which introduce additional selection pressures and constraints, significantly influence antibody breadth development, in a way that depends crucially on the temporal pattern of immunization (or selection forces). Curiously, a less diverse B cell seed may even favor the expansion and dominance of cross-reactive clones, but only when conflicting selection forces are presented in series rather than in a mixture. Moreover, the level of frustration due to evolutionary conflict dictates the degree of distraction. We further describe how antigenic histories select evolutionary paths of B cell lineages and determine the predominant mode of antibody responses. Sequential immunization with mutationally distant variants is shown to robustly induce bnAbs that focus on conserved elements of the target epitope, by thwarting strain-specific and distracted lineages. An optimal range of antigen dose underlies a fine balance between efficient adaptation and persistent reaction. These findings provide mechanistic guides to aid in design of vaccine strategies against fast mutating pathogens.

  10. A Cross-Reactive Monoclonal Antibody to Nematode Haemoglobin Enhances Protective Immune Responses to Nippostrongylus brasiliensis

    Science.gov (United States)

    Nieuwenhuizen, Natalie E.; Meter, Jeanne M.; Horsnell, William G.; Hoving, J. Claire; Fick, Lizette; Sharp, Michael F.; Darby, Matthew G.; Parihar, Suraj P.; Brombacher, Frank; Lopata, Andreas L.

    2013-01-01

    Background Nematode secreted haemoglobins have unusually high affinity for oxygen and possess nitric oxide deoxygenase, and catalase activity thought to be important in protection against host immune responses to infection. In this study, we generated a monoclonal antibody (48Eg) against haemoglobin of the nematode Anisakis pegreffii, and aimed to characterize cross-reactivity of 4E8g against haemoglobins of different nematodes and its potential to mediate protective immunity against a murine hookworm infection. Methodology/Principal Findings Immunoprecipitation was used to isolate the 4E8g-binding antigen in Anisakis and Ascaris extracts, which were identified as haemoglobins by peptide mass fingerprinting and MS/MS. Immunological cross-reactivity was also demonstrated with haemoglobin of the rodent hookworm N. brasiliensis. Immunogenicity of nematode haemoglobin in mice and humans was tested by immunoblotting. Anisakis haemoglobin was recognized by IgG and IgE antibodies of Anisakis-infected mice, while Ascaris haemoglobin was recognized by IgG but not IgE antibodies in mouse and human sera. Sequencing of Anisakis haemoglobin revealed high similarity to haemoglobin of a related marine nematode, Psuedoterranova decipiens, which lacks the four –HKEE repeats of Ascaris haemoglobin important in octamer assembly. The localization of haemoglobin in the different parasites was examined by immunohistochemistry and associated with the excretory-secretary ducts in Anisakis, Ascaris and N. brasiliensis. Anisakis haemoglobin was strongly expressed in the L3 stage, unlike Ascaris haemoglobin, which is reportedly mainly expressed in adult worms. Passive immunization of mice with 4E8g prior to infection with N. brasiliensis enhanced protective Th2 immunity and led to a significant decrease in worm burdens. Conclusion The monoclonal antibody 4E8g targets haemoglobin in broadly equivalent anatomical locations in parasitic nematodes and enhances host immunity to a hookworm

  11. Complexity of Human Antibody Response to Dengue Virus: Implication for Vaccine Development

    Directory of Open Access Journals (Sweden)

    Wen-Yang Tsai

    2017-07-01

    Full Text Available The four serotypes of dengue virus (DENV are the leading cause of arboviral diseases in humans. Decades of efforts have made remarkable progress in dengue vaccine development. Despite the first dengue vaccine (dengvaxia from Sanofi Pasteur, a live-attenuated tetravalent chimeric yellow fever-dengue vaccine, has been licensed by several countries since 2016, its overall moderate efficacy (56.5–60.8% in the presence of neutralizing antibodies during the Phase 2b and 3 trials, lower efficacy among dengue naïve compared with dengue experienced individuals, and increased risk of hospitalization among young children during the follow-up highlight the need for a better understanding of humoral responses after natural DENV infection. Recent studies of more than 300 human monoclonal antibodies (mAbs against DENV have led to the discovery of several novel epitopes on the envelope protein recognized by potent neutralizing mAbs. This information together with in-depth studies on polyclonal sera and B-cells following natural DENV infection has tremendous implications for better immunogen design for a safe and effective dengue vaccine. This review outlines the progress in our understanding of mouse mAbs, human mAbs, and polyclonal sera against DENV envelope and precursor membrane proteins, two surface proteins involved in vaccine development, following natural infection; analyses of these discoveries have provided valuable insight into new strategies involving molecular technology to induce more potent neutralizing antibodies and less enhancing antibodies for next-generation dengue vaccine development.

  12. Antibody responses against xenotropic murine leukemia virus-related virus envelope in a murine model.

    Directory of Open Access Journals (Sweden)

    Natalia Makarova

    2011-04-01

    Full Text Available Xenotropic murine leukemia virus-related virus (XMRV was recently discovered to be the first human gammaretrovirus that is associated with chronic fatigue syndrome and prostate cancer (PC. Although a mechanism for XMRV carcinogenesis is yet to be established, this virus belongs to the family of gammaretroviruses well known for their ability to induce cancer in the infected hosts. Since its original identification XMRV has been detected in several independent investigations; however, at this time significant controversy remains regarding reports of XMRV detection/prevalence in other cohorts and cell type/tissue distribution. The potential risk of human infection, coupled with the lack of knowledge about the basic biology of XMRV, warrants further research, including investigation of adaptive immune responses. To study immunogenicity in vivo, we vaccinated mice with a combination of recombinant vectors expressing codon-optimized sequences of XMRV gag and env genes and virus-like particles (VLP that had the size and morphology of live infectious XMRV.Immunization elicited Env-specific binding and neutralizing antibodies (NAb against XMRV in mice. The peak titers for ELISA-binding antibodies and NAb were 1:1024 and 1:464, respectively; however, high ELISA-binding and NAb titers were not sustained and persisted for less than three weeks after immunizations.Vaccine-induced XMRV Env antibody titers were transiently high, but their duration was short. The relatively rapid diminution in antibody levels may in part explain the differing prevalences reported for XMRV in various prostate cancer and chronic fatigue syndrome cohorts. The low level of immunogenicity observed in the present study may be characteristic of a natural XMRV infection in humans.

  13. Immunomodulatory activity of andrographolide on macrophage activation and specific antibody response

    Science.gov (United States)

    Wang, Wei; Wang, Jing; Dong, Sheng-fu; Liu, Chun-hong; Italiani, Paola; Sun, Shu-hui; Xu, Jing; Boraschi, Diana; Ma, Shi-ping; Qu, Di

    2010-01-01

    Aim: To investigate the immunomodulatory effects of andrographolide on both innate and adaptive immune responses. Methods: Andrographolide (10 μg/mL in vitro or 1 mg/kg in vivo) was used to modulate LPS-induced classical activated (M1) or IL-4-induced alternative activated (M2) macrophages in vitro and humor immune response to HBsAg in vivo. Cytokine gene expression profile (M1 vs M2) was measured by real-time PCR, IL-12/IL-10 level was detected by ELISA, and surface antigen expression was evaluated by flow cytometry, whereas phosphorylation level of ERK 1/2 and AKT was determined by Western blot. The level of anti-HBs antibodies in HBsAg immunized mice was detected by ELISA, and the number of HBsAg specific IL-4-producing splenocyte was enumerated by ELISPOT. Results: Andrographolide treatment in vitro attenuated either LPS or IL-4 induced macrophage activation, inhibited both M1 and M2 cytokines expression and decreased IL-12/IL-10 ratio (the ratio of M1/M2 polarization). Andrographolide down-regulated the expression of mannose receptor (CD206) in IL-4 induced macrophages and major histocompability complex/costimulatory molecules (MHC I, CD40, CD80, CD86) in LPS-induced macrophages. Correspondingly, anti-HBs antibody production and the number of IL-4-producing splenocytes were reduced by in vivo administration of andrographolide. Reduced phosphorylation levels of ERK1/2 and AKT were observed in macrophages treated with andrographolide. Conclusion: Andrographolide can modulate the innate and adaptive immune responses by regulating macrophage phenotypic polarization and Ag-specific antibody production. MAPK and PI3K signaling pathways may participate in the mechanisms of andrographolide regulating macrophage activation and polarization. PMID:20139902

  14. Pre-existing neutralizing antibody mitigates B cell dysregulation and enhances the Env-specific antibody response in SHIV-infected rhesus macaques.

    Directory of Open Access Journals (Sweden)

    Juan Pablo Jaworski

    Full Text Available Our central hypothesis is that protection against HIV infection will be powerfully influenced by the magnitude and quality of the B cell response. Although sterilizing immunity, mediated by pre-formed abundant and potent antibodies is the ultimate goal for B cell-targeted HIV vaccine strategies, scenarios that fall short of this may still confer beneficial defenses against viremia and disease progression. We evaluated the impact of sub-sterilizing pre-existing neutralizing antibody on the B cell response to SHIV infection. Adult male rhesus macaques received passive transfer of a sub-sterilizing amount of polyclonal neutralizing immunoglobulin (Ig purified from previously infected animals (SHIVIG or control Ig prior to intra-rectal challenge with SHIVSF162P4 and extensive longitudinal sampling was performed. SHIVIG treated animals exhibited significantly reduced viral load and increased de novo Env-specific plasma antibody. Dysregulation of the B cell profile was grossly apparent soon after infection in untreated animals; exemplified by a ≈50% decrease in total B cells in the blood evident 2-3 weeks post-infection which was not apparent in SHIVIG treated animals. IgD+CD5+CD21+ B cells phenotypically similar to marginal zone-like B cells were highly sensitive to SHIV infection, becoming significantly decreased as early as 3 days post-infection in control animals, while being maintained in SHIVIG treated animals, and were highly correlated with the induction of Env-specific plasma antibody. These results suggest that B cell dysregulation during the early stages of infection likely contributes to suboptimal Env-specific B cell and antibody responses, and strategies that limit this dysregulation may enhance the host's ability to eliminate HIV.

  15. Epstein-Barr virus but not cytomegalovirus is associated with reduced vaccine antibody responses in Gambian infants.

    Directory of Open Access Journals (Sweden)

    Beth Holder

    2010-11-01

    Full Text Available Epstein-Barr virus (EBV and cytomegalovirus (CMV are persistent herpesviruses that have various immunomodulatory effects on their hosts. Both viruses are usually acquired in infancy in Sub-Saharan Africa, a region where childhood vaccines are less effective than in high income settings. To establish whether there is an association between these two observations, we tested the hypothesis that infection with one or both viruses modulate antibody responses to the T-cell independent meningococcal polysaccharide vaccine and the T-cell dependent measles vaccines.Infection with EBV and CMV was diagnosed by the presence of virus-specific IgM in the peripheral blood or by the presence of IgG at higher levels than that found in umbilical cord blood. Anti-meningococcus IgG and IgM were quantified by ELISA. Anti-measles antibody responses were quantified by haemagglutinin antibody inhibition assay. Infants infected with EBV had reduced IgG and IgM antibody responses to meningococcal polysaccharides and to measles vaccine. Infection with CMV alone predicted no changes in the response to meningococcal polysaccharide. While CMV alone had no discernable effect on the antibody response to measles, the response of infants infected with both CMV and EBV was similar to that of infants infected with neither, suggesting that the effects of CMV infection countered the effects of EBV on measles antibody responses.The results of this exploratory study indicate that infection with EBV is associated with reduced antibody responses to polysaccharides and to measles vaccine, but suggest that the response to T-cell dependent antigens such as measles haemagglutinin may be restored by infection with CMV.

  16. Serologic profile of a cohort of pigs and antibody response to an autogenous vaccine for Actinobacillus suis.

    Science.gov (United States)

    Lapointe, L; D'Allaire, S; Lacouture, S; Gottschalk, M

    2001-01-01

    Actinobacillus suis is a commensal opportunistic pathogen in swine. However, in recent years, an increasing prevalence of clinical signs associated with A. suis has been observed in high health status herds in North America. The objectives of the study were to assess the kinetics of antibodies to A. suis in pigs from a herd showing clinical signs of A. suis infection and, to evaluate the antibody response in gilts following vaccination with an autogenous vaccine. An enzyme-linked immunosorbent assay (ELISA) using a saline extract of boiled-formalinized whole cells of a field strain as the coating antigen was standardized. This ELISA was used as a tool for monitoring, in a comparative way, the variations in A. suis antibody levels. The herd selected for the serologic profile was negative for Actinobacillus pleuropneumoniae infection and showed clinical signs of A. suis infection in 16 to 19-week-old pigs. A cohort of 20 pigs was blood sampled at 5, 8, 12, and 16 weeks of age. The lowest level of serum antibodies was observed between weeks 8 and 12, this probably corresponding to a decrease in maternal immunity. A marked increase in the antibody response was seen at 16-week of age, at the approximate time of onset of A. suis clinical signs in the herd. The evaluation of serum antibody responses to an autogenous vaccine revealed that the humoral immunity of gilts further increased following vaccination although the level of antibodies was already high prior to vaccination. The magnitude of the response to vaccination was higher when the level of antibodies was low prior to the first injection. The ELISA test seems to detect antibodies against the O-chain LPS.

  17. Influence of routes and administration parameters on antibody response of pigs following DNA vaccination

    DEFF Research Database (Denmark)

    Barfoed, Annette Malene; Kirstensen, Birte; Dannemann-Jensen, Tove

    2004-01-01

    Using the nucleoprotein of porcine reproductive and respiratory syndrome virus as model antigen, we optimised parameters for gene gun vaccination of pigs, including firing pressure and vaccination site. As criteria for optimisation, we characterised particle penetration and local tissue damage...... by histology. For selected combinations, vaccination efficiency in terms of antibody response was studied. Gene gun vaccination on ear alone was as efficient as a multi-site (ear, thorax, inguinal area, tongue mucosa) gene gun approach, and more efficient than combined intramuscular (i.m.)/intradermal (i.......d.) injection of plasmid DNA. This indicates, that the ear is an attractive site for gene gun vaccination of pigs....

  18. Antibody responses in pregnancy-induced transmammary transmission of Ancylostoma caninum hookworm larvae.

    Science.gov (United States)

    Arasu, P; Heller, A

    1999-09-20

    Third stage larvae of the Ancylostoma caninum hookworm nematode have the capacity to infect a dog, abort the normal maturation pathway to become blood-feeding intestinal worms, and instead distribute throughout the body in a developmentally arrested state that is relatively resilient to most chemotherapeutic agents. During pregnancy, a percentage of the arrested larvae reactivate and transmit via the mammary glands to infect the nursing puppies with resulting iron-deficiency anemia and potential mortality. To determine if the suppression of parasite-specific antibody responses during pregnancy facilitates the reactivation and transmammary transfer of hookworm larvae, a murine model of A. caninum infection was used to compare the infected versus uninfected animals that were either bred or not bred. Initial comparisons of genetically divergent BALB/c versus C57BL/6 mice showed that both the strains mounted strong Th2 biased IgG1 and IgE antibody responses to A. caninum infection. Using the BALB/c strain for the breeding analyses, it was confirmed that larval transfer to the mouse pups only occurred during the post-partum lactational period. In the dams, levels of total and antigen-specific IgG1 and total IgE were highly correlated with parasite burden. During most phases of pregnancy and lactation, infected dams had lower total IgG1, IgG2a and IgE levels as compared to unbred mice at comparable times post-infection; this downward modulation of antibody responses supports the established dogma of a generalized immunosuppression associated with pregnancy. However, at parturition and post-partum lactation, antigen-specific IgG1 levels measured at 1:5000 serum dilutions were comparable between bred and unbred mice, and antigen-specific IgG2a levels at 1:100 serum dilutions were also not significantly different except for a marginal reduction in the bred mice at the lactational timepoint. The comparable anti-A. caninum IgG1 levels between bred and unbred mice, and low

  19. Antiviral Polymer Therapeutics

    DEFF Research Database (Denmark)

    Smith, Anton Allen Abbotsford

    2014-01-01

    The field of drug delivery is in essence an exercise in engineered pharmacokinetics. Methods of doing so have been developed through the introduction of a vehicle carrying the drug, either by encapsulation or covalent attachment. The emergence of polymer therapeutics in anticancer therapy has...... garnered a great deal of interest due to the substantial room for improvement inherent to conventional chemotherapeutic agents. Chemotherapeutic agents and antiviral agents have a lot of features in common due to both of them typically targeting endogenous targets, unlike antibacterial compounds, though...... the examples of polymer therapeutics being applied as an antiviral treatment are few and far in-between. This work aims to explore antiviral therapeutics, specifically in context of hepatitis virus C (HCV) and HIV. The current treatment of hepatitis C consists of a combination of drugs, of which ribavirin...

  20. Improvement of liver stiffness in patients with hepatitis C virus infection who received direct-acting antiviral therapy and achieved sustained virological response.

    Science.gov (United States)

    Tada, Toshifumi; Kumada, Takashi; Toyoda, Hidenori; Mizuno, Kazuyuki; Sone, Yasuhiro; Kataoka, Saki; Hashinokuchi, Shinichi

    2017-12-01

    There is insufficient research on whether direct-acting antiviral (DAA) therapy can improve liver fibrosis in patients with chronic hepatitis C virus (HCV). We evaluated sequential changes in liver stiffness using shear wave elastography in patients with HCV who received DAA therapy. A total of 210 patients with HCV who received daclatasvir and asunaprevir therapy and achieved sustained virological response (SVR) were analyzed. Liver stiffness, as evaluated by shear wave elastography, and laboratory data were assessed before treatment (baseline), at end of treatment (EOT), and at 24 weeks after EOT (SVR24). Alanine aminotransferase levels (ALT) decreased over time, and there were significant differences between baseline and EOT and between EOT and SVR24. Although platelet counts did not significantly differ between baseline and EOT, they increased significantly from EOT to SVR24. The median (interquartile range) liver stiffness values at baseline, EOT, and SVR24 were 10.2 (7.7-14.7), 8.8 (7.1-12.1), and 7.6 (6.3-10.3) kPa, respectively (P  2.0 (n = 75), the liver stiffness values at baseline, EOT, and SVR24 were 9.6 (7.7-15.2), 9.2 (7.3-12.1), and 7.7 (6.3-10.1) kPa, respectively (P < 0.001, baseline vs EOT; P < 0.001, EOT vs SVR24). These results suggest that early improvement of liver stiffness starts during the administration of DAAs in patients who achieve SVR, and this effect is particularly pronounced in patients with progressive liver fibrosis. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  1. Ribavirin steady-state plasma level is a predictor of sustained virological response in hepatitis C-infected patients treated with direct-acting antivirals.

    Science.gov (United States)

    van Tilborg, M; Lieveld, F I; Smolders, E J; van Erpecum, K J; de Kanter, C T M M; Maan, R; van der Valk, M; Arends, J E; Dofferhoff, A S M; Blokzijl, H; Bijmolen, M; Drenth, J P H; de Knegt, R J; Burger, D M

    2017-11-01

    In the era of highly effective direct-acting antivirals (DAAs) for treatment of patients with chronic hepatitis C virus (HCV) infection, ribavirin (RBV) is still considered beneficial in certain patients. To assess the association between RBV steady-state plasma levels and sustained virological response (SVR). Consecutive HCV-infected patients treated with DAAs plus RBV from four Dutch academic medical centres were enrolled. RBV steady-state plasma levels were prospectively measured at treatment week 8 using validated assays. Logistic regression analyses were performed to assess the influence of RBV steady-state plasma level on SVR, and RBV therapeutic range was explored using area under the ROC curve analyses. A total of 183 patients were included, of whom 85% had one or more difficult-to-cure characteristics (ie treatment experienced, HCV genotype 3, cirrhosis). The majority was treated with a sofosbuvir-based regimen and 163 (89%) patients achieved SVR. Median RBV dose was 12.9 (interquartile range 11.2-14.7) mg/kg/d, and median RBV steady-state plasma level was 2.66 (1.95-3.60) mg/L. In multivariable analyses, higher RBV steady-state plasma level (adjusted odds ratio 1.79 [95% CI 1.09-2.93]) was an independent predictor of SVR. With regard to the optimal RBV therapeutic range, 2.28 mg/L was the optimal lower cut-off for achieving SVR and 3.61 mg/L was the upper cut-off for preventing significant anaemia (Haemoglobin steady-state plasma level was an independent predictor of SVR. © 2017 John Wiley & Sons Ltd.

  2. Equine Arteritis Virus Elicits a Mucosal Antibody Response in the Reproductive Tract of Persistently Infected Stallions.

    Science.gov (United States)

    Carossino, Mariano; Wagner, Bettina; Loynachan, Alan T; Cook, R Frank; Canisso, Igor F; Chelvarajan, Lakshman; Edwards, Casey L; Nam, Bora; Timoney, John F; Timoney, Peter J; Balasuriya, Udeni B R

    2017-10-01

    Equine arteritis virus (EAV) has the ability to establish persistent infection in the reproductive tract of the stallion (carrier) and is continuously shed in its semen. We have recently demonstrated that EAV persists within stromal cells and a subset of lymphocytes in the stallion accessory sex glands in the presence of a significant local inflammatory response. In the present study, we demonstrated that EAV elicits a mucosal antibody response in the reproductive tract during persistent infection with homing of plasma cells into accessory sex glands. The EAV-specific immunoglobulin isotypes in seminal plasma included IgA, IgG1, IgG3/5, and IgG4/7. Interestingly, seminal plasma IgG1 and IgG4/7 possessed virus-neutralizing activity, while seminal plasma IgA and IgG3/5 did not. However, virus-neutralizing IgG1 and IgG4/7 in seminal plasma were not effective in preventing viral infectivity. In addition, the serological response was primarily mediated by virus-specific IgM and IgG1, while virus-specific serum IgA, IgG3/5, IgG4/7, and IgG6 isotype responses were not detected. This is the first report characterizing the immunoglobulin isotypes in equine serum and seminal plasma in response to EAV infection. The findings presented herein suggest that while a broader immunoglobulin isotype diversity is elicited in seminal plasma, EAV has the ability to persist in the reproductive tract, in spite of local mucosal antibody and inflammatory responses. This study provides further evidence that EAV employs complex immune evasion mechanisms during persistence in the reproductive tract that warrant further investigation. Copyright © 2017 American Society for Microbiology.

  3. Prevalence and clinical relevance of occult hepatitis B in the fibrosis progression and antiviral response to INF therapy in HIV-HCV-coinfected patients.

    Science.gov (United States)

    Laguno, Montserrat; Larrousse, Maria; Blanco, José Luis; Leon, Agathe; Milinkovic, Ana; Martínez-Rebozler, Maria; Loncá, Montserrat; Martinez, Esteban; Sanchez-Tapias, Jose Maria; de Lazzari, Elisa; Gatell, José Maria; Costa, Josep; Mallolas, Josep

    2008-04-01

    Occult hepatitis B virus (HBV) infection is diagnosed when HBc antibodies (HBcAb) and HBV DNA are detectable in serum while hepatitis B surface antigen (HBsAg) is not. This situation has been frequently described in patients with chronic hepatitis C virus (HCV) infection. The objective of this study was to evaluate the prevalence of occult hepatitis B in HIV-HCV-coinfected patients and its clinical relevance in liver histology and viral response after interferon therapy for HCV. A total of 238 HIV-HCV-infected patients,negative for HBsAg, were included. Serum samples were analyzed for the presence of HBV DNA and HBcAb.HBV DNA quantification was determined with the Cobas TaqMan HBV Test (detection limit 6 IU/ml). Data from liver biopsy and laboratory tests were also analyzed. HBcAb resulted in 142 (60%) patients, being the independent associated factors: male gender, previous history of intravenous drug use, age, CD4 count,and HAV antibody presence. Among 90 HBcAb patients that we could analyze, HBV DNA was positive in 15 (16.7% of occult hepatitis B infection in this group, and 6.3% in the whole HIV-HCV cohort studied). No baseline factors, liver histology, or HCV therapy response were related to the presence of HBV DNA. We found that occult hepatitis B is a frequent condition present in at least 6.3% of our HCV-HIV patients and in more than 16% of those with HBcAb. Despite the high prevalence, this phenomenon does not seem to affect the clinical evolution of chronic hepatitis C or modify the viral response to interferon-based HCV therapies

  4. Serum antibody levels correlate with oral fungal cell numbers and influence the patients' response to chronic paracoccidioidomycosis.

    Science.gov (United States)

    de Carli, Marina Lara; Cardoso, Beatriz Cristina Bachião; Malaquias, Luiz Cosme Cotta; Nonogaki, Suely; Pereira, Alessandro Antônio Costa; Sperandio, Felipe Fornias; Hanemann, João Adolfo Costa

    2015-06-01

    Paracoccidioidomycosis (PCM) is a neglected fungal disease that elicits an important granulomatous inflammatory reaction which aims to isolate the fungi and resolve the infection; besides the innate cellular response, the patients' sera may contain different levels of antibodies directed against PCM's pathogenic agent: Paracoccidioides brasiliensis (Pb). The aim of the study was to assess the distinct serum antibody levels of 19 chronic PCM patients and to associate these levels to the granulomatous inflammatory response and presence of fungi in oral lesions caused by Pb. The presence of Pb was detected and counted within oral tissues using immunohistochemistry; antibody levels were classified as negative, low-grade, moderate or high-grade groups. The Kruskal-Wallis and Dunn's test were used to verify possible associations among the groups. Interestingly, lower antibody titres were associated with lesser numbers of Pb, which favours the cellular response over the humoral response to fight PCM. On the other hand, negative serological results were linked to a higher presence of Pb in the tissues, indicating that a deficient humoral response supports the fungal proliferation. The number of Pb was conveniently associated with the level of serum antibodies, showing that the humoral immune response is required, however, not solely responsible to restrain the dissemination of Pb. © 2015 Blackwell Verlag GmbH.

  5. Broad-spectrum antiviral properties of andrographolide.

    Science.gov (United States)

    Gupta, Swati; Mishra, K P; Ganju, Lilly

    2017-03-01

    Andrographolide, a diterpenoid, is known for its anti-inflammatory effects. It can be isolated from various plants of the genus Andrographis, commonly known as 'creat'. This purified compound has been tested for its anti-inflammatory effects in various stressful conditions, such as ischemia, pyrogenesis, arthritis, hepatic or neural toxicity, carcinoma, and oxidative stress, Apart from its anti-inflammatory effects, andrographolide also exhibits immunomodulatory effects by effectively enhancing cytotoxic T cells, natural killer (NK) cells, phagocytosis, and antibody-dependent cell-mediated cytotoxicity (ADCC). All these properties of andrographolide form the foundation for the use of this miraculous compound to restrain virus replication and virus-induced pathogenesis. The present article covers antiviral properties of andrographolide in variety of viral infections, with the hope of developing of a new highly potent antiviral drug with multiple effects.

  6. Intracellular antibody-mediated immunity and the role of TRIM21.

    Science.gov (United States)

    McEwan, William A; Mallery, Donna L; Rhodes, David A; Trowsdale, John; James, Leo C

    2011-11-01

    Protection against bacterial and viral pathogens by antibodies has always been thought to end at the cell surface. Once inside the cell, a pathogen was understood to be safe from humoral immunity. However, it has now been found that antibodies can routinely enter cells attached to viral particles and mediate an intracellular immune response. Antibody-coated virions are detected inside the cell by means of an intracellular antibody receptor, TRIM21, which directs their degradation by recruitment of the ubiquitin-proteasome system. In this article we assess how this discovery alters our view of the way in which antibodies neutralise viral infection. We also consider the antiviral function of TRIM21 in the context of its other reported roles in immune signalling and autoimmunity. Finally, we discuss the conceptual implications of intracellular antibody immunity and how it alters our view of the discrete separation of extracellular and intracellular environments. Copyright © 2011 WILEY Periodicals, Inc.

  7. A large population-based association study between HLA and KIR genotypes and measles vaccine antibody responses.

    Science.gov (United States)

    Ovsyannikova, Inna G; Schaid, Daniel J; Larrabee, Beth R; Haralambieva, Iana H; Kennedy, Richard B; Poland, Gregory A

    2017-01-01

    Human antibody response to measles vaccine is highly variable in the population. Host genes contribute to inter-individual antibody response variation. The killer cell immunoglobulin-like receptors (KIR) are recognized to interact with HLA molecules and possibly influence humoral immune response to viral antigens. To expand on and improve our previous work with HLA genes, and to explore the genetic contribution of KIR genes to the inter-individual variability in measles vaccine-induced antibody responses, we performed a large population-based study in 2,506 healthy immunized subjects (ages 11 to 41 years) to identify HLA and KIR associations with measles vaccine-induced neutralizing antibodies. After correcting for the large number of statistical tests of allele effects on measles-specific neutralizing antibody titers, no statistically significant associations were found for either HLA or KIR loci. However, suggestive associations worthy of follow-up in other cohorts include B*57:01, DQB1*06:02, and DRB1*15:05 alleles. Specifically, the B*57:01 allele (1,040 mIU/mL; p = 0.0002) was suggestive of an association with lower measles antibody titer. In contrast, the DQB1*06:02 (1,349 mIU/mL; p = 0.0004) and DRB1*15:05 (2,547 mIU/mL; p = 0.0004) alleles were suggestive of an association with higher measles antibodies. Notably, the associations with KIR genotypes were strongly nonsignificant, suggesting that KIR loci in terms of copy number and haplotypes are not likely to play a major role in antibody response to measles vaccination. These findings refine our knowledge of the role of HLA and KIR alleles in measles vaccine-induced immunity.

  8. Immunoglobulin G1 Allotype Influences Antibody Subclass Distribution in Response to HIV gp140 Vaccination

    Directory of Open Access Journals (Sweden)

    Sven Kratochvil

    2017-12-01

    Full Text Available Antibody subclasses exhibit extensive polymorphisms (allotypes that could potentially impact the quality of HIV-vaccine induced B cell responses. Allotypes of immunoglobulin (Ig G1, the most abundant serum antibody, have been shown to display altered functional properties in regard to serum half-life, Fc-receptor binding and FcRn-mediated mucosal transcytosis. To investigate the potential link between allotypic IgG1-variants and vaccine-generated humoral responses in a cohort of 14 HIV vaccine recipients, we developed a novel protocol for rapid IgG1-allotyping. We combined PCR and ELISA assays in a dual approach to determine the IgG1 allotype identity (G1m3 and/or G1m1 of trial participants, using human plasma and RNA isolated from PBMC. The IgG1-allotype distribution of our participants mirrored previously reported results for caucasoid populations. We observed elevated levels of HIV gp140-specific IgG1 and decreased IgG2 levels associated with the G1m1-allele, in contrast to G1m3 carriers. These data suggest that vaccinees homozygous for G1m1 are predisposed to develop elevated Ag-specific IgG1:IgG2 ratios compared to G1m3-carriers. This elevated IgG1:IgG2 ratio was further associated with higher FcγR-dimer engagement, a surrogate for potential antibody-dependent cellular cytotoxicity (ADCC and antibody-dependent cellular phagocytosis (ADCP function. Although preliminary, these results suggest that IgG1 allotype may have a significant impact on IgG subclass distribution in response to vaccination and associated Fc-mediated effector functions. These results have important implications for ongoing HIV vaccine efficacy studies predicated on engagement of FcγR-mediated cellular functions including ADCC and ADCP, and warrant further investigation. Our novel allotyping protocol provides new tools to determine the potential impact of IgG1 allotypes on vaccine efficacy.

  9. Evolution of the HIV-1 Envelope Glycoprotein Genes and Neutralizing Antibody Response in an Individual with Broadly Cross Neutralizing Antibodies

    Science.gov (United States)

    2010-08-31

    FBS, L-glutamine, penicillin, streptomycin (Gibeo), tylosin (Sigma), and puromycin. All cell cultures were maintained in a humidified atmosphere...white walled, flat- bottomed tissue culture plates (Costar, Coming NY). The virus-antibody mixtures were then combined with 1-2 x 104 HOS-CD4+-CCR5...all lineages combined obtained from 1986-1993 to sCD4 and eight cross-reactive mAbs targeting distinct neutralization epitope regions. We chose

  10. Heritability of antibody isotype and subclass responses to Plasmodium falciparum antigens.

    Directory of Open Access Journals (Sweden)

    Nancy O Duah

    2009-10-01

    Full Text Available It is important to understand the extent to which genetic factors regulate acquired immunity to common infections. A classical twin study design is useful to estimate the heritable component of variation in measurable immune parameters.This study assessed the relative heritability of different plasma antibody isotypes and subclasses (IgG1, IgG2, IgG3, IgG4, IgM, IgA and IgE naturally acquired to P. falciparum blood stage antigens AMA1, MSP1-19, MSP2 (two allelic types and MSP3 (two allelic types. Separate analyses were performed on plasma from 213 pairs of Gambian adult twins, 199 child twin pairs sampled in a dry season when there was little malaria transmission, and another set of 107 child twin pairs sampled at the end of the annual wet season when malaria was common. There were significantly positive heritability (h(2 estimates for 48% (20/42 of the specific antibody assays (for the seven isotypes and subclasses to the six antigens tested among the adults, 48% (20/42 among the children in the dry season and 31% (13/42 among the children in the wet season. In children, there were significant heritability estimates for IgG4 reactivity against each of the antigens, and this subclass had higher heritability than the other subclasses and isotypes. In adults, 75% (15/20 of the significantly heritable antigen-specific isotype responses were attributable to non-HLA class II genetic variation, whereas none showed a significant HLA contribution.Genome-wide approaches are now warranted to map the major genetic determinants of variable antibody isotype and subclass responses to malaria, alongside evaluation of their impact on infection and disease. Although plasma levels of IgG4 to malaria antigens are generally low, the exceptionally high heritability of levels of this subclass in children deserves particular investigation.

  11. A microculture system for generating haemolytic antibody responses from human tonsillar lymphocytes.

    Science.gov (United States)

    Booth, R J

    1979-01-01

    Small numbers of Ficoll-Hypaque purified human tonsillar lymphocytes were stimulated with PWM to produce SRBC-specific PFC in a microculture system. The magnitude of the response varied among different tonsils but was typically between 200 and 1000 PFC/10(6) cells cultured. Little or no response was observed in the absence of PWM. SRBC failed to stimulate a SRBC-specific response and the presence of this antigen in PWM-stimulated cultures depressed the response. The time of the maximum response was inversely related to the number of cells cultured. In addition, the duration of the response was limited by rapid depletion of critical medium requirements and/or build up of inhibitory factors especially when the cell concentration exceeded 5 x 10(5) cells/culture. This effect could be partially overcome by daily feeding of cultures with fresh medium. Fractionation studies indicated a requirement for both T and B cell populations. Constant efficiency of PFC production with respect to cell number could be achieved by the addition of inactivated autologous 'filler' cells. The significance of these results and applicability of the microculture system to a detailed analysis of human antibody responses will be discussed.

  12. Ophthalmic antiviral chemotherapy : An overview

    Directory of Open Access Journals (Sweden)

    Athmanathan Sreedharan

    1997-01-01

    Full Text Available Antiviral drug development has been slow due to many factors. One such factor is the difficulty to block the viral replication in the cell without adversely affecting the host cell metabolic activity. Most of the antiviral compounds are analogs of purines and pyramidines. Currently available antiviral drugs mainly inhibit viral nucleic acid synthesis, hence act only on actively replicating viruses. This article presents an overview of some of the commonly used antiviral agents in clinical ophthalmology.

  13. The clonal antibody response to Pseudomonas aeruginosa heat shock protein is highly diverse in cystic fibrosis patients

    DEFF Research Database (Denmark)

    Ulanova, M; Petersen, T D; Ciofu, O

    1997-01-01

    The GroEL protein of Pseudomonas aeruginosa belongs to the bacterial 60-65 kDa heat shock protein family. A strong antibody response to GroEL has been found in cystic fibrosis (CF) patients with chronic pulmonary infection caused by P. aeruginosa. Clonotypes of IgG1 and IgG2 antibodies against Gro...... antibody clones against GroEL. The appearance of new clones with time reflected the long duration of the chronic infection. A striking addition of new clonotypes during the observation period occurred when a new unrelated bacterium (Burkholderia cepacia) had become established as a cause of the pulmonary...

  14. Cryptosporidiosis in HIV/AIDS patients in Kenya: clinical features, epidemiology, molecular characterization and antibody responses.

    Science.gov (United States)

    Wanyiri, Jane W; Kanyi, Henry; Maina, Samuel; Wang, David E; Steen, Aaron; Ngugi, Paul; Kamau, Timothy; Waithera, Tabitha; O'Connor, Roberta; Gachuhi, Kimani; Wamae, Claire N; Mwamburi, Mkaya; Ward, Honorine D

    2014-08-01

    We investigated the epidemiological and clinical features of cryptosporidiosis, the molecular characteristics of infecting species and serum antibody responses to three Cryptosporidium-specific antigens in human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients in Kenya. Cryptosporidium was the most prevalent enteric pathogen and was identified in 56 of 164 (34%) of HIV/AIDS patients, including 25 of 70 (36%) with diarrhea and 31 of 94 (33%) without diarrhea. Diarrhea in patients exclusively infected with Cryptosporidium was significantly associated with the number of children per household, contact with animals, and water treatment. Cryptosporidium hominis was the most prevalent species and the most prevalent subtype family was Ib. Patients without diarrhea had significantly higher serum IgG levels to Chgp15, Chgp40 and Cp23, and higher fecal IgA levels to Chgp15 and Chgp40 than those with diarrhea suggesting that antibody responses to these antigens may be associated with protection from diarrhea and supporting further investigation of these antigens as vaccine candidates. © The American Society of Tropical Medicine and Hygiene.

  15. Antibody response between pigs of Piau and a commercial breed naturally infected with Porcine circovirus 2

    Directory of Open Access Journals (Sweden)

    L.H.S. Bulos

    Full Text Available ABSTRACT Brazilian pig population is made up of several naturalized breeds; among them the Piau breed is known for its rusticity and large fat stores. The naturalized breeds, in comparison with commercial ones, may have an increased resistance to diseases circulating in their territory. Thus, this study aimed to verify if there are differences between the serologic profile against Porcine circovirus 2 (PCV2 of Piau pigs and that of a commercial breed from a farm naturally infected by PCV2. The serum viral load was measured by qPCR, and levels of anti-PCV2 antibodies were measured by ELISA. The results showed that the serum viral load was similar across all animals. However, Piau piglets showed higher levels of antibodies compared to commercial piglets (P= 0.05, while sows of the commercial breed showed higher levels than the Piau breed (P< 0.01. There was not a statistical difference between pigs of different production stages in the seroprevalence of PCV2 or the blood viral load. This work demonstrates that, with regard to a natural PCV2 infection, the Piau breed has a different humoral immune response compared to the response developed by the commercial pigs. The results support the importance of conservation of native breeds.

  16. Effect of Echinacea purpurea (Asteraceae) aqueous extract on antibody response to Bothrops asper venom and immune cell response.

    Science.gov (United States)

    Chaves, Fernando; Chacón, Mauricio; Badilla, Beatriz; Arévalo, Carolina

    2007-03-01

    The effect of aqueous extract of Echinacea purpurea roots on the murine antibody response to Bothrops asper snake venom in vivo was studied. Three groups were used. Group #1, baseline control, was treated with snake venom plus PBS. Group #2 was treated with snake venom plus sodium alginate as adjuvant (routine method used at Instituto Clodomiro Picado), and group #3 or experimental group, was treated with snake venom plus aqueous extract ofE. purpurea root as adjuvant. In all groups, the first inoculation was done with Freund's complete adjuvant (FCA). By the time of the second bleeding, mice in group #3 showed a remarkable increment in the level of anti-venom antibodies compared with those in groups #1 or #2. In vitro immune cell proliferation as a response to aqueous extract of E. purpurea root was studied using human lymphocytes activated with different lectins (Con A, PHA and PWM). In all cases, increase in percentage of lymphoproliferation was greater when E. purpurea root extract was used in addition to individual lectins.

  17. Antibody responses to HIV-1 antigens are higher in HIV-1(+) intravenous drug users than in HIV-1(+) homosexuals.

    Science.gov (United States)

    Jiang, J D; Bekesi, G J

    2001-07-01

    Immune responses to HIV-1 infection of 42 HIV-1-positive asymptomatic intravenous drug users (IVDUs) were compared with those of 135 HIV-1-infected asymptomatic homosexual men in the present study. Twenty-five HIV-1(-) individuals served as normal controls. The comparison included antibody responses to five computer-predicted epitopes of HIV-1 p17, and viral proteins gp120 and p24 as well as p17. Major immunophenotypes were also investigated. Results showed that antibody responses to the five epitopes were significantly higher in the IVDUs. A larger proportion of the IVDUs, with respect to that of homosexuals, showed positive antibody responses to p24 and p17, respectively. However, the antibody response to gp120 was similar between the two cohorts. Immunophenotyping showed that HIV-1(+) homosexuals had higher profiles in most of the major subsets than did the IVDUs, especially in the total count of lymphocytes, absolute numbers of CD3+ cells and CD8+ cells. It appeared that the HIV-1(+) IVDU cohort had higher antibody responses to most of the viral antigens, but had lower levels of lymphocyte subsets in comparison with HIV(+) homosexuals.

  18. The dynamics of HCV-specific antibody responses in HIV/HCV patients on long-term antiretroviral therapy.

    Science.gov (United States)

    Lee, Silvia; Laiman, Alfred; French, Martyn A; Flexman, James; Watson, Mark W; Price, Patricia

    2017-06-01

    Antibody responses have not been fully characterised in chronically HIV/HCV patients receiving antiretroviral therapy (ART). Seventeen HIV/HCV patients receiving ART were followed for a median (range) interval of 597 (186-766) weeks. Prior to ART, HIV/HCV patients had lower levels of antibodies reactive with HCV core and JFH-1, and lower genotype cross-reactive neutralising antibodies (nAb) titres, than HCV patients. Levels of JFH-1 reactive antibody increased on ART, irrespective of CD4 + T-cell counts or changes in serum ALT levels. The appearance of nAb coincided with control of HCV viral replication in five HIV/HCV patients. In other patients, HCV viral loads remained elevated despite nAb responses. Sustained virological responses following HCV therapy were associated with reduced antibody responses to JFH-1 and core but elevated responses to non-structural proteins. We conclude that nAb responses alone may fail to clear HCV, but contribute to control of viral replication in some HIV/HCV patients responding to ART. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. In Situ Liver Expression of HBsAg/CD3-Bispecific Antibodies for HBV Immunotherapy

    Directory of Open Access Journals (Sweden)

    Robert L. Kruse

    2017-12-01

    Full Text Available Current therapies against hepatitis B virus (HBV do not reliably cure chronic infection, necessitating new therapeutic approaches. The T cell response can clear HBV during acute infection, and the adoptive transfer of antiviral T cells during bone marrow transplantation can cure patients of chronic HBV infection. To redirect T cells to HBV-infected hepatocytes, we delivered plasmids encoding bispecific antibodies directed against the viral surface antigen (HBsAg and CD3, expressed on almost all T cells, directly into the liver using hydrodynamic tail vein injection. We found a significant reduction in HBV-driven reporter gene expression (184-fold in a mouse model of acute infection, which was 30-fold lower than an antibody only recognizing HBsAg. While bispecific antibodies triggered, in part, antigen-independent T cell activation, antibody production within hepatocytes was non-cytotoxic. We next tested the bispecific antibodies in a different HBV mouse model, which closely mimics the transcriptional template for HBV, covalently closed circular DNA (cccDNA. We found that the antiviral effect was noncytopathic, mediating a 495-fold reduction in HBsAg levels at day 4. At day 33, bispecific antibody-treated mice exhibited 35-fold higher host HBsAg immunoglobulin G (IgG antibody production versus untreated groups. Thus, gene therapy with HBsAg/CD3-bispecific antibodies represents a promising therapeutic strategy for patients with HBV.

  20. Antibody and T cell responses to Fusobacterium nucleatum and Treponema denticola in health and chronic periodontitis.

    Directory of Open Access Journals (Sweden)

    Jieun Shin

    Full Text Available The characteristics of the T cell response to the members of oral flora are poorly understood. We characterized the antibody and T cell responses to FadA and Td92, adhesins from Fusobacterium nucleatum, an oral commensal, and Treponema denticola, a periodontal pathogen, respectively. Peripheral blood and saliva were obtained from healthy individuals and patients with untreated chronic periodontitis (CP, n = 11 paris and after successful treatment of the disease (n = 9. The levels of antigen-specific antibody were measured by ELISA. In plasma, IgG1 was the most abundant isotype of Ab for both Ags, followed by IgA and then IgG4. The levels of FadA-specific salivary IgA (sIgA were higher than Td92-specific sIgA and the FadA-specific IgA levels observed in plasma. However, the periodontal health status of the individuals did not affect the levels of FadA- or Td92-specific antibody. Even healthy individuals contained FadA- and Td92-specific CD4(+ T cells, as determined by the detection of intracytoplasmic CD154 after short-term in vitro stimulation of peripheral blood mononuclear cells (PBMCs with the antigens. Patients with CP tended to possess increased numbers of FadA- and Td92-specific CD4(+ T cells but reduced numbers of Td92-specific Foxp3(+CD4(+ Tregs than the healthy subjects. Both FadA and Td92 induced the production of IFNγ and IL-10 but inhibited the secretion of IL-4 by PBMCs. In conclusion, F. nucleatum induced Th3 (sIgA- and Th1 (IFNγ and IgG1-dominant immune responses, whereas T. denticola induced a Th1 (IFNγ and IgG1-dominant response. This IFNγ-dominant cytokine response was impaired in CP patients, and the Td92-induced IFNγ levels were negatively associated with periodontal destruction in patients. These findings may provide new insights into the homeostatic interaction between the immune system and oral bacteria and the pathogenesis of periodontitis.

  1. HP-1γ Controls High-Affinity Antibody Response to T-Dependent Antigens.

    Science.gov (United States)

    Ha, Ngoc; Pham, Duc-Hung; Shahsafaei, Aliakbar; Naruse, Chie; Asano, Masahide; Thai, To-Ha

    2014-01-01

    In vitro observations suggest a role for the mouse heterochromatin protein 1γ (HP-1γ) in the immune system. However, it has not been shown if and how HP-1γ contributes to immunity in vivo. Here we show that in mice, HP-1γ positively regulates the germinal center reaction and high-affinity antibody response to thymus (T)-dependent antigens by limiting the size of CD8(+) regulatory T-cell (Treg) compartment without affecting progenitor B- or T-cell-development. Moreover, HP-1γ does not control cell proliferation or class switch recombination. Haploinsufficiency of cbx-3 (gene encoding HP-1γ) is sufficient to expand the CD8(+) Treg population and impair the immune response in mice despite the presence of wild-type HP-1α and HP-1β. This is the first in vivo evidence demonstrating the non-redundant role of HP-1γ in immunity.

  2. Antiviral Drugs: Seasonal Flu

    Centers for Disease Control (CDC) Podcasts

    2010-09-29

    In this podcast, Dr. Joe Bresee explains the nature of antiviral drugs and how they are used for seasonal flu.  Created: 9/29/2010 by National Center for Immunization and Respiratory Diseases (NCIRD).   Date Released: 9/29/2010.

  3. Broad-spectrum inhibition of common respiratory RNA viruses by a pyrimidine synthesis inhibitor with involvement of the host antiviral response.

    Science.gov (United States)

    Cheung, Nam Nam; Lai, Kin Kui; Dai, Jun; Kok, Kin Hang; Chen, Honglin; Chan, Kwok-Hung; Yuen, Kwok-Yung; Kao, Richard Yi Tsun

    2017-05-01

    Our previous screening of 50 240 structurally diverse compounds led to the identification of 39 influenza A virus infection inhibitors (Kao R.Y., Yang D., Lau L.S., Tsui W.H., Hu L. et al. Nat Biotechnol 2010;28:600-605). Further screening of these compounds against common respiratory viruses led to the discovery of compound FA-613. This inhibitor exhibited low micromolar antiviral activity against various influenza A and B virus strains, including the highly pathogenic influenza A strains H5N1 and H7N9, enterovirus A71, respiratory syncytial virus, human rhinovirus A, SARS- and MERS-coronavirus. No significant cellular toxicity was observed at the effective concentrations. Animal studies showed an improved survival rate in BALB/c mice that received intranasal FA-613 treatments against a lethal dose infection of A/HK/415742Md/2009 (H1N1). Further cell-based assays indicated that FA-613 interfer with the de novo pyrimidine biosynthesis pathway by targeting the dihydroorotate dehydrogenase. Surprisingly, FA-613 lost its antiviral potency in the interferon-deficient Vero cell line, while maintaining its inhibitory activity in an interferon-competent cell line which showed elevated expression of host antiviral genes when infected in the presence of FA-613. Further investigation of the specific connection between pyrimidine synthesis inhibition and the induction of host innate immunity might aid clinical development of this type of drug in antiviral therapies. Therefore, in acute cases of respiratory tract infections, when rapid diagnostics of the causative agent are not readily available, an antiviral drug with properties like FA-613 could prove to be very valuable.

  4. Antibody response following Hepatitis B vaccination in peritoneal dialysis patients: does normalized urea clearance matter?

    Directory of Open Access Journals (Sweden)

    Erkan Dervisoglu

    2011-01-01

    Full Text Available OBJECTIVES: Data on the factors that contribute to the antibody response to hepatitis B virus vaccination in peritoneal dialysis patients are scarce. The current study was conducted on a group of peritoneal dialysis patients to learn how the response to hepatitis B virus vaccination varies according to the patient's clearance of urea normalized to total body water (Kt/V. METHODS: A convenience sample of 33 peritoneal dialysis patients (13 women and 20 men, with a mean age of 49¡12 years was administered double doses (20 μg IM in each deltoid muscle of recombinant hepatitis B vaccine at 0, 1, 2, and 6 months. Response to immunization was measured at one to three months after the final dose of vaccine. The subjects were divided into groups according to the level of antibodies to hepatitis B surface antigen (anti-HBs, including non-responders ( 100 IU/L. RESULTS: Among non-responders, weak responders, and good responders, significant differences were found in age (54 ± 12 vs. 56 ± 9 vs. 45¡12 years, respectively; p = 0.049 and recombinant human erythropoietin use (20 vs. 29 vs. 76%, respectively; p = 0.016. No significant differences in weekly total Kt/V (p = 0.704, weekly peritoneal Kt/V (p = 0.064 and residual glomerular filtration rate (p = 0.355 were found across the three groups. CONCLUSIONS: Delivered clearance measured by weekly peritoneal Kt/V and total clearance measured by weekly total Kt/V did not predict the response to hepatitis B virus vaccination in patients on peritoneal dialysis.

  5. Covalent Linkage of HIV-1 Trimers to Synthetic Liposomes Elicits Improved B Cell and Antibody Responses.

    Science.gov (United States)

    Bale, Shridhar; Goebrecht, Geraldine; Stano, Armando; Wilson, Richard; Ota, Takayuki; Tran, Karen; Ingale, Jidnyasa; Zwick, Michael B; Wyatt, Richard T

    2017-08-15

    We have demonstrated that a liposomal array of well-ordered trimers enhances B cell activation, germinal center formation, and the elicitation of tier-2 autologous neutralizing antibodies. Previously, we coupled well-ordered cleavage-independent NFL trimers via their C-terminal polyhistidine tails to nickel lipids integrated into the lipid bilayer. Despite favorable in vivo effects, concern remained over the potentially longer-term in vivo instability of noncovalent linkage of the trimers to the liposomes. Accordingly, we tested both cobalt coupling and covalent linkage of the trimers to the liposomes by reengineering the polyhistidine tail to include a free cysteine on each protomer of model BG505 NFL trimers to allow covalent linkage. Both cobalt and cysteine coupling resulted in a high-density array of NFL trimers that was stable in both 20% mouse serum and 100 mM EDTA, whereas the nickel-conjugated trimers were not stable under these conditions. Binding analysis and calcium flux with anti-Env-specific B cells confirmed that the trimers maintained conformational integrity following coupling. Following immunization of mice, serologic analysis demonstrated that the covalently coupled trimers elicited Env-directed antibodies in a manner statistically significantly improved compared to soluble trimers and nickel-conjugated trimers. Importantly, the covalent coupling not only enhanced gp120-directed responses compared to soluble trimers, it also completely eliminated antibodies directed to the C-terminal His tag located at the "bottom" of the spike. In contrast, soluble and noncovalent formats efficiently elicited anti-His tag antibodies. These data indicate that covalent linkage of well-ordered trimers to liposomes in high-density array displays multiple advantages in vitro and in vivo IMPORTANCE Enveloped viruses typically encode a surface-bound glycoprotein that mediates viral entry into host cells and is a primary target for vaccine design. Liposomes with

  6. The Antibody-Secreting Cell Response to Infection: Kinetics and Clinical Applications

    Directory of Open Access Journals (Sweden)

    Michael J. Carter

    2017-06-01

    Full Text Available Despite the availability of advances in molecular diagnostic testing for infectious disease, there is still a need for tools that advance clinical care and public health. Current methods focus on pathogen detection with unprecedented precision, but often lack specificity. In contrast, the host immune response is highly specific for the infecting pathogen. Serological studies are rarely helpful in clinical settings, as they require acute and convalescent antibody testing. However, the B cell response is much more rapid and short-lived, making it an optimal target for determining disease aetiology in patients with infections. The performance of tests that aim to detect circulating antigen-specific antibody-secreting cells (ASCs has previously been unclear. Test performance is reliant on detecting the presence of ASCs in the peripheral blood. As such, the kinetics of the ASC response to infection, the antigen specificity of the ASC response, and the methods of ASC detection are all critical. In this review, we summarize previous studies that have used techniques to enumerate ASCs during infection. We describe the emergence, peak, and waning of these cells in peripheral blood during infection with a number of bacterial and viral pathogens, as well as malaria infection. We find that the timing of antigen-specific ASC appearance and disappearance is highly conserved across pathogens, with a peak response between day 7 and day 8 of illness and largely absent following day 14 since onset of symptoms. Data show a sensitivity of ~90% and specificity >80% for pathogen detection using ASC-based methods. Overall, the summarised work indicates that ASC-based methods may be very sensitive and highly specific for determining the etiology of infection and have some advantages over current methods. Important areas of research remain, including more accurate definition of the timing of the ASC response to infection, the biological mechanisms underlying variability

  7. A rapid immunization strategy with a live attenuated tetravalent dengue vaccine elicits protective neutralizing antibody responses in non-human primates

    Directory of Open Access Journals (Sweden)

    Yuping eAmbuel

    2014-06-01

    Full Text Available Dengue viruses (DENVs cause approximately 390 million cases of DENV infections annually and over 3 billion people worldwide are at risk of infection. No dengue vaccine is currently available nor is there an antiviral therapy for DENV infections. We have developed a tetravalent live-attenuated DENV vaccine (TDV that consists of a molecularly characterized attenuated DENV-2 strain (TDV-2 and three chimeric viruses containing the pre-membrane and envelope genes of DENV-1, -3 and -4 expressed in the context of the TDV-2 genome. To impact dengue vaccine delivery in endemic areas and immunize travelers, a simple and rapid immunization strategy (RIS is preferred. We investigated RIS consisting of two full vaccine doses being administered subcutaneously or intradermally on the initial vaccination visit (day 0 at two different anatomical locations with a needle-free disposable syringe jet injection (DSJI delivery devices (PharmaJet in non-human primates (NHP. This vaccination strategy resulted in efficient priming and induction of neutralizing antibody responses to all four DENV serotypes comparable to those elicited by the traditional prime and boost (two months later vaccination schedule. In addition, the vaccine induced CD4+ and CD8+ T cells producing IFN-γ, IL-2, and TNF-α, and targeting the DENV-2 NS1, NS3 and NS5 proteins. Moreover, vaccine-specific T cells were cross-reactive with the non-structural NS3 and NS5 proteins of DENV-4. When animals were challenged with DENV-2 they were protected with no detectable viremia, and exhibited sterilizing immunity (no increase of neutralizing titers post- challenge. RIS could decrease vaccination visits and provide quick immune response to all four DENV serotypes. This strategy could increase vaccination compliance and would be especially advantageous for travelers into endemic areas.

  8. Treatment with belimumab in systemic lupus erythematosus does not impair antibody response to 13-valent pneumococcal conjugate vaccine.

    Science.gov (United States)

    Nagel, J; Saxne, T; Geborek, P; Bengtsson, A A; Jacobsen, S; Svaerke Joergensen, C; Nilsson, J-Å; Skattum, L; Jönsen, A; Kapetanovic, M C

    2017-09-01

    Background/purpose The objective of this study was to explore the impact of systemic lupus erythematosus and belimumab given in addition to standard of care therapy on 13-valent conjugated pneumococcal vaccine (PCV13) response. Methods Forty-seven systemic lupus erythematosus patients and 21 healthy controls were immunized with a single dose of 13-valent conjugated pneumococcal vaccine. Forty systemic lupus erythematosus patients were treated with traditional disease-modifying anti rheumatic drugs, 11 of those received belimumab in addition, and 32 patients were treated with concomitant prednisolone. Quantification of serotype specific IgG levels to 12 pneumococcal capsular polysaccharides was performed in serum taken before and four to six weeks after vaccination using multiplex fluorescent microsphere immunoassay. IgG levels against serotypes 23F and 6B were also analyzed using standard enzyme-linked immunosorbent assays. Opsonophagocytic assay was performed on serotype 23F to evaluate the functionality of the antibodies. Pre- and post-vaccination log transformed antibody levels were compared to determine the impact of systemic lupus erythematosus diagnosis and different treatments on antibody response. Results Systemic lupus erythematosus patients as a group showed lower post-vaccination antibody levels and lower fold increase of antibody levels after vaccination compared to controls ( p = 0.02 and p = 0.009, respectively). Systemic lupus erythematosus patients treated with belimumab in addition to standard of care therapy or with only hydroxychloroquine did not differ compared to controls, whereas the other treatment groups had significantly lower fold increase of post-vaccination antibody levels. Higher age was associated with lower post-vaccination antibody levels among systemic lupus erythematosus patients. Conclusion Belimumab given in addition to traditional disease-modifying anti rheumatic drugs or prednisolone did not further impair antibody

  9. Antibody and T-cell responses associated with experimental human malaria infection or vaccination show limited relationships.

    Science.gov (United States)

    Walker, Karen M; Okitsu, Shinji; Porter, David W; Duncan, Christopher; Amacker, Mario; Pluschke, Gerd; Cavanagh, David R; Hill, Adrian V S; Todryk, Stephen M

    2015-05-01

    This study examined specific antibody and T-cell responses associated with experimental malaria infection or malaria vaccination, in malaria-naive human volunteers within phase I/IIa vaccine trials, with a view to investigating inter-relationships between these types of response. Malaria infection was via five bites of Plasmodium falciparum-infected mosquitoes, with individuals reaching patent infection by 11-12 days, having harboured four or five blood-stage cycles before drug clearance. Infection elicited a robust antibody response against merozoite surface protein-119 , correlating with parasite load. Classical class switching was seen from an early IgM to an IgG1-dominant response of increasing affinity. Malaria-specific T-cell responses were detected in the form of interferon-γ and interleukin-4 (IL-4) ELIspot, but their magnitude did not correlate with the magnitude of antibody or its avidity, or with parasite load. Different individuals who were immunized with a virosome vaccine comprising influenza antigens combined with P. falciparum antigens, demonstrated pre-existing interferon-γ, IL-2 and IL-5 ELIspot responses against the influenza antigens, and showed boosting of anti-influenza T-cell responses only for IL-5. The large IgG1-dominated anti-parasite responses showed limited correlation with T-cell responses for magnitude or avidity, both parameters being only negatively correlated for IL-5 secretion versus anti-apical membrane antigen-1 antibody titres. Overall, these findings suggest that cognate T-cell responses across a range of magnitudes contribute towards driving potentially effective antibody responses in infection-induced and vaccine-induced immunity against malaria, and their existence during immunization is beneficial, but magnitudes are mostly not inter-related. © 2014 John Wiley & Sons Ltd.

  10. HIV-1 superinfection in women broadens and strengthens the neutralizing antibody response.

    Directory of Open Access Journals (Sweden)

    Valerie Cortez

    Full Text Available Identifying naturally-occurring neutralizing antibodies (NAb that are cross-reactive against all global subtypes of HIV-1 is an important step toward the development of a vaccine. Establishing the host and viral determinants for eliciting such broadly NAbs is also critical for immunogen design. NAb breadth has previously been shown to be positively associated with viral diversity. Therefore, we hypothesized that superinfected individuals develop a broad NAb response as a result of increased antigenic stimulation by two distinct viruses. To test this hypothesis, plasma samples from 12 superinfected women each assigned to three singly infected women were tested against a panel of eight viruses representing four different HIV-1 subtypes at matched time points post-superinfection (~5 years post-initial infection. Here we show superinfected individuals develop significantly broader NAb responses post-superinfection when compared to singly infected individuals (RR = 1.68, CI: 1.23-2.30, p = 0.001. This was true even after controlling for NAb breadth developed prior to superinfection, contemporaneous CD4+ T cell count and viral load. Similarly, both unadjusted and adjusted analyses showed significantly greater potency in superinfected cases compared to controls. Notably, two superinfected individuals were able to neutralize variants from four different subtypes at plasma dilutions >1∶300, suggesting that their NAbs exhibit elite activity. Cross-subtype breadth was detected within a year of superinfection in both of these individuals, which was within 1.5 years of their initial infection. These data suggest that sequential infections lead to augmentation of the NAb response, a process that may provide insight into potential mechanisms that contribute to the development of antibody breadth. Therefore, a successful vaccination strategy that mimics superinfection may lead to the development of broad NAbs in immunized individuals.

  11. Antibody response to rabies vaccination in captive and freeranging wolves (Canis lupus)

    Science.gov (United States)

    Federoff, N.E.

    2001-01-01

    Fourteen captive and five free-ranging Minnesota gray wolves (Canis lupus) were tested for the presence of rabies virus neutralizing antibodies (RVNA) after vaccination with an inactivated canine rabies vaccine. Blood was collected from all wolves prior to vaccination and at 1 mo postvaccination (PV) and from all captive and three wild wolves at 3 mo PV. In addition, one free-ranging wolf was sampled at 4 mo PV, and two free-ranging wolves were sampled at 6 mo PV. All wolves were seronegative prior to vaccination. RVNA were detected in 14 (100%) captive wolves and in four of five (80%) free-ranging wolves. The geometric mean titer of the captive wolves at 1 mo PV was significantly higher (P = 0.023) than in the free-ranging wolves. Five of 13 (38.5%) captive wolves and none of the three (0%) free-ranging wolves had measurable RVNA at 3 mo PV. No measurable RVNA were detected in the serum samples collected from the free-ranging wolves at 4 and 6 mo PV. These results should be interpreted with caution because of the small number of free-ranging wolves tested. Further research is needed to properly assess immune function and antibody response to vaccination in captive wolves in comparison with their free-ranging counterparts.

  12. Neutralising antibody response in domestic cats immunised with a commercial feline immunodeficiency virus (FIV) vaccine.

    Science.gov (United States)

    Bęczkowski, Paweł M; Harris, Matthew; Techakriengkrai, Navapon; Beatty, Julia A; Willett, Brian J; Hosie, Margaret J

    2015-02-18

    Across human and veterinary medicine, vaccines against only two retroviral infections have been brought to market successfully, the vaccines against feline leukaemia virus (FeLV) and feline immunodeficiency virus (FIV). FeLV vaccines have been a global success story, reducing virus prevalence in countries where uptake is high. In contrast, the more recent FIV vaccine was introduced in 2002 and the degree of protection afforded in the field remains to be established. However, given the similarities between FIV and HIV, field studies of FIV vaccine efficacy are likely to advise and inform the development of future approaches to HIV vaccination. Here we assessed the neutralising antibody response induced by FIV vaccination against a panel of FIV isolates, by testing blood samples collected from client-owned vaccinated Australian cats. We examined the molecular and phenotypic properties of 24 envs isolated from one vaccinated cat that we speculated might have become infected following natural exposure to FIV. Cats vaccinated against FIV did not display broadly neutralising antibodies, suggesting that protection may not extend to some virulent recombinant strains of FIV circulating in Australia. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  13. Comparison of specificities of serum antibody responses of horses to clinical infections caused by Streptococcus equi or zooepidemicus.

    Science.gov (United States)

    Velineni, Sridhar; DeNegri, Rafaela; Artiushin, Sergey C; Timoney, John F

    2015-11-18

    Streptococcus zooepidemicus (Sz) and its clonal derivative Streptococcus equi (Se) share greater than 96% DNA identity and elicit immune responses to many shared proteins. Identification of proteins uniquely targeted by the immune response to each infection would have diagnostic value. The aim of the study was to compare serum antibody responses of horses infected by Se or Sz. Antibody levels were measured to panels of recombinant proteins of Sz and Se in sera of horses and ponies before and after experimental and naturally occurring invasive infections by these organisms. Antibody responses to an Se extract vaccine were also measured. Sera diluted 1:200 were assayed in triplicate using optimum concentrations of 9 and 14 immunoreactive proteins of Se and Sz, respectively. Bound IgG was detected using HRP-Protein G conjugate. Antibodies specific for SeM-N2, IdeE2, Se42.0 and Se75.3 (SEQ2190) were elicited by Se but not by Sz infection. Commercial Se extract vaccine did not elicit responses to IdeE2 or Se75.3. Sz infections resulted in significant (p<0.01) responses to Sz115, SzM, ScpC, SzP, MAP and streptokinase an indication these proteins are expressed during opportunistic invasions of the respiratory tract. FSR and HylC specific responses were unique to infections by Sz. The data indicate antibodies to IdeE2, Se75.3 and SeM-N2 may be used to distinguish infection by Se from that caused by the closely related Sz. Se infection, but not vaccination with Se extract elicits antibody to IdeE2 and Se75.3. Copyright © 2015. Published by Elsevier B.V.

  14. Stringently Defined Otitis Prone Children Demonstrate Deficient Naturally Induced Mucosal Antibody Response to Moraxella catarrhalis Proteins

    Directory of Open Access Journals (Sweden)

    Dabin Ren

    2017-08-01

    Full Text Available Moraxella catarrhalis (Mcat is a prominent mucosal pathogen causing acute otitis media (AOM. We studied Mcat nasopharyngeal (NP colonization, AOM frequency and mucosal antibody responses to four vaccine candidate Mcat proteins: outer membrane protein (OMP CD, oligopeptide permease (Opp A, hemagglutinin (Hag, and Pilin A clade 2 (PilA2 from stringently defined otitis prone (sOP children, who experience the greatest burden of disease, compared to non-otitis prone (NOP children. sOP children had higher NP colonization of Mcat (30 vs. 22%, P = 0.0003 and Mcat-caused AOM rates (49 vs. 24%, P < 0.0001 than NOP children. Natural acquisition of mucosal antibodies to Mcat proteins OMP CD (IgG, P < 0.0001, OppA (IgG, P = 0.018, Hag (IgG and IgA, both P < 0.0001, and PilA2 (IgA, P < 0.0001 was lower in sOP than NOP children. Higher levels of mucosal IgG to Hag (P = 0.039 and PilA2 (P = 0.0076, and IgA to OMP CD (P = 0.010, OppA (P = 0.030, and PilA2 (P = 0.043 were associated with lower carriage of Mcat in NOP but not sOP children. Higher levels of mucosal IgG to OMP CD (P = 0.0070 and Hag (P = 0.0003, and IgA to Hag (P = 0.0067 at asymptomatic colonization than those at onset of AOM were associated with significantly lower rate of Mcat NP colonization progressing to AOM in NOP compared to sOP children (3 vs. 26%, P < 0.0001. In conclusion, sOP children had a diminished mucosal antibody response to Mcat proteins, which was associated with higher frequencies of asymptomatic NP colonization and NP colonization progressing to Mcat-caused AOM. Enhancing Mcat antigen-specific mucosal immune responses to levels higher than achieved by natural exposure will be necessary to prevent AOM in sOP children.

  15. Naturally acquired antibody responses to recombinant Pfs230 and Pfs48/45 transmission blocking vaccine candidates

    DEFF Research Database (Denmark)

    Jones, Sophie; Grignard, Lynn; Nebie, Issa

    2015-01-01

    for the future evaluation of vaccine immunogenicity and efficacy in populations naturally exposed to malaria. METHODS: We determined naturally acquired antibody responses to the recombinant proteins Pfs48/45-10C and Pfs230-230CMB in children from three malaria endemic settings in Ghana, Tanzania and Burkina Faso......OBJECTIVES: Pfs48/45 and Pfs230 are Plasmodium falciparum sexual stage proteins and promising malaria transmission-blocking vaccine candidates. Antibody responses against these proteins may be naturally acquired and target antigens may be under selective pressure. This has consequences....... CONCLUSIONS: We conclude there are naturally acquired antibody responses to both vaccine candidates which have functional relevance by reducing the transmissibility of infected individuals. We identified genetic polymorphisms, in pfs48/45 which exhibited geographical specificity....

  16. Dissecting the hemagglutinin head and stalk-specific IgG antibody response in healthcare workers following pandemic H1N1 vaccination.

    Science.gov (United States)

    Tete, Sarah M; Krammer, Florian; Lartey, Sarah; Bredholt, Geir; Wood, John; Skrede, Steinar; Cox, Rebecca J

    2016-01-01

    Traditionally, neutralising antibodies that are directed to the major surface glycoprotein hemagglutinin (HA) head domain are measured as surrogate correlates of protection against influenza. In addition to neutralization, hemagglutinin-specific antibodies may provide protection by mediating antibody-dependent cellular cytotoxicity (ADCC). During the 2009 pandemic, vaccination induced HA-specific antibodies that were mostly directed to the conserved HA stalk domain. However, the protective role of these antibodies has not been investigated in detail. We quantified the HA head and stalk-specific antibodies, their avidity, ability to neutralise virus and activate natural killer cells in an ADCC assay. We analyzed sera obtained from 14 healthcare workers who had low hemagglutination inhibition (HI) antibody titres at 3 months after pandemic H1N1 vaccination as well as from 22 controls. Vaccination resulted in a HA stalk dominant antibody response in both low responders and controls. Revaccination of low responders, 5 months later, resulted in a boost in antibodies, with HA head-specific antibodies dominating the response. Comparative analysis of head and stalk antibody avidities revealed that stalk-specific antibodies were qualitatively superior. Furthermore, stalk-specific antibodies mediated virus neutralization and had significantly higher ADCC activity than head-specific antibodies. Despite the head and stalk-specific antibodies being lower in low responders, they had comparable antibody avidity, ADCC functionality and neutralising capacity to those of controls who had high HI titres post-vaccination. Thus, our study has demonstrated that HA stalk-specific antibodies may have an important role in protection through neutralization and ADCC in low responders who do not maintain seroprotective HI antibodies.

  17. Intratracheally administered pathogen-associated molecular patterns affect antibody responses of poultry.

    Science.gov (United States)

    Ploegaert, T C W; De Vries Reilingh, G; Nieuwland, M G B; Lammers, A; Savelkoul, H F J; Parmentier, H K

    2007-08-01

    Various potential immune-modulating microbially derived pathogen-associated molecular patterns (PAMP), or so called homotopes, are present in high concentrations in the environment of food animals. In previous studies, intravenously administered PAMP had variable effects on specific primary and secondary immune responses of poultry to systemically administered antigens. In the present study, we evaluated the effects of intratracheal (i.t.) challenge with the PAMP lipopolysaccharide, lipoteichoic acid (LTA), and Zymosan-A (containing 1,3 beta-glucan) on primary and secondary (total) antibody (Ab) responses and (isotype) IgM, IgG, and IgA responses to systemically administered human serum albumin (HuSA), and Ab titers to infectious bursal disease (Gumboro virus) and infectious bronchitis vaccines in layer hens at 9 and 22 wk of age. Birds were challenged via the trachea with PAMP for 5 consecutive days prior to primary and secondary immunization with HuSA. Intratracheally administered LTA and, to a minor extent, lipopolysaccharide significantly enhanced secondary total and IgG Ab responses to HuSA. 1,3 beta-Glucan did not significantly affect Ab responses to HuSA. All birds challenged with PAMP showed a decreased BW. Higher total Ab titers to infectious bursal disease and infectious bronchitis were found in birds challenged with LTA. The present results indicate that i.t. administered PAMP affect the humoral immune responsiveness of poultry, which may lead to an enhanced status of immune reactivity. Furthermore, our results suggest that the hygienic status of the environment influences BW (gain). The consequences of immune modulation by airborne PAMP or hygienic conditions in chicken husbandry for vaccine delivery and immune responsiveness of poultry are discussed.

  18. The Complexity of a Dengue Vaccine : A Review of the Human Antibody Response

    NARCIS (Netherlands)

    Flipse, Jacky; Smit, Jolanda M.

    Dengue is the most prevalent mosquito-borne viral disease worldwide. Yet, there are no vaccines or specific antivirals available to prevent or treat the disease. Several dengue vaccines are currently in clinical or preclinical stages. The most advanced vaccine is the chimeric tetravalent CYD-TDV

  19. Kinetic and HPV infection effects on cross-type neutralizing antibody and avidity responses induced by Cervarix®

    Science.gov (United States)

    Kemp, Troy J.; Safaeian, Mahboobeh; Hildesheim, Allan; Pan, Yuanji; Penrose, Kerri J.; Porras, Carolina; Schiller, John T.; Lowy, Douglas R.; Herrero, Rolando; Pinto, Ligia A.

    2012-01-01

    Background We previously demonstrated that Cervarix® elicits antibody responses against vaccine-related types for which clinical efficacy was demonstrated (HPV-31 and -45). Here, we evaluated the kinetics of neutralization titers and avidity of Cervarix®-induced antibodies up to 36 months of follow-up in unexposed and HPV infected women. Methods A subset of women who participated in the Cost Rica HPV-16/18 Vaccine Trial had pre- and post-vaccination sera tested for antibody responses to HPV-16, -18, -31, -45, and -58 using a pseudovirion-based neutralization assay, and HPV-16 antibody avidity using an HPV-16 L1 VLP (virus-like particle)-based ELISA developed in our laboratory. Results In uninfected women, neutralizing antibody titers did not reach significance until after the 3rd dose for HPV-31 (month 12, p=0.009) and HPV-45 (month 12, p=0.003), but then persisted up to month 36 (HPV-31, p=0.01; HPV-45, p=0.002). Individuals infected with HPV-16 or HPV-31 at enrollment developed a significantly higher median antibody response to the corresponding HPV type after one dose, but there was not a difference between median titers after three doses compared to the HPV negative group. Median HPV-16 antibody avidity and titer increased over time up to month 12; however, the HPV-16 avidity did not correlate well with HPV-16 neutralizing antibody titers at each time point examined, except for month 6. The median avidity levels were higher in HPV-16 infected women at month 1 (p=0.04) and lower in HPV-16 infected women at month 12 (p=0.006) compared to the HPV negative women. Conclusions The persistence of cross-neutralization titers at month 36 suggests cross-reactive antibody responses are likely to persist long-term and are not influenced by infection status at enrollment. However, the weak correlation between avidity and neutralization titers emphasizes the need for examining avidity in efficacy studies to determine if high avidity antibodies play a critical role in

  20. Theobromine Is Responsible for the Effects of Cocoa on the Antibody Immune Status of Rats.

    Science.gov (United States)

    Camps-Bossacoma, Mariona; Pérez-Cano, Francisco J; Franch, Àngels; Castell, Margarida

    2018-03-01

    A 10% cocoa-enriched diet influences immune system functionality including the prevention of the antibody response and the induction of lower immunoglobulin (Ig) concentrations. However, neither cocoa polyphenols nor cocoa fiber can totally explain these immunoregulatory properties. This study aimed to establish the influence of cocoa theobromine in systemic and intestinal Ig concentrations and to determine the effect of cocoa or theobromine feeding on lymphoid tissue lymphocyte composition. Three-week-old female Lewis rats were fed either a standard diet (AIN-93M; RF group), a 10% cocoa diet (CC group), or a 0.25% theobromine diet (the same amount provided by the cocoa diet; TB group) in 2 separate experiments that lasted 19 (experiment 1) or 8 (experiment 2) d. Serum IgG, IgM, IgA, and intestinal secretory IgA (sIgA) concentrations were determined. In addition, at the end of experiment 2, thymus, mesenteric lymph node (MLN), and spleen lymphocyte populations were analyzed. Both CC and TB groups in experiments 1 and 2 showed similar serum IgG, IgM, and IgA and intestinal sIgA concentrations, which were lower than those in the RF group (46-98% lower in experiment 1 and 23-91% lower in experiment 2; P theobromine diets similarly changed the thymocyte composition by increasing CD4-CD8- (+133%) and CD4+CD8- (+53%) proportions (P theobromine in cocoa plays an immunoregulatory role that is responsible for cocoa's influence on both systemic and intestinal antibody concentrations and also for modifying lymphoid tissue lymphocyte composition in young healthy Lewis rats. The majority of these changes are observed after a single week of being fed a diet containing 0.25% theobromine.

  1. Smallpox Antiviral Drug

    Science.gov (United States)

    2007-01-01

    phogenic proteolysis is crucial for simple RNA viruses such as poliovirus and HIV, and also appears to play a central role in the assembly of more...al particles [14]; unidirectional packaging of bacteriophage T4 DNA [15]; completion of the infectious poliovirus virion in a flexible configuration...effects of an antiviral both in vitro and in vivo. Some viruses have not been adapted to grow in tissue culture cells or due to their genetic makeup are

  2. Impact of child malnutrition on the specific anti-Plasmodium falciparum antibody response

    Directory of Open Access Journals (Sweden)

    Fillol Florie

    2009-06-01

    Full Text Available Abstract Background In sub-Saharan Africa, preschool children represent the population most vulnerable to malaria and malnutrition. It is widely recognized that malnutrition compromises the immune function, resulting in higher risk of infection. However, very few studies have investigated the relationship between malaria, malnutrition and specific immunity. In the present study, the anti-Plasmodium falciparum IgG antibody (Ab response was evaluated in children according to the type of malnutrition. Methods Anthropometric assessment and blood sample collection were carried out during a cross-sectional survey including rural Senegalese preschool children. This cross-sectional survey was conducted in July 2003 at the onset of the rainy season. Malnutrition was defined as stunting (height-for-age P. falciparum whole extracts (schizont antigens was assessed by ELISA in sera of the included children. Results Both the prevalence of anti-malarial immune responders and specific IgG Ab levels were significantly lower in malnourished children than in controls. Depending on the type of malnutrition, wasted children and stunted children presented a lower specific IgG Ab response than their respective controls, but this difference was significant only in stunted children (P = 0.026. This down-regulation of the specific Ab response seemed to be explained by severely stunted children (HAZ ≤ -2.5 compared to their controls (P = 0.03, while no significant difference was observed in mildly stunted children (-2.5 P. falciparum Ab response appeared to be independent of the intensity of infection. Conclusion Child malnutrition, and particularly stunting, may down-regulate the anti-P. falciparum Ab response, both in terms of prevalence of immune responders and specific IgG Ab levels. This study provides further evidence for the influence of malnutrition on the specific anti-malarial immune response and points to the importance of taking into account child

  3. Bacille Calmette-Guérin (BCG) vaccination at birth and antibody responses to childhood vaccines. A randomised clinical trial.

    Science.gov (United States)

    Nissen, Thomas Nørrelykke; Birk, Nina Marie; Smits, Gaby; Jeppesen, Dorthe Lisbeth; Stensballe, Lone Graff; Netea, Mihai G; van der Klis, Fiona; Benn, Christine Stabell; Pryds, Ole

    2017-04-11

    BCG vaccination has been associated with beneficial non-specific effects on child health. Some immunological studies have reported heterologous effects of vaccines on antibody responses to heterologous vaccines. Within a randomised clinical trial of Bacille Calmette-Guérin (BCG) vaccination at birth, The Danish Calmette Study, we investigated the effect of BCG at birth on the antibody response to the three routine vaccines against DiTeKiPol/Act-Hib and Prevenar 13 in a subgroup of participants. Within 7days after birth, children were randomised 1:1 to BCG vaccination or to the control group (no intervention). After three routine vaccinations given at age 3, 5 and 12months, antibodies against DiTeKiPol/Act-Hib and Prevenar 13 (Streptococcus pneumoniae serotype type 4, 6B, 9V, 14, 18C, 19F and 23F) were measured 4weeks after the third vaccine dose. Among the 300 included children (178 BCG; 122 controls), almost all children (>96%) had antibody responses above the protective levels. Overall BCG vaccination at birth did not affect the antibody level. When stratifying by 'age at randomisation' we found a possible inducing effect of BCG on antibodies against B. pertussis and all pneumococcal serotypes, when BCG was given after the first day of life. Girls had significantly higher antibody levels for Haemophilus influenza type b and pneumococcus than boys. Three routine vaccinations with DiTeKiPol/Act-Hib and Prevenar 13 induced sero-protective levels in almost all children. No overall effect of neonatal BCG vaccination was observed. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  4. Formulation of a killed whole cell pneumococcus vaccine - effect of aluminum adjuvants on the antibody and IL-17 response.

    Science.gov (United States)

    Hogenesch, Harm; Dunham, Anisa; Hansen, Bethany; Anderson, Kathleen; Maisonneuve, Jean-Francois; Hem, Stanley L

    2011-07-29

    Streptococcus pneumoniae causes widespread morbidity and mortality. Current vaccines contain free polysaccharides or protein-polysaccharide conjugates, and do not induce protection against serotypes that are not included in the vaccines. An affordable and broadly protective vaccine is very desirable. The goal of this study was to determine the optimal formulation of a killed whole cell pneumococcal vaccine with aluminum-containing adjuvants for intramuscular injection. Four aluminium-containing adjuvants were prepared with different levels of surface phosphate groups resulting in different adsorptive capacities and affinities for the vaccine antigens. Mice were immunized three times and the antigen-specific antibody titers and IL-17 responses in blood were analyzed. Although all adjuvants induced significantly higher antibody titers than antigen without adjuvant, the vaccine containing aluminum phosphate adjuvant (AP) produced the highest antibody response when low doses of antigen were used. Aluminum hydroxide adjuvant (AH) induced an equal or better antibody response at high doses compared with AP. Vaccines formulated with AH, but not with AP, induced an IL-17 response. The vaccine formulated with AH was stable and retained full immunogenicity when stored at 4°C for 4 months. Antibodies are important for protection against systemic streptococcal disease and IL-17 is critical in the prevention of nasopharyngeal colonization by S. pneumoniae in the mouse model. The formulation of the whole killed bacterial cells with AH resulted in a stable vaccine that induced both antibodies and an IL-17 response. These experiments underscore the importance of formulation studies with aluminium containing adjuvants for the development of stable and effective vaccines.

  5. HIV-1 Env- and Vpu-Specific Antibody-Dependent Cellular Cytotoxicity Responses Associated with Elite Control of HIV.

    Science.gov (United States)

    Madhavi, Vijaya; Wines, Bruce D; Amin, Janaki; Emery, Sean; Lopez, Ester; Kelleher, Anthony; Center, Rob J; Hogarth, P Mark; Chung, Amy W; Kent, Stephen J; Stratov, Ivan

    2017-09-15

    Studying HIV-infected individuals who control HIV replication (elite controllers [ECs]) enables exploration of effective anti-HIV immunity. HIV Env-specific and non-Env-specific antibody-dependent cellular cytotoxicity (ADCC) may contribute to protection from progressive HIV infection, but the evidence is limited. We recruited 22 ECs and matched them with 44 viremic subjects. HIV Env- and Vpu-specific ADCC responses in sera were studied using a novel enzyme-linked immunosorbent assay (ELISA)-based dimeric recombinant soluble FcγRIIIa (rsFcγRIIIa)-binding assay, surface plasmon resonance, antibody-dependent natural killer (NK) cell activation assays, and ADCC-mediated killing assays. ECs had higher levels of HIV Env-specific antibodies capable of binding FcγRIIIa, activating NK cells, and mediating granzyme B activity (all P Env-specific and Vpu epitope-specific ADCC in effective immune responses against HIV among ECs. Our findings have implications for understanding the role of ADCC in HIV control. IMPORTANCE Understanding immune responses associated with elite control of HIV may aid the development of immunotherapeutic and vaccine strategies for controlling HIV infection. Env is a major HIV protein target of functional antibody responses that are heightened in ECs. Interestingly, EC antibodies also target Vpu, an accessory protein crucial to HIV, which degrades CD4 and antagonizes tetherin. Antibodies specific to Vpu are a common feature of the immune response of ECs that may prove to be of functional importance to the design of improved ADCC-based immunotherapy and preventative HIV vaccines. Copyright © 2017 American Society for Microbiology.

  6. The influence of age and maternal antibodies on the postvaccinal response against swine influenza viruses in pigs.

    Science.gov (United States)

    Markowska-Daniel, Iwona; Pomorska-Mól, Małgorzata; Pejsak, Zygmunt

    2011-07-15

    The influence of age and maternal immunity on the development and duration of postvaccinal humoral response against swine influenza viruses (SIV) were investigated under experimental conditions. Piglets born to immune and non-immune sows were vaccinated twice with bivalent inactivated vaccine. Vaccination was done according to 5 different schedules: 1+4, 1+8, 4+8, 8+10 or 8+12 weeks of age. Antibodies to the haemagglutinin type 1 and 3 were determined using the haemagglutination inhibition (HI) test. Maternally derived antibodies (MDA) against H1N1 and H3N2 in the serum of unvaccinated piglets born to immune sows were above the positive level until about 13-14 and 9-10 weeks of life, respectively. No serological responses were seen in any of the groups after the first vaccination. After the second dose of vaccine production of antibodies was observed even before the complete disappearance of maternal antibodies. MDA, however, were associated with reduced antibody response. In MDA-negative piglets, an active humoral postvaccinal response was developed in all vaccinated pigs. The age at which the vaccine was given was associated with the differences in the magnitude of antibody response to SIV. In general those pigs that were vaccinated for the first time at the age of 1 week, developed lower maximum titres after the second vaccination, and become seronegative earlier than pigs that were vaccinated for the first time at 4 or 8 weeks of age. Copyright © 2011 Elsevier B.V. All rights reserved.

  7. What is the impact of a country-wide scale-up in antiviral therapy on the characteristics and sustained viral response rates of patients treated for hepatitis C?

    Science.gov (United States)

    McDonald, Scott A; Innes, Hamish A; Hayes, Peter C; Dillon, John F; Mills, Peter R; Goldberg, David J; Barclay, Stephen; Allen, Sam; Fox, Ray; Fraser, Andrew; Kennedy, Nicholas; Bhattacharyya, Diptendu; Hutchinson, Sharon J

    2015-02-01

    The global burden associated with hepatitis C virus (HCV) infection has prompted a scale-up of antiviral therapy. Hitherto, no data exist on the impact of scaling-up, on the characteristics of treated populations, or on sustained viral response (SVR) rates. We assessed the country-wide scale-up of antiviral therapy in Scotland, a country which nationally monitors uptake of and response to HCV treatment. Data for patients, initiated on combined pegylated interferon and ribavirin therapy at 13 specialist HCV clinics in 2001-2010, were extracted from the Scottish HCV Clinical Database (n=3895). Patient characteristics included age, genotype, PWID (people who inject drugs) status, prison referral, and diagnosed cirrhosis. Temporal trends in covariates and adjusted effects on a SVR were examined via mixed-effects regression. The number of patients starting treatment increased from 237 in 2001-2002 to 1560 in 2009-2010, with an increasing trend in SVR from 44% to 57% over this period. For a given clinic, between 2001/2 and 2010 there was a decrease in the odds of those treated being diagnosed with cirrhosis (odds ratio [OR]=0.84 per year), and increasing temporal trends for those treated being PWID (OR=1.08) and prison referrals (OR=1.06). Adjusting for covariates, the proportion of a given clinic's patients achieving SVR was positively associated with the percentage of PWID (OR=1.01 per percent increase; 95% confidence interval [CI]: 1.00-1.02) and genotype 2/3 (OR=1.03; 95% CI: 1.02-1.04). Despite changes in patient characteristics, a country-wide scale-up of antiviral therapy did not compromise SVR rates. Results are highly relevant to countries planning on scaling-up treatment, given the forthcoming availability of new interferon-free therapies. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  8. Effects of sublethal gamma radiation on T and B cell activity in the antibody response of mice

    International Nuclear Information System (INIS)

    Carlson, D.E.; Lubet, R.A.

    1976-01-01

    The relative radiosensitivity of T and B cells was followed in sublethally irradiated mice reconstituted with bone marrow cells, thymus cells, or both, and simultaneously challenged with sheep erythrocytes. Numbers of antibody-forming cells in recipient spleens were determined on days 4 to 8. In this assay the response of mice given bone marrow cells was limited by the amount of residual T cell activity, while the response of mice given thymus cells was limited by the residual B cell activity. Although residual activity of both T and B cells was suppressed in mice given 300 to 700 rad at 80 rad/min, residual B cell activity was consistently lower in these animals. When antibody responses were initiated at intervals after irradiation, B cell activity was clearly limiting by 48 hr after 500 or 600 rad. The activity of both T and B cells was sensitive to differences in dose rate between 8 and 80 rad/min. The 4 to 7 fold dose-rate sensitivity of T cells paralleled that of differentially irradiated nonreconstituted mice. In contrast, dose-rate dependence of B cell activity varied from 10- to 20-fold between 8 and 80 rad/min. These results suggest that radiation suppression of antibody responses in mice is highly dependent upon B cell sensitivity, and that dose-rate dependence of the antibody response may be explained in large part by differential sensitivity of B cells

  9. Multi-epitope Models Explain How Pre-existing Antibodies Affect the Generation of Broadly Protective Responses to Influenza.

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    Veronika I Zarnitsyna

    2016-06-01

    Full Text Available The development of next-generation influenza vaccines that elicit strain-transcendent immunity against both seasonal and pandemic viruses is a key public health goal. Targeting the evolutionarily conserved epitopes on the stem of influenza's major surface molecule, hemagglutinin, is an appealing prospect, and novel vaccine formulations show promising results in animal model systems. However, studies in humans indicate that natural infection and vaccination result in limited boosting of antibodies to the stem of HA, and the level of stem-specific antibody elicited is insufficient to provide broad strain-transcendent immunity. Here, we use mathematical models of the humoral immune response to explore how pre-existing immunity affects the ability of vaccines to boost antibodies to the head and stem of HA in humans, and, in particular, how it leads to the apparent lack of boosting of broadly cross-reactive antibodies to the stem epitopes. We consider hypotheses where binding of antibody to an epitope: (i results in more rapid clearance of the antigen; (ii leads to the formation of antigen-antibody complexes which inhibit B cell activation through Fcγ receptor-mediated mechanism; and (iii masks the epitope and prevents the stimulation and proliferation of specific B cells. We find that only epitope masking but not the former two mechanisms to be key in recapitulating patterns in data. We discuss the ramifications of our findings for the development of vaccines against both seasonal and pandemic influenza.

  10. Murine CR1/2 targeted antigenized single-chain antibody fragments induce transient low affinity antibodies and negatively influence an ongoing immune response.

    Science.gov (United States)

    Prechl, József; Molnár, Eszter; Szekeres, Zsuzsanna; Isaák, Andrea; Papp, Krisztián; Balogh, Péter; Erdei, Anna

    2007-01-01

    We have generated a single-chain antibody which recognizes murine CR1/2 and carries a genetically fused influenza hemagglutinin derived peptide. Theoretically such a construct is able to crosslink the B cell antigen receptor and CR1/2 on peptide specific B cells. The construct was able to reach its CR1/2 positive target cells, yet intraperitoneal delivery of the construct elicited an IgM response only slightly exceeding that induced by the free peptide. Providing T cell help by the injection of peptide specific lymphocytes did not alter the response in essence, that is anti-peptide IgG was not detectable even after booster immunizations. When used as a booster vaccine following injection of the peptide in adjuvant, the construct even inhibited the development of IgG1 and IgG3 anti-peptide antibodies. These data indicate that although targeting of antigen to CR1/2 on B cells can enhance transient proliferation or differentiation of antigen specific B cells it cannot induce strong, longlasting humoral immune responses. Furthermore, CR1/2 targeting constructs may negatively influence an ongoing immune reaction.

  11. Mannosylated mucin-type immunoglobulin fusion proteins enhance antigen-specific antibody and T lymphocyte responses.

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    Gustaf Ahlén

    Full Text Available Targeting antigens to antigen-presenting cells (APC improve their immunogenicity and capacity to induce Th1 responses and cytotoxic T lymphocytes (CTL. We have generated a mucin-type immunoglobulin fusion protein (PSGL-1/mIgG(2b, which upon expression in the yeast Pichia pastoris became multivalently substituted with O-linked oligomannose structures and bound the macrophage mannose receptor (MMR and dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN with high affinity in vitro. Here, its effects on the humoral and cellular anti-ovalbumin (OVA responses in C57BL/6 mice are presented.OVA antibody class and subclass responses were determined by ELISA, the generation of anti-OVA CTLs was assessed in (51Cr release assays using in vitro-stimulated immune spleen cells from the different groups of mice as effector cells and OVA peptide-fed RMA-S cells as targets, and evaluation of the type of Th cell response was done by IFN-γ, IL-2, IL-4 and IL-5 ELISpot assays.Immunizations with the OVA - mannosylated PSGL-1/mIgG(2b conjugate, especially when combined with the AbISCO®-100 adjuvant, lead to faster, stronger and broader (with regard to IgG subclass OVA IgG responses, a stronger OVA-specific CTL response and stronger Th1 and Th2 responses than if OVA was used alone or together with AbISCO®-100. Also non-covalent mixing of mannosylated PSGL-1/mIgG(2b, OVA and AbISCO®-100 lead to relatively stronger humoral and cellular responses. The O-glycan oligomannoses were necessary because PSGL-1/mIgG(2b with mono- and disialyl core 1 structures did not have this effect.Mannosylated mucin-type fusion proteins can be used as versatile APC-targeting molecules for vaccines and as such enhance both humoral and cellular immune responses.

  12. Insights into antiviral innate immunity revealed by studying hepatitis C virus.

    Science.gov (United States)

    Horner, Stacy M

    2015-08-01

    Experimental studies on the interactions of the positive strand RNA virus hepatitis C virus (HCV) with the host have contributed to several discoveries in the field of antiviral innate immunity. These include revealing the antiviral sensing pathways that lead to the induction of type I interferon (IFN) during HCV infection and also the importance of type III IFNs in the antiviral immune response to HCV. These studies on HCV/host interactions have contributed to our overall understanding of viral sensing and viral evasion of the antiviral intracellular innate immune response. In this review, I will highlight how these studies of HCV/host interactions have led to new insights into antiviral innate immunity. Overall, I hope to emphasize that studying antiviral immunity in the context of virus infection is necessary to fully understand antiviral immunity and how it controls the outcome of viral infection. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Study on Anti-Hepatitis B Surface Antibody Titer and Specific Interferon Gamma Response Among Dentists

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    Manoochehr Makvandi

    2017-01-01

    Full Text Available Background Hepatitis B virus (HBV is a major problem for healthcare workers worldwide, and among them, dentists are at risk of acquiring HBV infection. The prevalence of HBV infection has been reported among the dentists in different regions of the world. Since none of the available drugs can clear HBV infection, the presence of effective immunity against HBV infection is important to prevent HBV infection. Objectives This study aimed at determining HBs antibody and specific HBV gamma interferon among the dentists, who received hepatitis B vaccine. Methods The blood samples were collected from 40 dentists, including 7 endodontics, 2 oral and maxillofacial radiologist, 4 periodontics, 11 oral and maxillofacial surgeons, 6 implantologists, 3 orthodontics, 1 oral and maxillofacial pathologist, 2 esthetic and restorative dentists, and 4 doctors of dental surgery (DDS at from dental college of Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran during December, 2013. Overall, 31 (77.5% dentists had already received 3 doses of recombinant hepatitis B vaccine, and 9 (22.5% had received only two doses of the vaccine. Their sera were tested for HBsAb and anti-HBc-IgG by the Enzyme Linked Immunosorbent Assay (ELISA test. The lymphocyte of individuals was separated from their blood sample by Ficoll-Hypaque, cells were washed with phosphate buffered saline (PBS by centrifugation, and finally the pellet cells was resuspended in RPMI-1640 media. Separated cells were exposed to 2.5 µg of purified recombinant HBs antigen, and supernatants were collected after 72 hours and tested for detection of specific interferon γ level by ELISA test. Results Overall, 97.5% of dentists showed positive HBs antibody test results while 36 showed (90% positive test results for specific interferon γ against hepatitis B virus infection. Conclusions High coverage of 97.5% immune response against hepatitis B infection was found, indicating high efficacy of recombinant

  14. Antibody response of healthy children to pandemic A/H1N1/2009 influenza virus

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    Esposito Susanna

    2011-12-01

    Full Text Available Abstract Background Little is known about the proportion of pediatric pandemic A/H1N1/2009 influenza cases who showed seroconversion, the magnitude of this seroconversion, or the factors that can affect the antibody level evoked by the pandemic A/H1N1/2009 influenza. Aims of this study were to analyse antibody responses and the factors associated with high antibody titres in a cohort of children with naturally acquired A/H1N1/2009 influenza infection confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR. Results Demographic, clinical and virologic data were collected from 69 otherwise healthy children with pandemic A/H1N1/2009 influenza (27 females, mean age ± SD: 5.01 ± 4.55 years. Their antibody levels against pandemic A/H1N1/2009 and seasonal A/H1N1 influenza viruses were evaluated by measuring hemagglutination-inhibiting antibodies using standard assays. Sixty-four patients (92.8% with pandemic A/H1N1/2009 influenza had A/H1N1/2009 antibody levels of ≥40, whereas only 28/69 (40.6% were seroprotected against seasonal A/H1N1 influenza virus. Those who were seroprotected against seasonal A/H1N1 virus were significantly older, significantly more often hospitalised, had a diagnosis of pneumonia significantly more frequently, and were significantly more often treated with oseltamivir than those who were not seroprotected (p Conclusions Otherwise healthy children seem to show seroprotective antibody titres after natural infection with pandemic A/H1N1/2009 influenza virus. The strength of the immune response seems to be related to the severity of the disease, but not to previous seasonal A/H1N1 influenza immunity.

  15. [Antiviral properties of basidiomycetes metabolites].

    Science.gov (United States)

    Avtonomova, A V; Krasnopolskaya, L M

    2014-01-01

    The data on the antiviral action of the Ganoderma lucidum, Lentinus edodes, Grifola frondosa, Agaricus brasiliensis and other basidiomycetes metabolites are summurized. The metabolites of these species of basidiomycetes exhibit a direct antiviral effect on herpes simplex virus types I and II, human immunodeficiency virus (HIV), hepatitis B virus, vesicular stomatitis virus, influenza virus, Epstein-Barr virus, and others. Moreover, metabolites of basidiomycetes increased antiviral immunity.

  16. Mitochondria and antiviral innate immunity

    OpenAIRE

    Koshiba, Takumi; Bashiruddin, Nasir; Kawabata, Shunichiro

    2011-01-01

    Mitochondria, dynamic organelles that undergo continuous cycles of fusion and fission, are the powerhouses of eukaryotic cells. Recent research indicates that mitochondria also act as platforms for antiviral immunity in vertebrates. Mitochondrial-mediated antiviral immunity depends on activation of the retinoic acid-inducible gene I (RIG-I)-like receptors signal transduction pathway and the participation of the mitochondrial outer membrane adaptor protein “mitochondrial antiviral signaling (M...

  17. Delayed BCG immunization does not alter antibody responses to EPI vaccines in HIV-exposed and -unexposed South African infants.

    Science.gov (United States)

    Hesseling, Anneke C; Blakney, Anna K; Jones, Christine E; Esser, Monika M; de Beer, Corena; Kuhn, Louise; Cotton, Mark F; Jaspan, Heather B

    2016-07-12

    Bacille Calmette-Guérin (BCG) is routinely given at birth in tuberculosis-endemic settings due to its protective effect against disseminated tuberculosis in infants. BCG is however contraindicated in HIV-infected infants. We investigated whether delaying BCG vaccination to 14 weeks of age affected vaccine-induced antibody responses to Haemophilus influenzae type b (Hib)-conjugate, pertussis, tetanus and Hepatitis B (HBV) vaccines, in HIV-exposed uninfected (HEU) and -unexposed uninfected (HUU) infants. Infants were randomized to receive BCG at birth or at 14 weeks of age. Blood was taken at 14, 24, and 52 weeks of age and analyzed for Hib, pertussis, tetanus and HBV specific antibodies. BCG was given either at birth (106 infants, 51 HEU) or at 14 weeks of age (74 infants, 50 HEU). The timing of BCG vaccination did not influence the antibody response to any antigen studied. However, in a non-randomized comparison, HEU infants had higher Hib antibody concentrations at weeks 14 and 24 (p=0.001 and BCG vaccination, was associated with antibody concentrations to Hib, pertussis, HBV and tetanus primary immunization. DOH-27-1106-1520. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Cross-reactive IgE antibody responses to tropomyosins from Ascaris lumbricoides and cockroach.

    Science.gov (United States)

    Santos, Ana Beatriz R; Rocha, Gutemberg M; Oliver, Constance; Ferriani, Virgínia P L; Lima, Rodrigo C; Palma, Mário S; Sales, Valéria S F; Aalberse, Rob C; Chapman, Martin D; Arruda, L Karla

    2008-04-01

    Evidence indicates that infection with Ascaris lumbricoides may promote development of allergy and asthma. To study the role of tropomyosin, a pan-allergen in invertebrates, in IgE responses to A lumbricoides. Recombinant A lumbricoides and Periplaneta americana tropomyosins were expressed in Pichia pastoris. Levels of IgE to tropomyosins from A lumbricoides and P americana were determined by chimeric ELISA in sera from 119 children living in a parasite-endemic area and 112 patients with cockroach allergy from the allergy clinics. Presence of tropomyosin in A lumbricoides larvae at L3 stage was evaluated by immunofluorescence using mAb 1A6, directed against mite tropomyosin. Molecular modeling of P americana and A lumbricoides tropomyosins was performed by using the MODELLER program. A lumbricoides tropomyosin showed 69% to 98% sequence identity to tropomyosins from other invertebrates. The predicted structure of A lumbricoides tropomyosin was similar to that of P americana tropomyosin and showed the characteristic coiled-coil structure. Strong correlation was found for IgE antibodies to tropomyosins from A lumbricoides and P americana in sera from children living in a parasite-endemic area and from patients with cockroach allergy. Larvae of A lumbricoides reacted strongly with mAb 1A6. Tropomyosin induces IgE responses in A lumbricoides-infected children and in patients allergic to cockroach.

  19. Human antibody responses after dengue virus infection are highly cross-reactive to Zika virus

    Science.gov (United States)

    Priyamvada, Lalita; Quicke, Kendra M.; Hudson, William H.; Onlamoon, Nattawat; Sewatanon, Jaturong; Edupuganti, Srilatha; Pattanapanyasat, Kovit; Chokephaibulkit, Kulkanya; Mulligan, Mark J.; Wilson, Patrick C.; Ahmed, Rafi; Suthar, Mehul S.; Wrammert, Jens

    2016-01-01

    Zika virus (ZIKV) is an emerging mosquito-borne flavivirus of significant public health concern. ZIKV shares a high degree of sequence and structural homology compared with other flaviviruses, including dengue virus (DENV), resulting in immunological cross-reactivity. Improving our current understanding of the extent and characteristics of this immunological cross-reactivity is important, as ZIKV is presently circulating in areas that are highly endemic for dengue. To assess the magnitude and functional quality of cross-reactive immune responses between these closely related viruses, we tested acute and convalescent sera from nine Thai patients with PCR-confirmed DENV infection against ZIKV. All of the sera tested were cross-reactive with ZIKV, both in binding and in neutralization. To deconstruct the observed serum cross-reactivity in depth, we also characterized a panel of DENV-specific plasmablast-derived monoclonal antibodies (mAbs) for activity against ZIKV. Nearly half of the 47 DENV-reactive mAbs studied bound to both whole ZIKV virion and ZIKV lysate, of which a subset also neutralized ZIKV. In addition, both sera and mAbs from the dengue-infected patients enhanced ZIKV infection of Fc gamma receptor (FcγR)-bearing cells in vitro. Taken together, these findings suggest that preexisting immunity to DENV may impact protective immune responses against ZIKV. In addition, the extensive cross-reactivity may have implications for ZIKV virulence and disease severity in DENV-experienced populations. PMID:27354515

  20. Interpretation of serum antibody response to Anoplocephala perfoliata in relation to parasite burden and faecal egg count

    DEFF Research Database (Denmark)

    Kjaer, L.N.; Lungholt, M.M.; Nielsen, M.K.

    2007-01-01

    of development and gross pathological mucosal lesions were recorded and compared with serum antibody responses and faecal egg counts. Faecal egg counts were determined in samples from A. perfoliata infected horses using a semi-quantitative centrifugation/flotation technique. Blood samples collected at slaughter...

  1. Filarial-specific antibody response in East African bancroftian filariasis: effects of host infection, clinical disease, and filarial endemicity

    DEFF Research Database (Denmark)

    Jaoko, Walter G; Simonsen, Paul E; Meyrowitsch, Dan W

    2006-01-01

    The effect of host infection, chronic clinical disease, and transmission intensity on the patterns of specific antibody responses in Bancroftian filariasis was assessed by analyzing specific IgG1, IgG2, IgG3, IgG4, and IgE profiles among adults from two communities with high and low Wuchereria...

  2. Differential expression of IgE and IgG4 specific antibody responses in asymptomatic and chronic human filariasis

    NARCIS (Netherlands)

    Kurniawan, A.; Yazdanbakhsh, M.; van Ree, R.; Aalberse, R.; Selkirk, M. E.; Partono, F.; Maizels, R. M.

    1993-01-01

    A population of 164 adult individuals resident in an area endemic for Brugia malayi lymphatic filariasis has been studied for humoral immune responses to filarial parasites. Antibody levels to Ag extracted from adult worms were determined for each of the IgG subclasses, for IgM and for IgE. The

  3. Bacille Calmette-Guerin (BCG) vaccination at birth and antibody responses to childhood vaccines. A randomised clinical trial

    NARCIS (Netherlands)

    Nissen, T.N.; Birk, N.M.; Smits, G.; Jeppesen, D.L.; Stensballe, L.G.; Netea, M.G.; Klis, F. van der; Benn, C.S.; Pryds, O.

    2017-01-01

    INTRODUCTION: BCG vaccination has been associated with beneficial non-specific effects on child health. Some immunological studies have reported heterologous effects of vaccines on antibody responses to heterologous vaccines. Within a randomised clinical trial of Bacille Calmette-Guerin (BCG)

  4. Antibody responses measured by various serologic tests in pigs orally inoculated with low numbers of Toxoplasma gondii oocysts

    DEFF Research Database (Denmark)

    Dubey, J. P.; Andrews, C.D.; Lind, Peter

    1996-01-01

    Objective-To follow antibody responses measured by various serologic tests in pigs orally inoculated with low (less than or equal to 10 oocysts) numbers of Toxoplasma gondii oocysts. Animals-24, 2- to 3-month-old pigs. Procedure-Pigs (n = 42) were inoculated orally with 10 (14 pigs) or 1 (28 pigs...

  5. Serum antibody responses in pigs trickle-infected with Ascaris and Trichuris

    DEFF Research Database (Denmark)

    Kringel, Helene; Thamsborg, Stig Milan; Petersen, Heidi Huus

    2015-01-01

    A humoral immune response following helminth infection in pigs is well documented. However, it has been difficult to confirm the existence of antibody mediated resistance against the large roundworm, Ascaris suum, and whipworm, Trichuris suis, in experimental settings by correlating worm burdens ...

  6. Human immune response to anti-carcinoembryonic antigen murine monoclonal antibodies.

    Science.gov (United States)

    Losman, M J; DeJager, R L; Monestier, M; Sharkey, R M; Goldenberg, D M

    1990-02-01

    We previously demonstrated that patients with carcinoembryonic antigen [CEA]-producing neoplastic tumors, treated with murine monoclonal antibody to CEA, produced antibodies directed against the constant regions [human anti-mouse antibody (HAMA)] and the idiotypes [anti-Id] of these murine immunoglobulins. In this study, we describe a method for analyzing the presence of such antibodies in the sera of these patients. The HAMAs were measured by enzyme immunoassay and removed by immunoadsorption on Affi-Gel mouse IgG. The unabsorbed fraction contained the anti-Id antibodies; their presence was demonstrated by binding to the CEA monoclonal antibody (Ab1). The specificity of the binding was assessed by preincubating the sera with Ab1 and measuring the residual nonspecific binding. When specific binding was detected, the anti-Id antibodies were isolated by adsorption and elution on Affi-Gel Ab1. The anti-Id antibodies were fixed on enzyme immunoassay plates and incubated with a panel of mouse anti-human immunoglobulin to determine their isotypes. In a first series of 24 patients, HAMAs were found in 20 cases and anti-Id antibodies in 19 cases. The isolation of a specific IgG to Ab1 was achieved in 2 cases. In an ongoing series, the HAMA and anti-Id antibodies were detected in all five patients given injections of another monoclonal antibody to CEA. In two patients an IgG1 kappa anti-Id was isolated from the serum. The potential therapeutic effect of these antibodies is under investigation.

  7. Broadly Neutralizing Antibody Responses in a Large Longitudinal Sub-Saharan HIV Primary Infection Cohort.

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    Elise Landais

    2016-01-01

    Full Text Available Broadly neutralizing antibodies (bnAbs are thought to be a critical component of a protective HIV vaccine. However, designing vaccines immunogens able to elicit bnAbs has proven unsuccessful to date. Understanding the correlates and immunological mechanisms leading to the development of bnAb responses during natural HIV infection is thus critical to the design of a protective vaccine. The IAVI Protocol C program investigates a large longitudinal cohort of primary HIV-1 infection in Eastern and South Africa. Development of neutralization was evaluated in 439 donors using a 6 cross-clade pseudo-virus panel predictive of neutralization breadth on larger panels. About 15% of individuals developed bnAb responses, essentially between year 2 and year 4 of infection. Statistical analyses revealed no influence of gender, age or geographical origin on the development of neutralization breadth. However, cross-clade neutralization strongly correlated with high viral load as well as with low CD4 T cell counts, subtype-C infection and HLA-A*03(- genotype. A correlation with high overall plasma IgG levels and anti-Env IgG binding titers was also found. The latter appeared not associated with higher affinity, suggesting a greater diversity of the anti-Env responses in broad neutralizers. Broadly neutralizing activity targeting glycan-dependent epitopes, largely the N332-glycan epitope region, was detected in nearly half of the broad neutralizers while CD4bs and gp41-MPER bnAb responses were only detected in very few individuals. Together the findings suggest that both viral and host factors are critical for the development of bnAbs and that the HIV Env N332-glycan supersite may be a favorable target for vaccine design.

  8. Serological analysis of human anti-human antibody responses in colon cancer patients treated with repeated doses of humanized monoclonal antibody A33.

    Science.gov (United States)

    Ritter, G; Cohen, L S; Williams, C; Richards, E C; Old, L J; Welt, S

    2001-09-15

    Mouse monoclonal antibody A33 (mAb A33) recognizes a M(r) 43,000 cell surface glycoprotein (designated A33) expressed in human colonic epithelium and colon cancer but absent from most other normal tissues. In patients, mAb A33 localizes with high specificity to colon cancer and is retained for up to 6 weeks in the cancer but cleared rapidly from normal colon (5-6 days). As a carrier of (125)I or (131)I, mAb A33 has shown antitumor activity. Induction of strong human anti-mouse antibody (immunoglobulin; HAMA) responses in patients, however, limits the use of the murine mAb A33 to very few injections. A humanized version of this antibody (huAb A33) has been prepared for Phase I and II clinical studies in patients with colon cancer. In those studies, immunogenicity of huAb A33 has been monitored using a novel, highly sensitive BIACORE method, which allows measurement of human anti-human antibodies (HAHAs) without the use of secondary reagents. We found that 63% (26 of 41) of the patients treated with repeated doses of huAb A33 developed HAHAs against a conformational antigenic determinant located in the V(L) and V(H) regions of huAb A33. Detailed serological analysis showed two distinct types of HAHAs. HAHA of type I (49% of patients) was characterized by an early onset with peak HAHA levels after 2 weeks of treatment, which declined with ongoing huAb A33 treatment. HAHA of type II (17% of patients) was characterized by a typically later onset of HAHA than in type I and by progressively increasing HAHA levels with each subsequent huAb A33 administration. Colon cancer patients with type I HAHAs did not develop infusion-related adverse events. In contrast, HAHA of type II was indicative of infusion-related adverse events. By using this new method, we were able to distinguish these two types of HAHAs in patients while on antibody treatment, allowing patients to be removed from study prior to the onset of severe infusion-related adverse events.

  9. Vault nanocapsules as adjuvants favor cell-mediated over antibody-mediated immune responses following immunization of mice.

    Directory of Open Access Journals (Sweden)

    Upendra K Kar

    Full Text Available BACKGROUND: Modifications of adjuvants that induce cell-mediated over antibody-mediated immunity is desired for development of vaccines. Nanocapsules have been found to be viable adjuvants and are amenable to engineering for desired immune responses. We previously showed that natural nanocapsules called vaults can be genetically engineered to elicit Th1 immunity and protection from a mucosal bacterial infection. The purpose of our study was to characterize immunity produced in response to OVA within vault nanoparticles and compare it to another nanocarrier. METHODOLOGY AND PRINCIPAL FINDINGS: We characterized immunity resulting from immunization with the model antigen, ovalbumin (OVA encased in vault nanocapsules and liposomes. We measured OVA responsive CD8(+ and CD4(+ memory T cell responses, cytokine production and antibody titers in vitro and in vivo. We found that immunization with OVA contain in vaults induced a greater number of anti-OVA CD8(+ memory T cells and production of IFNγ plus CD4(+ memory T cells. Also, modification of the vault body could change the immune response compared to OVA encased in liposomes. CONCLUSIONS/SIGNIFICANCE: These experiments show that vault nanocapsules induced strong anti-OVA CD8(+ and CD4(+ T cell memory responses and modest antibody production, which markedly differed from the immune response induced by liposomes. We also found that the vault nanocapsule could be modified to change antibody isotypes in vivo. Thus it is possible to create a vault nanocapsule vaccine that can result in the unique combination of immunogen-responsive CD8(+ and CD4(+ T cell immunity coupled with an IgG1 response for future development of vault nanocapsule-based vaccines against antigens for human pathogens and cancer.

  10. T cell regulation of the thymus-independent antibody response to trinitrophenylated-Brucella abortus (TNP-BA)

    Energy Technology Data Exchange (ETDEWEB)

    Tanay, A.; Strober, S.

    1985-06-01

    The authors have previously observed a reduction of the T cell-dependent primary antibody response to dinitrophenylated keyhole limpet hemocyanin, and an enhancement of the T cell-independent response to trinitrophenylated Brucella abortus (TNP-BA) in BALB/c mice after treatment with total lymphoid irradiation (TLI). To elucidate the relative contribution of T and B cells to the enhanced T cell-independent antibody responses after TLI, a syngeneic primary adoptive transfer system was utilized whereby irradiated hosts were reconstituted with unfractionated spleen cells or a combination of purified T and B cells from TLI-treated and untreated control mice. Antibody responses of purified splenic B cells from TLI-treated BALB/c mice (TLI/B) to TNP-BA were enhanced 10-fold as compared with those of unfractionated (UF) spleen cells or B cells from normal (NL) BALB/c mice (NL/UF and NL/B, respectively). Splenic T cells from normal animals (NL/T) suppressed the anti-TNP-BA response of TLI/B by more than 100-fold. NL/T neither suppressed nor enhanced the response of NL/B. On the other hand, T cells from TLI-treated mice (TLI/T) enhanced by 100-fold the anti-TNP-BA response of NL/B, but neither suppressed nor enhanced the response of TLI/B. Thus, T cells can regulate the T cell-independent antibody response to TNP-BA. However, experimental manipulation of the T and B cell populations is needed to demonstrate the regulatory functions.

  11. A Potent Virus-Specific Antibody-Secreting Cell Response to Acute Enterovirus 71 Infection in Children.

    Science.gov (United States)

    Huang, Kuan-Ying Arthur; Lin, Jainn-Jim; Chiu, Cheng-Hsun; Yang, Shuan; Tsao, Kuo-Chien; Huang, Yhu-Chering; Lin, Tzou-Yien

    2015-09-01

    Enterovirus 71 (EV71) remains a leading pathogen for acute infectious diseases in children, especially in Asia. The cellular basis for establishing a virus-specific antibody response to acute EV71 infections is unclear in children. We studied the magnitude of virus-specific antibody-secreting B cells (ASCs) and its relationship with serological response, clinical parameters, and virological parameters among children with laboratory-confirmed EV71 infection. A potent EV71 genogroup B- and virus-specific ASC response was detected in the first week of illness among genotype B5 EV71-infected children. The cross-reactive EV71-specific ASC response to genogroup C viral antigens composed about 10% of the response. The EV71-specific ASC response in children aged ≥3 years produced immunoglobulin G predominantly, but immunoglobulin M was predominant in younger children. Proliferation marker was expressed by the majority of circulating ASCs in the acute phase of EV71 infection. Virus-specific ASC responses significantly correlated with throat viral load, fever duration, and serological genogroup-specific neutralization titer. The presence of a virus-specific ASC response serves an early cellular marker of an EV71-specific antibody response. Further detailed study of EV71-specific ASCs at the monoclonal level is crucial to delineate the specificity and function of antibody immunity in children. © The Author 2015. 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. Study of the impact of Th17/Treg balance in peripheral and mucosal sites over the functionality of the antiviral T-cell responses and HIV immunopathogenesis

    OpenAIRE

    Falivene, Juliana

    2016-01-01

    Las subpoblaciones de linfocitos Th17 y T regulatorios (Treg) han sido relacionados con la progresión a enfermedad en el contexto de la infección por HIV-1. Sin embargo, su relación con la respuesta adaptativa T CD8+ antiviral durante la infección aguda/temprana por HIV (PHI, primary HIV infection) no ha sido aún estudiada. En este contexto, el primer objetivo general de este trabajo de tesis consistió en analizar las subpoblaciones Th17 y Treg y su relación con la respuesta celular T CD8+ es...

  13. Intramuscular delivery of a cholera DNA vaccine primes both systemic and mucosal protective antibody responses against cholera.

    Science.gov (United States)

    Xu, Guifang; Wang, Shixia; Zhuang, Ling; Hackett, Anthony; Gu, Ling; Zhang, Lu; Zhang, Chunhua; Wang, Hua; Huang, Zuhu; Lu, Shan

    2009-06-12

    Cholera is a potentially lethal diarrhea disease caused by the gram-negative bacterium Vibrio cholerae. The need for an effective cholera vaccine is clearly indicated but the challenges of eliciting both systemic and mucosal immune responses remains a significant challenge. In the current report, we discovered that a DNA vaccine expressing a protective cholera antigen, cholera toxin B subunit (CTB), delivered parenterally can elicit both systemic and mucosal anti-CTB antibody responses in mice. The priming effect by DNA immunization was demonstrated by higher mucosal antibody responses following one boost with the inactivated cholera vaccine (KWC-B) delivered orally when compared to the twice oral administration of KWC-B alone. This finding indicates that DNA vaccines delivered parenterally are effective in eliciting mucosal protective immune responses--a unique advantage for DNA vaccination that has not yet been well realized and should bring value to the development of novel vaccination approaches against mucosally transmitted diseases.

  14. Neutralizing antibody response during human immunodeficiency virus type 1 infection: type and group specificity and viral escape

    DEFF Research Database (Denmark)

    Arendrup, M; Sönnerborg, A; Svennerholm, B

    1993-01-01

    demonstrated, suggesting that the majority of the change in neutralization sensitivity is driven by the selective pressure of type-specific NA. Furthermore, no differences were observed in sensitivity to neutralization by anti-carbohydrate neutralizing monoclonal antibodies or the lectin concanavalin A......The paradox that group-specific neutralizing antibodies (NA) exist in the majority of human immunodeficiency virus type 1 (HIV-1)-infected patients, whereas the NA response against autologous HIV-1 virus isolates is highly type-specific, motivated us to study the type- and group-specific NA...

  15. Salivary IgA antibody responses to Streptococcus mitis and Streptococcus mutans in preterm and fullterm newborn children.

    Science.gov (United States)

    Nogueira, Ruchele Dias; Sesso, Maria Lucia Talarico; Borges, Mariana Castro Loureiro; Mattos-Graner, Renata O; Smith, Daniel James; Ferriani, Virginia Paes Leme

    2012-06-01

    The intensities and specificities of salivary IgA antibody responses to antigens of Streptococcus mutans, the main pathogen of dental caries, may influence colonization by these organisms during the first 1.5 year of life. Thus, the ontogeny of salivary IgA responses to oral colonizers continues to warrant investigation, especially with regard to the influence of birth conditions, e.g. prematurity, on the ability of children to efficiently respond to oral microorganisms. In this study, we characterised the salivary antibody responses to two bacterial species which are prototypes of pioneer and pathogenic microorganisms of the oral cavity (Streptococcus mitis and Streptococcus mutans, respectively) in fullterm (FT) and preterm (PT) newborn children. Salivas from 123 infants (70 FT and 53 PT) were collected during the first 10h after birth and levels of IgA and IgM antibodies and the presence of S. mutans and S. mitis were analysed respectively by ELISA and by chequerboard DNA-DNA hybridization. Two subgroups of 24 FT and 24 PT children were compared with respect to patterns of antibody specificities against S. mutans and S. mitis antigens, using Western blot assays. Cross-adsorption of 10 infant's saliva was tested to S. mitis, S. mutans and Enterococcus faecalis antigens. Salivary levels of IgA at birth were 2.5-fold higher in FT than in PT children (Mann-Whitney; P<0.05). Salivary IgA antibodies reactive with several antigens of S. mitis and S. mutans were detected at birth in children with undetectable levels of those bacteria. Adsorption of infant saliva with cells of S. mutans produced a reduction of antibodies recognizing S. mitis antigens in half of the neonates. The diversity and intensity of IgA responses were lower in PT compared to FT children, although those differences were not significant. These data provide evidence that children have salivary IgA antibodies shortly after birth, which might influence the establishment of the oral microbiota, and that

  16. Effect of HIV infection on the acute antibody response to malaria antigens in children: an observational study

    Directory of Open Access Journals (Sweden)

    Kinyanjui Samson M

    2011-03-01

    Full Text Available Abstract Background In sub-Saharan Africa, the distributions of malaria and HIV widely overlap. Among pregnant and non-pregnant adults, HIV affects susceptibility to malaria, its clinical course and impairs antibody responses to malaria antigens. However, the relationship between the two diseases in childhood, when most deaths from malaria occur, is less clear. It was previously reported that HIV is associated with admission to hospital in rural Kenya with severe malaria among children, except in infancy. HIV-infected children with severe malaria were older, had higher parasite density and increased mortality, raising a hypothesis that HIV interferes with naturally acquired immunity to malaria, hence with little effect at younger ages (a shorter history of exposure. To test this hypothesis, levels of anti-merozoite and schizont extract antibodies were compared between HIV-infected and uninfected children who participated in the original study. Methods IgG responses to malaria antigens that are potential targets for immunity to malaria (AMA1, MSP2, MSP3 and schizont extract were compared between 115 HIV-infected and 115 age-matched, HIV-uninfected children who presented with severe malaria. The children were classified as high and low responders for each antigen and assigned antibody-response breadth scores according to the number of antigens to which they were responsive. A predictive logistic regression model was used to test if HIV was an effect modifier on the age-related acquisition of antibody responses, with age as a continuous variable. Results Point estimates of the responses to all antigens were lower amongst HIV-infected children, but this was only statistically significant for AMA1 (P = 0.028. HIV-infected children were less likely to be high responders to AMA1 [OR 0.44 (95%CI, 0.2-0.90 P = 0.024]. HIV was associated with a reduced breadth of responses to individual merozoite antigens (P = 0.02. HIV strongly modified the acquisition

  17. Effect of Echinacea purpurea (Asteraceae aqueous extract on antibody response to Bothrops asper venom and immune cell response

    Directory of Open Access Journals (Sweden)

    Fernando Chaves

    2007-03-01

    Full Text Available The effect of aqueous extract of Echinacea purpurea roots on the murine antibody response to Bothrops asper snake venom in vivo was studied. Three groups were used. Group #1, baseline control, was treated with snake venom plus PBS. Group #2 was treated with snake venom plus sodium alginate as adjuvant (routine method used at Instituto Clodomiro Picado, and group #3 or experimental group, was treated with snake venom plus aqueous extract of E. purpurea root as adjuvant. In all groups, the first inoculation was done with Freund’s complete adjuvant (FCA. By the time of the second bleeding, mice in group #3 showed a remarkable increment in the level of anti-venom antibodies compared with those in groups #1 or #2. In vitro immune cell proliferation as a response to aqueous extract of E. purpurea root was studied using human lymphocytes activated with different lectins (Con A, PHA and PWM. In all cases, increase in percentage of lymphoproliferation was greater when E. purpurea root extract was used in addition to individual lectins. Rev. Biol. Trop. 55 (1: 113-119. Epub 2007 March. 31.Se estudió in vivo, el efecto del extracto acuoso de las raíces de Echinacea purpurea en la respuesta de los anticuerpos murinos al veneno de la serpiente Bothrops asper. El grupo 1 control, fue tratado con el veneno y PBS. El grupo 2 con veneno y alginato de sodio (método utilizado en el Instituto Clodomiro Picado, y el grupo 3 o experimental, con veneno y extracto acuoso de las raíces de E. purpurea. En todos los grupos, la primera inmunización fue hecha con FCA (Freund’s Complete Adjuvant. En las muestras correspondientes a la segunda sangría, los ratones del grupo 3 mostraron un marcado incremento en el nivel de anticuerpos, en comparación con los ratones de los otros grupos. También se determinó la proliferación de células inmunes in vitro, como respuesta al extracto acuoso de la raíz de E. purpurea, utilizando linfocitos humanos activados con

  18. H. pylori-infection and antibody immune response in a rural Tanzanian population

    Directory of Open Access Journals (Sweden)

    Biggar Robert J

    2006-09-01

    Full Text Available Abstract Background Helicobacter pylori (H. pylori infection is ubiquitous in sub-Saharan Africa, but paradoxically gastric cancer is rare. Methods Sera collected during a household-based survey in rural Tanzania in 1985 were tested for anti-H. pylori IgG and IgG subclass antibodies by enzyme immunoassay. Odds ratios (OR and confidence intervals (CI of association of seropositivity with demographic variables were computed by logistic regression models. Results Of 788 participants, 513 were aged ≤17 years. H. pylori seropositivity increased from 76% at 0–4 years to 99% by ≥18 years of age. Seropositivity was associated with age (OR 11.5, 95% CI 4.2–31.4 for 10–17 vs. 0–4 years, higher birth-order (11.1; 3.6–34.1 for ≥3rd vs. 1st born, and having a seropositive next-older sibling (2.7; 0.9–8.3. Median values of IgG subclass were 7.2 for IgG1 and 2.0 for IgG2. The median IgG1/IgG2 ratio was 3.1 (IQR: 1.7–5.6, consistent with a Th2-dominant immune profile. Th2-dominant response was more frequent in children than adults (OR 2.4, 95% CI 1.3–4.4. Conclusion H. pylori seropositivity was highly prevalent in Tanzania and the immunological response was Th2-dominant. Th2-dominant immune response, possibly caused by concurrent bacterial or parasitic infections, could explain, in part, the lower risk of H. pylori-associated gastric cancer in Africa.

  19. Noninfectious retrovirus particles drive the APOBEC3/Rfv3 dependent neutralizing antibody response.

    Directory of Open Access Journals (Sweden)

    Diana S Smith

    2011-10-01

    Full Text Available Members of the APOBEC3 family of deoxycytidine deaminases counteract a broad range of retroviruses in vitro through an indirect mechanism that requires virion incorporation and inhibition of reverse transcription and/or hypermutation of minus strand transcripts in the next target cell. The selective advantage to the host of this indirect restriction mechanism remains unclear, but valuable insights may be gained by studying APOBEC3 function in vivo. Apobec3 was previously shown to encode Rfv3, a classical resistance gene that controls the recovery of mice from pathogenic Friend retrovirus (FV infection by promoting a more potent neutralizing antibody (NAb response. The underlying mechanism does not involve a direct effect of Apobec3 on B cell function. Here we show that while Apobec3 decreased titers of infectious virus during acute FV infection, plasma viral RNA loads were maintained, indicating substantial release of noninfectious particles in vivo. The lack of plasma virion infectivity was associated with a significant post-entry block during early reverse transcription rather than G-to-A hypermutation. The Apobec3-dependent NAb response correlated with IgG binding titers against native, but not detergent-lysed virions. These findings indicate that innate Apobec3 restriction promotes NAb responses by maintaining high concentrations of virions with native B cell epitopes, but in the context of low virion infectivity. Finally, Apobec3 restriction was found to be saturable in vivo, since increasing FV inoculum doses resulted in decreased Apobec3 inhibition. By analogy, maximizing the release of noninfectious particles by modulating APOBEC3 expression may improve humoral immunity against pathogenic human retroviral infections.

  20. Antibody response in cattle, sheep and rats to infection with γ-irradiated metacercariae of Fasciola hepatica

    International Nuclear Information System (INIS)

    Hughes, D.L.; Doy, T.G.

    1982-01-01

    Cattle, sheep and rats were infected orally with γ-irradiated metacercariae of Fasciola hepatica, or with normal metacercariae. The antibody response was monitored in each host to metacercarial tegument (T0), juvenile tegument (T1), adult tegument (T2) and gut antigens. The response was examined at weekly intervals for cattle and sheep throughout 15 weeks of infection and four weeks after infection in rats, using an indirect fluorescent antibody labelling technique. It was found that the irradiated metacercariae engendered a normal humoral response to T0, T1 and gut antigens in all three hosts although the antibody levels were somewhat reduced due to early death or stunting of the flukes. T0 and T1 appeared to be antigenically similar. Antibodies against T2 appeared late in the animals infected with γ-irradiated metacercariae and the titres attained were considerably lower than in the controls. The T2 antigen stimulus in the animals given γ-irradiated metacercariae was probably provided by flukes which 'broke through' the developmental barrier imposed by irradiation and which were found alive at autopsy. (author)

  1. Genetic variation and heritability of the antibody response to Mycobacterium avium subspecies paratuberculosis in Danish Hostein cows

    DEFF Research Database (Denmark)

    Mortensen, Hanne; Nielsen, Søren Saxmose; Berg, Peer

    2004-01-01

    The purpose of this study was to estimate the genetic variation and the heritability of the ability to establish an immune response by producing antibodies to Mycobacterium avium subsp. paratuberculosis. Antibody levels were determined using an ELISA and measuring optical density (OD) values from...... milk samples of 11,535 cows from 99 herds. The pedigree of the 11,535 cows and information about days in milk, parity, milk yield, and others were obtained from the Danish Cattle database. The statistical analyses were made using a bivariate mixed animal model. The bivariate model with daily milk yield...... and OD as dependent variables showed a significant heritability of the ability to produce Mycobacterium avium subsp. paratuberculosis antibodies of 0.102 (genetic variance = 0.054) and a nonsignificant genetic correlation of −0.037 between daily milk yield and OD. When a sire model was used...

  2. Chlamydia trachomatis and chlamydial heat shock protein 60-specific antibody and cell-mediated responses predict tubal factor infertility

    DEFF Research Database (Denmark)

    Tiitinen, A.; Surcel, H.-M.; Halttunen, M.

    2006-01-01

    BACKGROUND: To evaluate the role of Chlamydia trachomatis-induced humoral and cell-mediated immune (CMI) responses in predicting tubal factor infertility (TFI). METHODS: Blood samples were taken from 88 women with TFI and 163 control women. C. trachomatis and chlamydial heat shock protein 60 (CHSP......60)-specific immunoglobulin G (IgG) antibodies were analysed using enzyme-linked immunosorbent assay (ELISA) kits. Proliferative reactivity of peripheral blood mononuclear cells was studied in vitro against Chlamydia elementary body (EB) and recombinant CHSP60 antigens. RESULTS: C. trachomatis......-specific IgG antibodies were found more frequently (43.2 versus 13.5%), and the antibody levels were higher in the TFI cases than in the controls (P cases and 58.9% of the controls (P

  3. Antibody Responses of Cervids (Cervus elaphus) following Experimental Mycobacterium bovis Infection and the Implications for Immunodiagnosis ▿

    Science.gov (United States)

    Harrington, Noel P.; Surujballi, Om P.; Prescott, John F.; Duncan, J. Robert; Waters, W. Ray; Lyashchenko, Konstantin; Greenwald, Rena

    2008-01-01

    Captive and free-ranging wildlife animals are implicated in the maintenance and transmission of bovine tuberculosis and therefore pose a significant obstacle to eradication of the disease from domestic livestock. The current antemortem diagnostic method, the intradermal tuberculin skin test, is impractical for routine use with many wild animals. Antibody-based assays are particularly attractive because the animals are handled only once and immediate processing of the sample is not required. This report characterizes the antibody responses of red deer-elk hybrids (Cervus elaphus) against Mycobacterium bovis and subsequently evaluates the diagnostic performance of select antigens in a rapid-test format. Sequential serum samples were collected from 10 animals experimentally infected with M. bovis and 5 noninfected animals over a 7-month period postinfection (p.i.). Samples were evaluated by enzyme-linked immunosorbent assays, immunoblot analyses, and multiantigen print immunoassays for seroreactivity to mycobacterial antigens. Although all infected animals produced antibodies to M. bovis protein antigens, there was significant animal-to-animal variation in the kinetics and magnitudes of responses and the antigens recognized. The most frequently recognized antigens i