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Sample records for block irf3-mediated innate

  1. Recognition and Blocking of Innate Immunity Cells by Candida albicans Chitin ▿ †

    Science.gov (United States)

    Mora-Montes, Héctor M.; Netea, Mihai G.; Ferwerda, Gerben; Lenardon, Megan D.; Brown, Gordon D.; Mistry, Anita R.; Kullberg, Bart Jan; O'Callaghan, Chris A.; Sheth, Chirag C.; Odds, Frank C.; Brown, Alistair J. P.; Munro, Carol A.; Gow, Neil A. R.

    2011-01-01

    Chitin is a skeletal cell wall polysaccharide of the inner cell wall of fungal pathogens. As yet, little about its role during fungus-host immune cell interactions is known. We show here that ultrapurified chitin from Candida albicans cell walls did not stimulate cytokine production directly but blocked the recognition of C. albicans by human peripheral blood mononuclear cells (PBMCs) and murine macrophages, leading to significant reductions in cytokine production. Chitin did not affect the induction of cytokines stimulated by bacterial cells or lipopolysaccharide (LPS), indicating that blocking was not due to steric masking of specific receptors. Toll-like receptor 2 (TLR2), TLR4, and Mincle (the macrophage-inducible C-type lectin) were not required for interactions with chitin. Dectin-1 was required for immune blocking but did not bind chitin directly. Cytokine stimulation was significantly reduced upon stimulation of PBMCs with heat-killed chitin-deficient C. albicans cells but not with live cells. Therefore, chitin is normally not exposed to cells of the innate immune system but is capable of influencing immune recognition by blocking dectin-1-mediated engagement with fungal cell walls. PMID:21357722

  2. Innate Immune Signaling in Drosophila Blocks Insulin Signaling by Uncoupling PI(3,4,5P3 Production and Akt Activation

    Directory of Open Access Journals (Sweden)

    Stephen W. Roth

    2018-03-01

    Full Text Available In obese adipose tissue, Toll-like receptor signaling in macrophages leads to insulin resistance in adipocytes. Similarly, Toll signaling in the Drosophila larval fat body blocks insulin-dependent growth and nutrient storage. We find that Toll acts cell autonomously to block growth but not PI(3,4,5P3 production in fat body cells expressing constitutively active PI3K. Fat body Toll signaling blocks whole-animal growth in rictor mutants lacking TORC2 activity, but not in larvae lacking Pdk1. Phosphorylation of Akt on the Pdk1 site, Thr342, is significantly reduced by Toll signaling, and expression of mutant AktT342D rescues cell and animal growth, nutrient storage, and viability in animals with active Toll signaling. Altogether, these data show that innate immune signaling blocks insulin signaling at a more distal level than previously appreciated, and they suggest that manipulations affecting the Pdk1 arm of the pathway may have profound effects on insulin sensitivity in inflamed tissues.

  3. TTI-621 (SIRPαFc): A CD47-Blocking Innate Immune Checkpoint Inhibitor with Broad Antitumor Activity and Minimal Erythrocyte Binding.

    Science.gov (United States)

    Petrova, Penka S; Viller, Natasja Nielsen; Wong, Mark; Pang, Xinli; Lin, Gloria H Y; Dodge, Karen; Chai, Vien; Chen, Hui; Lee, Vivian; House, Violetta; Vigo, Noel T; Jin, Debbie; Mutukura, Tapfuma; Charbonneau, Marilyse; Truong, Tran; Viau, Stephane; Johnson, Lisa D; Linderoth, Emma; Sievers, Eric L; Maleki Vareki, Saman; Figueredo, Rene; Pampillo, Macarena; Koropatnick, James; Trudel, Suzanne; Mbong, Nathan; Jin, Liqing; Wang, Jean C Y; Uger, Robert A

    2017-02-15

    Purpose: The ubiquitously expressed transmembrane glycoprotein CD47 delivers an anti-phagocytic (do not eat) signal by binding signal-regulatory protein α (SIRPα) on macrophages. CD47 is overexpressed in cancer cells and its expression is associated with poor clinical outcomes. TTI-621 (SIRPαFc) is a fully human recombinant fusion protein that blocks the CD47-SIRPα axis by binding to human CD47 and enhancing phagocytosis of malignant cells. Blockade of this inhibitory axis using TTI-621 has emerged as a promising therapeutic strategy to promote tumor cell eradication. Experimental Design: The ability of TTI-621 to promote macrophage-mediated phagocytosis of human tumor cells was assessed using both confocal microscopy and flow cytometry. In vivo antitumor efficacy was evaluated in xenograft and syngeneic models and the role of the Fc region in antitumor activity was evaluated using SIRPαFc constructs with different Fc tails. Results: TTI-621 enhanced macrophage-mediated phagocytosis of both hematologic and solid tumor cells, while sparing normal cells. In vivo , TTI-621 effectively controlled the growth of aggressive AML and B lymphoma xenografts and was efficacious in a syngeneic B lymphoma model. The IgG1 Fc tail of TTI-621 plays a critical role in its antitumor activity, presumably by engaging activating Fcγ receptors on macrophages. Finally, TTI-621 exhibits minimal binding to human erythrocytes, thereby differentiating it from CD47 blocking antibodies. Conclusions: These data indicate that TTI-621 is active across a broad range of human tumors. These results further establish CD47 as a critical regulator of innate immune surveillance and form the basis for clinical development of TTI-621 in multiple oncology indications. Clin Cancer Res; 23(4); 1068-79. ©2016 AACR . ©2016 American Association for Cancer Research.

  4. Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity

    Science.gov (United States)

    Schoggins, John W.; MacDuff, Donna A.; Imanaka, Naoko; Gainey, Maria D.; Shrestha, Bimmi; Eitson, Jennifer L.; Mar, Katrina B.; Richardson, R. Blake; Ratushny, Alexander V.; Litvak, Vladimir; Dabelic, Rea; Manicassamy, Balaji; Aitchison, John D.; Aderem, Alan; Elliott, Richard M.; García-Sastre, Adolfo; Racaniello, Vincent; Snijder, Eric J.; Yokoyama, Wayne M.; Diamond, Michael S.; Virgin, Herbert W.; Rice, Charles M.

    2014-01-01

    The type I interferon (IFN) response protects cells from viral infection by inducing hundreds of interferon-stimulated genes (ISGs), some of which encode direct antiviral effectors. Recent screening studies have begun to catalogue ISGs with antiviral activity against several RNA and DNA viruses. However, antiviral ISG specificity across multiple distinct classes of viruses remains largely unexplored. Here we used an ectopic expression assay to screen a library of more than 350 human ISGs for effects on 14 viruses representing 7 families and 11 genera. We show that 47 genes inhibit one or more viruses, and 25 genes enhance virus infectivity. Comparative analysis reveals that the screened ISGs target positive-sense single-stranded RNA viruses more effectively than negative-sense single-stranded RNA viruses. Gene clustering highlights the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS, also known as MB21D1) as a gene whose expression also broadly inhibits several RNA viruses. In vitro, lentiviral delivery of enzymatically active cGAS triggers a STING-dependent, IRF3-mediated antiviral program that functions independently of canonical IFN/STAT1 signalling. In vivo, genetic ablation of murine cGAS reveals its requirement in the antiviral response to two DNA viruses, and an unappreciated contribution to the innate control of an RNA virus. These studies uncover new paradigms for the preferential specificity of IFN-mediated antiviral pathways spanning several virus families.

  5. Innate immunity

    African Journals Online (AJOL)

    various types of pathogen recognition receptors on epithelial cells and resident cells of the innate immune system, especially macrophages, initiate a localised inflammatory response characterised by an early influx of blood neutrophils.1,2. A comparison of the major characteristics of innate and adaptive immune responses ...

  6. Reclassifying Anaphylaxis to Neuromuscular Blocking Agents Based on the Presumed Patho-Mechanism: IgE-Mediated, Pharmacological Adverse Reaction or “Innate Hypersensitivity”?

    Directory of Open Access Journals (Sweden)

    David Spoerl

    2017-06-01

    Full Text Available Approximately 60% of perioperative anaphylactic reactions are thought to be immunoglobulin IgE mediated, whereas 40% are thought to be non-IgE mediated hypersensitivity reactions (both considered non-dose-related type B adverse drug reactions. In both cases, symptoms are elicited by mast cell degranulation. Also, pharmacological reactions to drugs (type A, dose-related may sometimes mimic symptoms triggered by mast cell degranulation. In case of hypotension, bronchospasm, or urticarial rash due to mast cell degranulation, identification of the responsible mechanism is complicated. However, determination of the type of the underlying adverse drug reaction is of paramount interest for the decision of whether the culprit drug may be re-administered. Neuromuscular blocking agents (NMBA are among the most frequent cause of perioperative anaphylaxis. Recently, it has been shown that NMBA may activate mast cells independently from IgE antibodies via the human Mas-related G-protein-coupled receptor member X2 (MRGPRX2. In light of this new insight into the patho-mechanism of pseudo-allergic adverse drug reactions, in which as drug-receptor interaction results in anaphylaxis like symptoms, we critically reviewed the literature on NMBA-induced perioperative anaphylaxis. We challenge the dogma that NMBA mainly cause IgE-mediated anaphylaxis via an IgE-mediated mechanism, which is based on studies that consider positive skin test to be specific for IgE-mediated hypersensitivity. Finally, we discuss the question whether MRGPRX2 mediated pseudo-allergic reactions should be re-classified as type A adverse reactions.

  7. Reclassifying Anaphylaxis to Neuromuscular Blocking Agents Based on the Presumed Patho-Mechanism: IgE-Mediated, Pharmacological Adverse Reaction or "Innate Hypersensitivity"?

    Science.gov (United States)

    Spoerl, David; Nigolian, Haig; Czarnetzki, Christoph; Harr, Thomas

    2017-06-07

    Approximately 60% of perioperative anaphylactic reactions are thought to be immunoglobulin IgE mediated, whereas 40% are thought to be non-IgE mediated hypersensitivity reactions (both considered non-dose-related type B adverse drug reactions). In both cases, symptoms are elicited by mast cell degranulation. Also, pharmacological reactions to drugs (type A, dose-related) may sometimes mimic symptoms triggered by mast cell degranulation. In case of hypotension, bronchospasm, or urticarial rash due to mast cell degranulation, identification of the responsible mechanism is complicated. However, determination of the type of the underlying adverse drug reaction is of paramount interest for the decision of whether the culprit drug may be re-administered. Neuromuscular blocking agents (NMBA) are among the most frequent cause of perioperative anaphylaxis. Recently, it has been shown that NMBA may activate mast cells independently from IgE antibodies via the human Mas-related G-protein-coupled receptor member X2 (MRGPRX2). In light of this new insight into the patho-mechanism of pseudo-allergic adverse drug reactions, in which as drug-receptor interaction results in anaphylaxis like symptoms, we critically reviewed the literature on NMBA-induced perioperative anaphylaxis. We challenge the dogma that NMBA mainly cause IgE-mediated anaphylaxis via an IgE-mediated mechanism, which is based on studies that consider positive skin test to be specific for IgE-mediated hypersensitivity. Finally, we discuss the question whether MRGPRX2 mediated pseudo-allergic reactions should be re-classified as type A adverse reactions.

  8. Innate immunity and adjuvants

    OpenAIRE

    Akira, Shizuo

    2011-01-01

    Innate immunity was for a long time considered to be non-specific because the major function of this system is to digest pathogens and present antigens to the cells involved in acquired immunity. However, recent studies have shown that innate immunity is not non-specific, but is instead sufficiently specific to discriminate self from pathogens through evolutionarily conserved receptors, designated Toll-like receptors (TLRs). Indeed, innate immunity has a crucial role in early host defence aga...

  9. Kidney and innate immunity.

    Science.gov (United States)

    Wang, Ying-Hui; Zhang, Yu-Gen

    2017-03-01

    Innate immune system is an important modulator of the inflammatory response during infection and tissue injury/repair. The kidney as a vital organ with high energy demand plays a key role in regulating the disease related metabolic process. Increasing research interest has focused on the immune pathogenesis of many kidney diseases. However, innate immune cells such as dendritic cells, macrophages, NK cells and a few innate lymphocytes, as well as the complement system are essential for renal immune homeostasis and ensure a coordinated balance between tissue injury and regeneration. The innate immune response provides the first line of host defense initiated by several classes of pattern recognition receptors (PRRs), such as membrane-bound Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), together with inflammasomes responsible for early innate immune response. Although the innate immune system is well studied, the research on the detailed relationship between innate immunity and kidney is still very limited. In this review, we will focus on the innate immune sensing system in renal immune homeostasis, as well as the corresponding pathogenesis of many kidney diseases. The pivotal roles of innate immunity in renal injury and regeneration with special emphasis on kidney disease related immunoregulatory mechanism are also discussed. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  10. MyD88 and STING Signaling Pathways Are Required for IRF3-Mediated IFN-β Induction in Response to Brucella abortus Infection

    Science.gov (United States)

    de Almeida, Leonardo A.; Carvalho, Natalia B.; Oliveira, Fernanda S.; Lacerda, Thais L. S.; Vasconcelos, Anilton C.; Nogueira, Lucas; Bafica, Andre; Silva, Aristóbolo M.; Oliveira, Sergio C.

    2011-01-01

    Type I interferons (IFNs) are cytokines that orchestrate diverse immune responses to viral and bacterial infections. Although typically considered to be most important molecules in response to viruses, type I IFNs are also induced by most, if not all, bacterial pathogens. In this study, we addressed the role of type I IFN signaling during Brucella abortus infection, a facultative intracellular bacterial pathogen that causes abortion in domestic animals and undulant fever in humans. Herein, we have shown that B. abortus induced IFN-β in macrophages and splenocytes. Further, IFN-β induction by Brucella was mediated by IRF3 signaling pathway and activates IFN-stimulated genes via STAT1 phosphorylation. In addition, IFN-β expression induced by Brucella is independent of TLRs and TRIF signaling but MyD88-dependent, a pathway not yet described for Gram-negative bacteria. Furthermore, we have identified Brucella DNA as the major bacterial component to induce IFN-β and our study revealed that this molecule operates through a mechanism dependent on RNA polymerase III to be sensed probably by an unknown receptor via the adaptor molecule STING. Finally, we have demonstrated that IFN-αβR KO mice are more resistant to infection suggesting that type I IFN signaling is detrimental to host control of Brucella. This resistance phenotype is accompanied by increased IFN-γ and NO production by IFN-αβR KO spleen cells and reduced apoptosis. PMID:21829705

  11. MyD88 and STING signaling pathways are required for IRF3-mediated IFN-β induction in response to Brucella abortus infection.

    Directory of Open Access Journals (Sweden)

    Leonardo A de Almeida

    Full Text Available Type I interferons (IFNs are cytokines that orchestrate diverse immune responses to viral and bacterial infections. Although typically considered to be most important molecules in response to viruses, type I IFNs are also induced by most, if not all, bacterial pathogens. In this study, we addressed the role of type I IFN signaling during Brucella abortus infection, a facultative intracellular bacterial pathogen that causes abortion in domestic animals and undulant fever in humans. Herein, we have shown that B. abortus induced IFN-β in macrophages and splenocytes. Further, IFN-β induction by Brucella was mediated by IRF3 signaling pathway and activates IFN-stimulated genes via STAT1 phosphorylation. In addition, IFN-β expression induced by Brucella is independent of TLRs and TRIF signaling but MyD88-dependent, a pathway not yet described for Gram-negative bacteria. Furthermore, we have identified Brucella DNA as the major bacterial component to induce IFN-β and our study revealed that this molecule operates through a mechanism dependent on RNA polymerase III to be sensed probably by an unknown receptor via the adaptor molecule STING. Finally, we have demonstrated that IFN-αβR KO mice are more resistant to infection suggesting that type I IFN signaling is detrimental to host control of Brucella. This resistance phenotype is accompanied by increased IFN-γ and NO production by IFN-αβR KO spleen cells and reduced apoptosis.

  12. Approaching archetypes: reconsidering innateness.

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    Goodwyn, Erik

    2010-09-01

    The question of innateness has hounded Jungian psychology since Jung originally postulated the archetype as an a priori structure within the psyche. During his life and after his death he was continually accused of Lamarckianism and criticized for his theory that the archetypes existed as prior structures. More recently, with the advent of genetic research and the human genome project, the idea that psychological structures can be innate has come under even harsher criticism even within Jungian thought. There appears to be a growing consensus that Jung's idea of innate psychological structures was misguided, and that perhaps the archetype-as-such should be abandoned for more developmental and 'emergent' theories of the psyche. The purpose of this essay is to question this conclusion, and introduce some literature on psychological innateness that appears relevant to this discussion. © 2010, The Society of Analytical Psychology.

  13. Innate Immunity and Neurodegeneration.

    Science.gov (United States)

    Labzin, Larisa I; Heneka, Michael T; Latz, Eicke

    2018-01-29

    The innate immune system plays diverse roles in health and disease. It represents the first line of defense against infection and is involved in tissue repair, wound healing, and clearance of apoptotic cells and cellular debris. Excessive or nonresolving innate immune activation can lead to systemic or local inflammatory complications and cause or contribute to the development of inflammatory diseases. In the brain, microglia represent the key innate immune cells, which are involved in brain development, brain maturation, and homeostasis. Impaired microglial function, either through aberrant activation or decreased functionality, can occur during aging and during neurodegeneration, and the resulting inflammation is thought to contribute to neurodegenerative diseases. This review highlights recent advances in our understanding of the influence of innate immunity on neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease.

  14. [Innate immunity and transplantation].

    Science.gov (United States)

    Ponticelli, Claudio

    2015-01-01

    Innate immunity is the first barrier against pathogen infection and has also the important function of activating the adaptive immunity. The receptors of innate immunity, such as toll-like receptors and other receptors, recognize as danger signals the molecular patterns of pathogens as well as those of endogenous molecules released by dying cells. The information is transmitted to adapter proteins that, through a chain of kinases that translate the signal to transcription factors regulating inflammatory genes. In the inflammatory milieu dendritic cells become mature, intercept the antigen and migrate to lymphoid organs where they present the antigen to naïve T cells. Complement also exerts an important role of bridge between innate and adaptive immunity. In donor-deceased kidney transplantation, the innate immunity is triggered in the donor by brain death and is aggravated by the cold ischemia and even more by reperfusion. Once activated, innate immunity produces a local inflammatory environment leading to dendritic cell maturation and complement activation. Dendritic cells present the alloantigen to T cells and induce their differentiation towards effector Th1 and Th17 while inhibiting Th2 and T regulatory cells. A main goal of the current research in transplantation is to obtain an immunological tolerance. Experimental studies showed the possibility of inducing operative tolerance in murine models and even in primates with the infusion of regulatory dendritic cells. However, there are no data with this technique in clinical transplantation.

  15. Emerging Concepts in Innate Immunity.

    Science.gov (United States)

    Pelka, Karin; De Nardo, Dominic

    2018-01-01

    This review introduces recent concepts in innate immunity highlighting some of the latest exciting findings. These include: the discovery of the initiator of pyroptosis, Gasdermin D, and mechanisms of inflammatory caspases in innate immune signaling; the formation of oligomeric signalosomes downstream of innate immune receptors; mechanisms that shape innate immune responses, such as cellular homeostasis, cell metabolism, and pathogen viability; rapid methods of cell-to-cell communication; the interplay between the host and its microbiome and the concept of innate immunological memory. Furthermore, we discuss open questions and illustrate how technological advances, such as CRISPR/Cas9, may provide important answers for outstanding questions in the field of innate immunity.

  16. Tick Innate Immunity.

    Czech Academy of Sciences Publication Activity Database

    Kopáček, Petr; Hajdušek, Ondřej; Burešová, Veronika; Daffre, S.

    2010-01-01

    Roč. 708, - (2010), 137-162 ISSN 0065-2598 R&D Projects: GA ČR GAP506/10/2136; GA MŠk(CZ) LC06009 Institutional research plan: CEZ:AV0Z60220518 Keywords : tick * pathogen transmission * innate immunity Subject RIV: EC - Immunology Impact factor: 1.379, year: 2010

  17. Adaptation in the innate immune system and heterologous innate immunity.

    Science.gov (United States)

    Martin, Stefan F

    2014-11-01

    The innate immune system recognizes deviation from homeostasis caused by infectious or non-infectious assaults. The threshold for its activation seems to be established by a calibration process that includes sensing of microbial molecular patterns from commensal bacteria and of endogenous signals. It is becoming increasingly clear that adaptive features, a hallmark of the adaptive immune system, can also be identified in the innate immune system. Such adaptations can result in the manifestation of a primed state of immune and tissue cells with a decreased activation threshold. This keeps the system poised to react quickly. Moreover, the fact that the innate immune system recognizes a wide variety of danger signals via pattern recognition receptors that often activate the same signaling pathways allows for heterologous innate immune stimulation. This implies that, for example, the innate immune response to an infection can be modified by co-infections or other innate stimuli. This "design feature" of the innate immune system has many implications for our understanding of individual susceptibility to diseases or responsiveness to therapies and vaccinations. In this article, adaptive features of the innate immune system as well as heterologous innate immunity and their implications are discussed.

  18. Defensins in innate immunity.

    Science.gov (United States)

    Zhao, Le; Lu, Wuyuan

    2014-01-01

    Defensins are a major family of antimicrobial peptides expressed predominantly in neutrophils and epithelial cells, and play important roles in innate immune defense against infectious pathogens. Their biological functions in and beyond innate immunity, structure and activity relationships, mechanisms of action, and therapeutic potential continue to be interesting research topics. This review examines recent progress in our understanding of alpha and theta-defensins - the two structural classes composed of members of myeloid origin. A novel mode of antibacterial action is described for human enteric alpha-defensin 6, which forms structured nanonets to entrap bacterial pathogens and protect against bacterial invasion of the intestinal epithelium. The functional multiplicity and mechanistic complexity of defensins under different experimental conditions contribute to a debate over the role of enteric alpha-defensins in mucosal immunity against HIV-1 infection. Contrary to common belief, hydrophobicity rather than cationicity plays a dominant functional role in the action of human alpha-defensins; hydrophobicity-mediated high-order assembly endows human alpha-defensins with an extraordinary ability to acquire structural diversity and functional versatility. Growing evidence suggests that theta-defensins offer the best opportunity for therapeutic development as a novel class of broadly active anti-infective and anti-inflammatory agents. Defensins are the 'Swiss army knife' in innate immunity against microbial pathogens. Their modes of action are often reminiscent of the story of 'The Blind Men and the Elephant'. The functional diversity and mechanistic complexity, as well as therapeutic potential of defensins, will continue to attract attention to this important family of antimicrobial peptides.

  19. Curating the innate immunity interactome.

    LENUS (Irish Health Repository)

    Lynn, David J

    2010-01-01

    The innate immune response is the first line of defence against invading pathogens and is regulated by complex signalling and transcriptional networks. Systems biology approaches promise to shed new light on the regulation of innate immunity through the analysis and modelling of these networks. A key initial step in this process is the contextual cataloguing of the components of this system and the molecular interactions that comprise these networks. InnateDB (http:\\/\\/www.innatedb.com) is a molecular interaction and pathway database developed to facilitate systems-level analyses of innate immunity.

  20. Hepatocytes: a key cell type for innate immunity.

    Science.gov (United States)

    Zhou, Zhou; Xu, Ming-Jiang; Gao, Bin

    2016-05-01

    Hepatocytes, the major parenchymal cells in the liver, play pivotal roles in metabolism, detoxification, and protein synthesis. Hepatocytes also activate innate immunity against invading microorganisms by secreting innate immunity proteins. These proteins include bactericidal proteins that directly kill bacteria, opsonins that assist in the phagocytosis of foreign bacteria, iron-sequestering proteins that block iron uptake by bacteria, several soluble factors that regulate lipopolysaccharide signaling, and the coagulation factor fibrinogen that activates innate immunity. In this review, we summarize the wide variety of innate immunity proteins produced by hepatocytes and discuss liver-enriched transcription factors (e.g. hepatocyte nuclear factors and CCAAT/enhancer-binding proteins), pro-inflammatory mediators (e.g. interleukin (IL)-6, IL-22, IL-1β and tumor necrosis factor-α), and downstream signaling pathways (e.g. signal transducer and activator of transcription factor 3 and nuclear factor-κB) that regulate the expression of these innate immunity proteins. We also briefly discuss the dysregulation of these innate immunity proteins in chronic liver disease, which may contribute to an increased susceptibility to bacterial infection in patients with cirrhosis.

  1. Innate and adaptive immunosenescence.

    Science.gov (United States)

    Agarwal, Shradha; Busse, Paula J

    2010-03-01

    To review the effect of increasing age on the immune system and some of its clinical implications. MEDLINE and PubMed searches were performed cross-referencing the keywords immunosenescence, aging, and immunity. Articles were reviewed for additional citations. Articles were reviewed and selected based on relevance to subject matter. The study of immunosenescence is complex and not completely understood. Aging affects both the innate and adaptive arms of the immune response. With increased age, there may be a decrease in phagocytosis, alteration of cellular migration, changes in cell populations and numbers, and a decreased ability to produce specific antibodies. Clinically, these changes potentially increase morbidity and mortality in elderly individuals through an increased rate of infections, malignancy, and autoimmunity. The process of aging is accompanied by diverse changes in immunity. Several therapeutic approaches are under investigation, including cytokine therapy, hormonal replacement, antioxidant supplementation, and caloric restriction, to attenuate or potentially reverse immunosenescence.

  2. Innate immune evasion by filoviruses.

    Science.gov (United States)

    Basler, Christopher F

    2015-05-01

    Ebola viruses and Marburg viruses, members of the filovirus family, cause severe hemorrhagic fever. The ability of these viruses to potently counteract host innate immune responses is thought to be an important component of viral pathogenesis. Several mechanisms of filoviral innate immune evasion have been defined and are reviewed here. These mechanisms include suppression of type I interferon (IFN) production; inhibition of IFN-signaling and mechanisms that either prevent cell stress responses or allow the virus to replicate in the face of such responses. A greater understanding of these innate immune evasion mechanisms may suggest novel therapeutic approaches for these deadly pathogens. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Targeting Innate Immunity for Type 1 Diabetes Prevention.

    Science.gov (United States)

    Needell, James C; Zipris, Danny

    2017-09-27

    Despite immense research efforts, type 1 diabetes (T1D) remains an autoimmune disease without a known trigger or approved intervention. Over the last three decades, studies have primarily focused on delineating the role of the adaptive immune system in the mechanism of T1D. The discovery of Toll-like receptors in the 1990s has advanced the knowledge on the role of the innate immune system in host defense as well as mechanisms that regulate adaptive immunity including the function of autoreactive T cells. Recent investigations suggest that inflammation plays a key role in promoting a large number of autoimmune disorders including T1D. Data from the LEW1.WR1 rat model of virus-induced disease and the RIP-B7.1 mouse model of diabetes suggest that innate immune signaling plays a key role in triggering disease progression. There is also evidence that innate immunity may be involved in the course of T1D in humans; however, a small number of clinical trials have shown that interfering with the function of the innate immune system following disease onset exerts only a modest effect on β-cell function. The data implying that innate immune pathways are linked with mechanisms of islet autoimmunity hold great promise for the identification of novel disease pathways that may be harnessed for clinical intervention. Nevertheless, more work needs to be done to better understand mechanisms by which innate immunity triggers β-cell destruction and assess the therapeutic value in blocking innate immunity for diabetes prevention.

  4. The Critical Role of Innate Immunity in Kidney Transplantation.

    Science.gov (United States)

    Cucchiari, David; Podestà, Manuel Alfredo; Ponticelli, Claudio

    2016-01-01

    For a long time now, kidney transplant rejection has been considered the consequence of either cellular or antibody-mediated reaction as a part of adaptive immunity response. The role of innate immunity, on the other hand, had been unclear for many years and was thought to be only ancillary. There is now consistent evidence that innate immune response is a condition necessary to activate the machinery of rejection. In this setting, the communication between antigen-presenting cells and T lymphocytes is of major importance. Indeed, T cells are unable to cause rejection if innate immunity is not activated. This field is currently being explored and several experiments in animal models have proved that blocking innate immunity activation can promote tolerance of the graft instead of rejection. The aim of this review is to systematically describe all the steps of innate immunity response in kidney transplant rejection, from antigen recognition to T-cells activation, with a focus on clinical consequences and possible future perspectives. © 2016 S. Karger AG, Basel.

  5. Innate immune evasion by filoviruses

    OpenAIRE

    Basler, Christopher F.

    2015-01-01

    Ebola viruses and Marburg viruses, members of the filovirus family, cause severe hemorrhagic fever. The ability of these viruses to potently counteract host innate immune responses is thought to be an important component of viral pathogenesis. Several mechanisms of filoviral innate immune evasion have been defined and are reviewed here. These mechanisms inclue suppression of type I interferon (IFN) production; inhibition of IFN-signaling and mechanisms that either prevent cell stress response...

  6. 'Towards a Conceptual Framework for Innate Immunity'

    OpenAIRE

    Twycross, Jamie; Aickelin, Uwe

    2005-01-01

    Innate immunity now occupies a central role in immunology. However, artificial immune system models have largely been inspired by adaptive not innate immunity. This paper reviews the biological principles and properties of innate immunity and, adopting a conceptual framework, asks how these can be incorporated into artificial models. The aim is to outline a meta-framework for models of innate immunity.

  7. Intercellular communication for innate immunity.

    Science.gov (United States)

    Nguyen, Tan A; Pang, Ken C; Masters, Seth L

    2017-06-01

    An effective innate immune response relies on the detection of pathogen associated molecular patterns (PAMPs) by various host pattern recognition receptors (PRRs) that result in the production of pro-inflammatory cytokines and chemokines. Viruses and bacteria have co-evolved with the immune system and developed multiple strategies to usurp or circumvent host machinery and blunt the innate immune response in infected cells. Recently, it has become apparent that infected or dying cells can transmit PAMPs and host PRR signalling proteins to uninfected bystander cells to thereby bypass pathogen evasion strategies, and potentiate innate immune signalling. This bystander activation of innate immunity represents an alternative method by which the host can control infections via cell-to-cell communication. In this review, we discuss what is currently known about the intercellular transfer of pathogen- or host-derived RNA, DNA and proteins from infected cells to neighbouring cells and how this impacts on host innate immunity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Alcohol, aging, and innate immunity.

    Science.gov (United States)

    Boule, Lisbeth A; Kovacs, Elizabeth J

    2017-07-01

    The global population is aging: in 2010, 8% of the population was older than 65 y, and that is expected to double to 16% by 2050. With advanced age comes a heightened prevalence of chronic diseases. Moreover, elderly humans fair worse after acute diseases, namely infection, leading to higher rates of infection-mediated mortality. Advanced age alters many aspects of both the innate and adaptive immune systems, leading to impaired responses to primary infection and poor development of immunologic memory. An often overlooked, yet increasingly common, behavior in older individuals is alcohol consumption. In fact, it has been estimated that >40% of older adults consume alcohol, and evidence reveals that >10% of this group is drinking more than the recommended limit by the National Institute on Alcohol Abuse and Alcoholism. Alcohol consumption, at any level, alters host immune responses, including changes in the number, phenotype, and function of innate and adaptive immune cells. Thus, understanding the effect of alcohol ingestion on the immune system of older individuals, who are already less capable of combating infection, merits further study. However, there is currently almost nothing known about how drinking alters innate immunity in older subjects, despite innate immune cells being critical for host defense, resolution of inflammation, and maintenance of immune homeostasis. Here, we review the effects of aging and alcohol consumption on innate immune cells independently and highlight the few studies that have examined the effects of alcohol ingestion in aged individuals. © Society for Leukocyte Biology.

  9. Population Blocks.

    Science.gov (United States)

    Smith, Martin H.

    1992-01-01

    Describes an educational game called "Population Blocks" that is designed to illustrate the concept of exponential growth of the human population and some potential effects of overpopulation. The game material consists of wooden blocks; 18 blocks are painted green (representing land), 7 are painted blue (representing water); and the remaining…

  10. Psoriasis: dysregulation of innate immunity

    NARCIS (Netherlands)

    Bos, J. D.; de Rie, M. A.; Teunissen, M. B. M.; Piskin, G.

    2005-01-01

    The current understanding of the function of natural killer (NK) T cells in innate immunity and their potential to control acquired specific immunity, as well as the remarkable efficacy of antitumour necrosis factor-alpha biological treatments in psoriasis, forces us to refine the current T-cell

  11. Ambient ozone and pulmonary innate immunity

    Science.gov (United States)

    Al-Hegelan, Mashael; Tighe, Robert M.; Castillo, Christian; Hollingsworth, John W.

    2013-01-01

    Ambient ozone is a criteria air pollutant that impacts both human morbidity and mortality. The effect of ozone inhalation includes both toxicity to lung tissue and alteration of the host immunologic response. The innate immune system facilitates immediate recognition of both foreign pathogens and tissue damage. Emerging evidence supports that ozone can modify the host innate immune response and that this response to inhaled ozone is dependent on genes of innate immunity. Improved understanding of the complex interaction between environmental ozone and host innate immunity will provide fundamental insight into the pathogenesis of inflammatory airways disease. We review the current evidence supporting that environmental ozone inhalation: (1) modifies cell types required for intact innate immunity, (2) is partially dependent on genes of innate immunity, (3) primes pulmonary innate immune responses to LPS, and (4) contributes to innate-adaptive immune system cross-talk. PMID:21132467

  12. HIV-1 infection of macrophages is dependent on evasion of innate immune cellular activation.

    Science.gov (United States)

    Tsang, Jhen; Chain, Benjamin M; Miller, Robert F; Webb, Benjamin L J; Barclay, Wendy; Towers, Greg J; Katz, David R; Noursadeghi, Mahdad

    2009-11-13

    The cellular innate immune response to HIV-1 is poorly characterized. In view of HIV-1 tropism for macrophages, which can be activated via pattern recognition receptors to trigger antimicrobial defences, we investigated innate immune responses to HIV-1 by monocyte-derived macrophages. In a model of productive HIV-1 infection, cellular innate immune responses to HIV-1 were investigated, at the level of transcription factor activation, specific gene expression and genome-wide transcriptional profiling. In addition, the viral determinants of macrophage responses and the physiological effect of innate immune cellular activation on HIV-1 replication were assessed. Productive HIV-1 infection did not activate nuclear factor-kappaB and interferon regulatory factor 3 transcription factors or interferon gene expression (IFN) and caused remarkably small changes to the host-cell transcriptome, with no evidence of inflammatory or IFN signatures. Evasion of IFN induction was not dependent on HIV-1 envelope-mediated cellular entry, inhibition by accessory proteins or reverse transcription of ssRNA that may reduce innate immune cellular activation by viral RNA. Furthermore, IFNbeta priming did not sensitize responses to HIV-1. Importantly, exogenous IFNbeta or stimulation with the RNA analogue poly I:C to simulate innate immune activation invoked HIV-1 restriction. We conclude that macrophages lack functional pattern recognition receptors for this virus and that HIV-1 tropism for macrophages helps to establish a foothold in the host without triggering innate immune cellular activation, which would otherwise block viral infection effectively.

  13. Adiponectin: a versatile player of innate immunity.

    Science.gov (United States)

    Luo, Yan; Liu, Meilian

    2016-04-01

    Adiponectin acts as a key regulator of the innate immune system and plays a major role in the progression of inflammation and metabolic disorders. Macrophages and monocytes are representative components of the innate immune system, and their proliferation, plasticity, and polarization are a key component of metabolic adaption. Innate-like lymphocytes such as group 2 innate lymphoid cells (ILC2s), natural killer T (NKT) cells, and gamma delta T (γδ T) cells are also members of the innate immune system and play important roles in the development of obesity and its related diseases. Adiponectin senses metabolic stress and modulates metabolic adaption by targeting the innate immune system under physiological and pathological conditions. Defining the mechanisms underlying the role of adiponectin in regulating innate immunity is crucial to adiponectin-based therapeutic intervention. © The Author (2016). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

  14. The Epitranscriptome and Innate Immunity.

    Directory of Open Access Journals (Sweden)

    Mary A O'Connell

    2015-12-01

    Full Text Available Our knowledge of the variety and abundances of RNA base modifications is rapidly increasing. Modified bases have critical roles in tRNAs, rRNAs, translation, splicing, RNA interference, and other RNA processes, and are now increasingly detected in all types of transcripts. Can new biological principles associated with this diversity of RNA modifications, particularly in mRNAs and long non-coding RNAs, be identified? This review will explore this question by focusing primarily on adenosine to inosine (A-to-I RNA editing by the adenine deaminase acting on RNA (ADAR enzymes that have been intensively studied for the past 20 years and have a wide range of effects. Over 100 million adenosine to inosine editing sites have been identified in the human transcriptome, mostly in embedded Alu sequences that form potentially innate immune-stimulating dsRNA hairpins in transcripts. Recent research has demonstrated that inosine in the epitranscriptome and ADAR1 protein establish innate immune tolerance for host dsRNA formed by endogenous sequences. Innate immune sensors that detect viral nucleic acids are among the readers of epitranscriptome RNA modifications, though this does preclude a wide range of other modification effects.

  15. Recall features and allorecognition in innate immunity.

    Science.gov (United States)

    Uehara, Hirofumi; Minami, Koichiro; Quante, Markus; Nian, Yeqi; Heinbokel, Timm; Azuma, Haruhito; Khal, Abdala El; Tullius, Stefan G

    2018-01-01

    Alloimmunity traditionally distinguishes short-lived, rapid and nonspecific innate immune responses from adaptive immune responses that are characterized by a highly specific response initiated in a delayed fashion. Key players of innate immunity such as natural killer (NK) cells and macrophages present the first-line defence of immunity. The concept of unspecific responses in innate immunity has recently been challenged. The discovery of pattern recognition receptors (PRRs) has demonstrated that innate immune cells respond in a semi-specific fashion through the recognition of pathogen-associated molecular patterns (PAMPs) representing conserved molecular structures shared by large groups of microorganisms. Although immunological memory has generally been considered as exclusive to adaptive immunity, recent studies have demonstrated that innate immune cells have the potential to acquire memory. Here, we discuss allospecific features of innate immunity and their relevance in transplantation. © 2017 Steunstichting ESOT.

  16. Innate immunity against hepatitis C virus.

    Science.gov (United States)

    Xu, Yongfen; Zhong, Jin

    2016-10-01

    Hepatitis C virus (HCV) infection tends persistent and causes chronic liver diseases, including inflammation, cirrhosis and hepatocellular carcinoma. Innate immune responses triggered by HCV infection, particularly the production of interferons and pro-inflammatory cytokines, shape the early host antiviral defense, and orchestrate subsequent HCV-specific adaptive immunity. Host has evolved multifaceted means to sense HCV infection to induce innate immune responses, whereas HCV has also developed elaborate strategies to evade immune attack. Recent studies in the field have provided many new insights into the interplay of HCV and innate immunity. In this review, we summarized these recent advances, focusing on pathogen recognition by innate sensors, newly discovered anti-HCV innate effectors and new viral strategies to evade innate immunity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Innate immunity in the pathogenesis of psoriasis.

    LENUS (Irish Health Repository)

    Sweeney, Cheryl M

    2011-12-01

    Psoriasis is a common, immune-mediated inflammatory skin disorder. T helper(h)1 and Th17 lymphocytes contribute to the pathogenesis of psoriasis through the release of inflammatory cytokines that promote further recruitment of immune cells, keratinocyte proliferation and sustained inflammation. The innate immune system is the first line of defence against infection and plays a crucial role in the initiation of the adaptive immune response. The presence of innate immune cells and their products in psoriatic skin plaques suggests a role for innate immunity in this disease. In addition, the innate immune system can direct the development of pathogenic Th cells in psoriasis. In this article, we will summarise the role of the innate immune system in psoriasis with particular emphasis on the role of cytokines, signalling pathways and cells of the innate immune system.

  18. Innate Immunity and Breast Milk

    Directory of Open Access Journals (Sweden)

    Nicole Theresa Cacho

    2017-05-01

    Full Text Available Human milk is a dynamic source of nutrients and bioactive factors; unique in providing for the human infant’s optimal growth and development. The growing infant’s immune system has a number of developmental immune deficiencies placing the infant at increased risk of infection. This review focuses on how human milk directly contributes to the infant’s innate immunity. Remarkable new findings clarify the multifunctional nature of human milk bioactive components. New research techniques have expanded our understanding of the potential for human milk’s effect on the infant that will never be possible with milk formulas. Human milk microbiome directly shapes the infant’s intestinal microbiome, while the human milk oligosaccharides drive the growth of these microbes within the gut. New techniques such as genomics, metabolomics, proteomics, and glycomics are being used to describe this symbiotic relationship. An expanded role for antimicrobial proteins/peptides within human milk in innate immune protection is described. The unique milieu of enhanced immune protection with diminished inflammation results from a complex interaction of anti-inflammatory and antioxidative factors provided by human milk to the intestine. New data support the concept of mucosal-associated lymphoid tissue and its contribution to the cellular content of human milk. Human milk stem cells (hMSCs have recently been discovered. Their direct role in the infant for repair and regeneration is being investigated. The existence of these hMSCs could prove to be an easily harvested source of multilineage stem cells for the study of cancer and tissue regeneration. As the infant’s gastrointestinal tract and immune system develop, there is a comparable transition in human milk over time to provide fewer immune factors and more calories and nutrients for growth. Each of these new findings opens the door to future studies of human milk and its effect on the innate immune system

  19. Interactions between the microbiota and innate and innate-like lymphocytes.

    Science.gov (United States)

    Constantinides, Michael G

    2018-03-01

    The microbiota, which consists of commensal bacteria, fungi, and viruses, limits the colonization of pathogens at barrier tissues and promotes immune homeostasis. The latter is accomplished through the induction and regulation of both innate and adaptive immune responses. Innate lymphocytes, which include the type-1 innate lymphoid cell (ILC1), NK cell, type-2 innate lymphoid cell (ILC2), type-3 innate lymphoid cell (ILC3), and lymphoid tissue inducer (LTi) cell populations, and innate-like lymphocytes, such as NKT cells, mucosal-associated invariant T (MAIT) cells, and γδ T cells, are uniquely capable of responding to the microbiota due to their tissue localization and rapid primary responses. In turn, through their effector functions, these lymphocyte populations modulate the composition of the microbiota and maintain the segregation of commensals. This review will focus on how innate and innate-like lymphocytes mediate the crosstalk with the microbiome. ©2017 Society for Leukocyte Biology.

  20. Nipah and hendra virus interactions with the innate immune system.

    Science.gov (United States)

    Basler, Christopher F

    2012-01-01

    Nipah virus and Hendra virus are related, highly pathogenic paramyxoviruses with unusually broad host ranges. Henipaviruses encode several proteins that block innate immune responses, and these are likely to serve as virulence factors. Specfically, four virus-encoded proteins, the phosphoprotein (P), the V protein, the W protein, and the C protein have each been demonstrated to counteract aspects of the interferon (IFN)-α/β response, a key component of the innate immune response to virus infection. The available data indicate that V and W can inhibit the production of IFNα/β in response to various stimuli, while the P, V, and W proteins also block the ability of IFNs to signal and induce an antiviral state in cells. The C protein also inhibits the antiviral effects of IFNα/β by a poorly characterized mechanism. Reverse genetics systems, which allow the generation of recombinant viruses bearing specific mutations, have demonstrated the importance of the viral IFN-antagonists for replication. With these systems in hand, the field is now poised to define how specific viral IFN-antagonist functions influence viral pathogenesis.

  1. Self-consuming innate immunity in Arabidopsis

    DEFF Research Database (Denmark)

    Hofius, Daniel; Mundy, John; Petersen, Morten

    2009-01-01

    . However, it has been unclear by which molecular mechanisms plants execute PCD during innate immune responses. We recently examined HR PCD in autophagy-deficient Arabidopsis knockout mutants (atg) and find that PCD conditioned by one class of plant innate immune receptors is suppressed in atg mutants...

  2. Neonatal innate immunity - A translational perspective

    NARCIS (Netherlands)

    Belderbos, M.E.

    2012-01-01

    Human newborns are highly susceptible to infections, which appears to be due to immaturity of the neonatal innate immune system. At birth, neonatal innate immune responses are characterized by decreased Th1-polarizing responses, whereas generation of Th2-polarizing and regulatory responses is

  3. Psoriasis, innate immunity, and gene pools

    NARCIS (Netherlands)

    Bos, Jan D.

    2007-01-01

    Recently, emphasis has shifted from T cells to innate (natural) immunity as the possible major culprit in psoriasis. All known elements of innate immune responses are up-regulated in psoriasis lesions, which must have a polygenetic origin. We hypothesize that urbanized populations have been under

  4. [Role of innate immunity in tolerance induction].

    Science.gov (United States)

    Dolgikh, M S

    2015-01-01

    This review considers the role of innate immunity in mechanisms of transplant tolerance and rejection, analyse the role of innate immunity cells (dendritic cells-DC, NK, must and other cells) in these processes, and the pathes of creation of tolerogenic DC for transplant rejection therapy and tolerance.

  5. Innate immunity in the nervous system

    NARCIS (Netherlands)

    Ramaglia, V.; Baas, F.

    2009-01-01

    The complement (C) system plays a central role in innate immunity and bridges innate and adaptive immune responses. A fine balance of C activation and regulation mediates the elimination of invading pathogens and the protection of the host from excessive C deposition on healthy tissues. If this

  6. Innate immunity in vertebrates: an overview.

    Science.gov (United States)

    Riera Romo, Mario; Pérez-Martínez, Dayana; Castillo Ferrer, Camila

    2016-06-01

    Innate immunity is a semi-specific and widely distributed form of immunity, which represents the first line of defence against pathogens. This type of immunity is critical to maintain homeostasis and prevent microbe invasion, eliminating a great variety of pathogens and contributing with the activation of the adaptive immune response. The components of innate immunity include physical and chemical barriers, humoral and cell-mediated components, which are present in all jawed vertebrates. The understanding of innate defence mechanisms in non-mammalian vertebrates is the key to comprehend the general picture of vertebrate innate immunity and its evolutionary history. This is also essential for the identification of new molecules with applications in immunopharmacology and immunotherapy. In this review, we describe and discuss the main elements of vertebrate innate immunity, presenting core findings in this field and identifying areas that need further investigation. © 2016 John Wiley & Sons Ltd.

  7. Innate immunity to Candida albicans

    Directory of Open Access Journals (Sweden)

    Yusuke Kiyoura

    2015-08-01

    Full Text Available Candida albicans is not a pathogen in healthy individuals, but can cause severe systemic candidiasis in immunocompromised patients. C. albicans has various virulence factors and activates the innate immune system. Specifically, C. albicans induces proinflammatory cytokine production in various cell types via many receptors, such as Toll-like receptors (TLRs and C-type lectin receptors (CLRs. This microorganism also promotes phagocytosis via CLRs on macrophages. In a previous study, we found that C. albicans induces the production of galectin-3, which is a known CLR that kills C. albicans. This review indicates that the use of mouthwash containing an antimicrobial peptide or protein might be a useful new oral care method for the prevention of oral candidiasis.

  8. Innate Interferons Regulate CNS Inflammation

    DEFF Research Database (Denmark)

    Dieu, Ruthe; Khorooshi, Reza M. H.; Mariboe, Anne

    Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) whose pathology is characterised by demyelination and axonal damage. This results from interplay between CNS-resident glia, infiltrating leukocytes and a plethora of cytokines and chemokines. Currently......, there is no cure for MS, however a standard first-line therapy is recombinant interferon (IFN)-beta. IFN-beta belongs to the family of type I IFNs, which also include IFN-alpha. These engage to one common receptor, IFNAR. Type I IFNs can be induced by several innate immune receptors, including toll-like receptors...... mass homeostasis. Whether RANK-signaling is capable of inducing type I IFNs within the CNS has not yet been studied. Preliminary data from IFN-beta-luciferase reporter mice already show that RANK-signaling by intrathecally applied RANKL can induce CNS-endogenous IFN-beta. Experiments in IFN...

  9. Adenoviruses types, cell receptors and local innate cytokines in adenovirus infection.

    Science.gov (United States)

    Chen, Rong-Fu; Lee, Chun-Yi

    2014-01-01

    Adenovirus is a common infectious pathogen in both children and adults. It is a significant cause of morbidity in immunocompetent people living in crowded living conditions and of mortality in immunocompromised hosts. It has more recently become a popular vehicle for gene therapy applications. The host response to wild-type infection and gene therapy vector exposure involves both virus entry receptor and the innate immune systems. Cell-mediated recognition of viruses via capsid components has received significant attention, principally thought to be regulated by the coxsackievirus-adenovirus receptor (CAR), CD46, integrins and heparin sulfate-containing proteoglycans. Antiviral innate immune responses are initiated by the infected cell, which activates the interferon response to block viral replication, while simultaneously releasing chemokines to attract neutrophils and NK cells. This review discusses the innate immune response primarily during wild-type adenovirus infection because this serves as the basis for understanding the response during both natural infection and exposure to adenovirus vectors.

  10. Addiction, adolescence, and innate immune gene induction

    Directory of Open Access Journals (Sweden)

    Fulton T Crews

    2011-04-01

    Full Text Available Repeated drug use/abuse amplifies psychopathology, progressively reducing frontal lobe behavioral control and cognitive flexibility while simultaneously increasing limbic temporal lobe negative emotionality. The period of adolescence is a neurodevelopmental stage characterized by poor behavioral control as well as strong limbic reward and thrill seeking. Repeated drug abuse and/or stress during this stage increase the risk of addiction and elevate activator innate immune signaling in the brain. Nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-κB is a key glial transcription factor that regulates proinflammatory chemokines, cytokines, oxidases, proteases, and other innate immune genes. Induction of innate brain immune gene expression (e.g., NF-κB facilitates negative affect, depression-like behaviors, and inhibits hippocampal neurogenesis. In addition, innate immune gene induction alters cortical neurotransmission consistent with loss of behavioral control. Studies with anti-oxidant, anti-inflammatory, and anti-depressant drugs as well as opiate antagonists link persistent innate immune gene expression to key behavioral components of addiction, e.g. negative affect-anxiety and loss of frontal cortical behavioral control. This review suggests that persistent and progressive changes in innate immune gene expression contribute to the development of addiction. Innate immune genes may represent a novel new target for addiction therapy.

  11. InnateDB: systems biology of innate immunity and beyond—recent updates and continuing curation

    Science.gov (United States)

    Breuer, Karin; Foroushani, Amir K.; Laird, Matthew R.; Chen, Carol; Sribnaia, Anastasia; Lo, Raymond; Winsor, Geoffrey L.; Hancock, Robert E. W.; Brinkman, Fiona S. L.; Lynn, David J.

    2013-01-01

    InnateDB (http://www.innatedb.com) is an integrated analysis platform that has been specifically designed to facilitate systems-level analyses of mammalian innate immunity networks, pathways and genes. In this article, we provide details of recent updates and improvements to the database. InnateDB now contains >196 000 human, mouse and bovine experimentally validated molecular interactions and 3000 pathway annotations of relevance to all mammalian cellular systems (i.e. not just immune relevant pathways and interactions). In addition, the InnateDB team has, to date, manually curated in excess of 18 000 molecular interactions of relevance to innate immunity, providing unprecedented insight into innate immunity networks, pathways and their component molecules. More recently, InnateDB has also initiated the curation of allergy- and asthma-related interactions. Furthermore, we report a range of improvements to our integrated bioinformatics solutions including web service access to InnateDB interaction data using Proteomics Standards Initiative Common Query Interface, enhanced Gene Ontology analysis for innate immunity, and the availability of new network visualizations tools. Finally, the recent integration of bovine data makes InnateDB the first integrated network analysis platform for this agriculturally important model organism. PMID:23180781

  12. InnateDB: systems biology of innate immunity and beyond--recent updates and continuing curation.

    Science.gov (United States)

    Breuer, Karin; Foroushani, Amir K; Laird, Matthew R; Chen, Carol; Sribnaia, Anastasia; Lo, Raymond; Winsor, Geoffrey L; Hancock, Robert E W; Brinkman, Fiona S L; Lynn, David J

    2013-01-01

    InnateDB (http://www.innatedb.com) is an integrated analysis platform that has been specifically designed to facilitate systems-level analyses of mammalian innate immunity networks, pathways and genes. In this article, we provide details of recent updates and improvements to the database. InnateDB now contains >196 000 human, mouse and bovine experimentally validated molecular interactions and 3000 pathway annotations of relevance to all mammalian cellular systems (i.e. not just immune relevant pathways and interactions). In addition, the InnateDB team has, to date, manually curated in excess of 18 000 molecular interactions of relevance to innate immunity, providing unprecedented insight into innate immunity networks, pathways and their component molecules. More recently, InnateDB has also initiated the curation of allergy- and asthma-related interactions. Furthermore, we report a range of improvements to our integrated bioinformatics solutions including web service access to InnateDB interaction data using Proteomics Standards Initiative Common Query Interface, enhanced Gene Ontology analysis for innate immunity, and the availability of new network visualizations tools. Finally, the recent integration of bovine data makes InnateDB the first integrated network analysis platform for this agriculturally important model organism.

  13. Antimicrobial peptides in innate immune responses

    DEFF Research Database (Denmark)

    Sorensen, O.E.; Borregaard, N.; Cole, A.M.

    2008-01-01

    Antimicrobial peptides (AMPs) are ancient effector molecules in the innate immune response of eukaryotes. These peptides are important for the antimicrobial efficacy of phagocytes and for the innate immune response mounted by epithelia of humans and other mammals. AMPs are generated either by de...... novo synthesis or by proteolytic cleavage from antimicrobially inactive proproteins. Studies of human diseases and animal studies have given important clues to the in vivo role of AMPs. It is now evident that dysregulation of the generation of AMPs in innate immune responses plays a role in certain...

  14. Innate Immune Effectors in Mycobacterial Infection

    Directory of Open Access Journals (Sweden)

    Hiroyuki Saiga

    2011-01-01

    Full Text Available Tuberculosis, which is caused by infection with Mycobacterium tuberculosis (Mtb, remains one of the major bacterial infections worldwide. Host defense against Mtb is mediated by a combination of innate and adaptive immune responses. In the last 15 years, the mechanisms for activation of innate immunity have been elucidated. Toll-like receptors (TLRs have been revealed to be critical for the recognition of pathogenic microorganisms including mycobacteria. Subsequent studies further revealed that NOD-like receptors and C-type lectin receptors are responsible for the TLR-independent recognition of mycobacteria. Several molecules, such as active vitamin D3, secretary leukocyte protease inhibitor, and lipocalin 2, all of which are induced by TLR stimulation, have been shown to direct innate immune responses to mycobacteria. In addition, Irgm1-dependent autophagy has recently been demonstrated to eliminate intracellular mycobacteria. Thus, our understanding of the mechanisms for the innate immune response to mycobacteria is developing.

  15. Roles for Innate Immunity in Combination Immunotherapies.

    Science.gov (United States)

    Moynihan, Kelly D; Irvine, Darrell J

    2017-10-01

    Immunity to infectious agents involves a coordinated response of innate and adaptive immune cells working in concert, with many feed-forward and regulatory interactions between both arms of the immune system. In contrast, many therapeutic strategies to augment immunity against tumors have focused predominantly on stimulation of adaptive immunity. However, a growing appreciation of the potential contributions of innate immune effectors to antitumor immunity, especially in the context of combination immunotherapy, is leading to novel strategies to elicit a more integrated immune response against cancer. Here we review antitumor activities of innate immune cells, mechanisms of their synergy with adaptive immune responses against tumors, and discuss recent studies highlighting the potential of combination therapies recruiting both innate and adaptive immune effectors to eradicate established tumors. Cancer Res; 77(19); 5215-21. ©2017 AACR . ©2017 American Association for Cancer Research.

  16. MAP kinase cascades in Arabidopsis innate immunity

    DEFF Research Database (Denmark)

    Rasmussen, Magnus Wohlfahrt; Roux, Milena Edna; Petersen, Morten

    2012-01-01

    Plant mitogen-activated protein kinase (MAPK) cascades generally transduce extracellular stimuli into cellular responses. These stimuli include the perception of pathogen-associated molecular patterns (PAMPs) by host transmembrane pattern recognition receptors which trigger MAPK-dependent innate ...

  17. Innate Immune Sensing and Response to Influenza

    Science.gov (United States)

    Pulendran, Bali; Maddur, Mohan S.

    2015-01-01

    Influenza viruses pose a substantial threat to human and animal health worldwide. Recent studies in mouse models have revealed an indispensable role for the innate immune system in defense against influenza virus. Recognition of the virus by innate immune receptors in a multitude of cell types activates intricate signaling networks, functioning to restrict viral replication. Downstream effector mechanisms include activation of innate immune cells and, induction and regulation of adaptive immunity. However, uncontrolled innate responses are associated with exaggerated disease, especially in pandemic influenza virus infection. Despite advances in the understanding of innate response to influenza in the mouse model, there is a large knowledge gap in humans, particularly in immunocom-promised groups such as infants and the elderly. We propose here, the need for further studies in humans to decipher the role of innate immunity to influenza virus, particularly at the site of infection. These studies will complement the existing work in mice and facilitate the quest to design improved vaccines and therapeutic strategies against influenza. PMID:25078919

  18. Antagonism of Innate Immunity by Paramyxovirus Accessory Proteins

    Directory of Open Access Journals (Sweden)

    Raychel Chambers

    2009-10-01

    Full Text Available Paramyxovirinae, a subfamily of Paramyxoviridae, are negative strand RNA viruses comprised of many important human and animal pathogens, which share a high degree of genetic and structural homology. The accessory proteins expressed from the P/V/C gene are major factors in the pathogenicity of the viruses, because of their ability to abrogate various facets of type I interferon (IFN induction and signaling. Most of the paramyxoviruses exhibit a commonality in their ability to antagonize innate immunity by blocking IFN induction and the Jak/STAT pathway. However, the manner in which the accessory proteins inhibit the pathway differs among viruses. Similarly, there are variations in the capability of the viruses to counteract intracellular detectors (RNA helicases, mda-5 and RIG-I. Furthermore, a functional specificity in the antagonism of the IFN response has been reported, suggesting that specificity in the circumvention of innate immunity restricts viral host range. Available evidence indicates that paramyxoviruses employ specific strategies to antagonize the IFN response of their specific hosts, which is one of the major factors that determine viral pathogenicity and host range.

  19. Manipulation of the innate immune response by human papillomaviruses.

    Science.gov (United States)

    Hong, Shiyuan; Laimins, Laimonis A

    2017-03-02

    The innate immune response constitutes the first line of defense against infections by pathogens. Successful pathogens such as human papillomaviruses (HPVs) have evolved mechanisms that target several points in these pathways including sensing of viral genomes, blocking the synthesis of interferons and inhibiting the action of JAK/STAT transcription factors. Disruption of these inhibitory mechanisms contributes to the ability of HPVs to establish persistent infections, which is the major etiological factor in the development of anogenital cancers. Interestingly, HPVs also positively activate several members of these pathways such as STAT-5 that are important for their differentiation-dependent life cycle. STAT-5 activation induces the ATM and ATR DNA damage response pathways that play critical roles in HPV genome amplification. Targeting of these pathways by pharmaceuticals can provide novel opportunities to inhibit infections by these important human pathogens. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Vitally important - does early innate immunity predict recruitment and adult innate immunity?

    Science.gov (United States)

    Vermeulen, Anke; Müller, Wendt; Eens, Marcel

    2016-03-01

    The immune system is one of the most important adaptations that has evolved to protect animals from a wide range of pathogens they encounter from early life onwards. During the early developmental period this is particularly true for the innate immunity, as other components of the immune system are, as yet, poorly developed. But innate immunity may not only be crucial for early life survival, but may also have long-lasting effects, for example if early life immunity reflects the functioning of the immune system as a whole. For this reason, we investigated the importance of four constitutive innate immune parameters (natural antibodies, complement activity, concentrations of haptoglobin, and concentrations of nitric oxide) for recruitment in free-living great tits. We compared nestling immunity of recruits with nestling immunity of their nonrecruited siblings. We also investigated within individual consistency of these innate immune parameters for those individuals that recruited, which may be taken as a measure of immune capacity. In accordance with previous studies, we found a clear effect of tarsus length and a trend for body mass on the likelihood to recruit. Nevertheless, we found no evidence that higher levels of constitutive innate immunity as a nestling facilitated local recruitment. Furthermore, individual innate immunity was not consistent across life stages, that is to say, nestling immune parameters did not determine, or respectively, reflect adult innate immune parameters. This plasticity in innate immune components may explain why we did not find long-lasting survival benefits.

  1. Innate Immunity and BK Virus: Prospective Strategies.

    Science.gov (United States)

    Kariminik, Ashraf; Yaghobi, Ramin; Dabiri, Shahriar

    2016-03-01

    Recent information demonstrated that BK virus reactivation is a dominant complication after kidney transplantation, which occurs because of immunosuppression. BK virus reactivation is the main reason of transplanted kidney losing. Immune response against BK virus is the major inhibitor of the virus reactivation. Therefore, improving our knowledge regarding the main parameters that fight against BK viruses can shed light on to direct new treatment strategies to suppress BK infection. Innate immunity consists of numerous cell systems and also soluble molecules, which not only suppress virus replication, but also activate adaptive immunity to eradicate the infection. Additionally, it appears that immune responses against reactivated BK virus are the main reasons for induction of BK virus-associated nephropathy (BKAN). Thus, improving our knowledge regarding the parameters and detailed mechanisms of innate immunity and also the status of innate immunity of the patients with BK virus reactivation and its complications can introduce new prospective strategies to either prevent or as therapy of the complication. Therefore, this review was aimed to collate the most recent data regarding the roles played by innate immunity against BK virus and also the status of innate immunity in the patients with reactivation BK virus and BKAN.

  2. Corruption of innate immunity by bacterial proteases.

    Science.gov (United States)

    Potempa, Jan; Pike, Robert N

    2009-01-01

    The innate immune system of the human body has developed numerous mechanisms to control endogenous and exogenous bacteria and thus prevent infections by these microorganisms. These mechanisms range from physical barriers such as the skin or mucosal epithelium to a sophisticated array of molecules and cells that function to suppress or prevent bacterial infection. Many bacteria express a variety of proteases, ranging from non-specific and powerful enzymes that degrade many proteins involved in innate immunity to proteases that are extremely precise and specific in their mode of action. Here we have assembled a comprehensive picture of how bacterial proteases affect the host's innate immune system to gain advantage and cause infection. This picture is far from being complete since the numbers of mechanisms utilized are as astonishing as they are diverse, ranging from degradation of molecules vital to innate immune mechanisms to subversion of the mechanisms to allow the bacterium to hide from the system or take advantage of it. It is vital that such mechanisms are elucidated to allow strategies to be developed to aid the innate immune system in controlling bacterial infections.

  3. Corruption of Innate Immunity by Bacterial Proteases

    Science.gov (United States)

    Potempa, Jan; Pike, Robert N.

    2009-01-01

    The innate immune system of the human body has developed numerous mechanisms to control endogenous and exogenous bacteria and thus prevent infections by these microorganisms. These mechanisms range from physical barriers such as the skin or mucosal epithelium to a sophisticated array of molecules and cells that function to suppress or prevent bacterial infection. Many bacteria express a variety of proteases, ranging from non-specific and powerful enzymes that degrade many proteins involved in innate immunity to proteases that are extremely precise and specific in their mode of action. Here we have assembled a comprehensive picture of how bacterial proteases affect the host’s innate immune system to gain advantage and cause infection. This picture is far from being complete since the numbers of mechanisms utilized are as astonishing as they are diverse, ranging from degradation of molecules vital to innate immune mechanisms to subversion of the mechanisms to allow the bacterium to hide from the system or take advantage of it. It is vital that such mechanisms are elucidated to allow strategies to be developed to aid the innate immune system in controlling bacterial infections. PMID:19756242

  4. Antiviral Protection via RdRP-Mediated Stable Activation of Innate Immunity.

    Science.gov (United States)

    Painter, Meghan M; Morrison, James H; Zoecklein, Laurie J; Rinkoski, Tommy A; Watzlawik, Jens O; Papke, Louisa M; Warrington, Arthur E; Bieber, Allan J; Matchett, William E; Turkowski, Kari L; Poeschla, Eric M; Rodriguez, Moses

    2015-12-01

    For many emerging and re-emerging infectious diseases, definitive solutions via sterilizing adaptive immunity may require years or decades to develop, if they are even possible. The innate immune system offers alternative mechanisms that do not require antigen-specific recognition or a priori knowledge of the causative agent. However, it is unclear whether effective stable innate immune system activation can be achieved without triggering harmful autoimmunity or other chronic inflammatory sequelae. Here, we show that transgenic expression of a picornavirus RNA-dependent RNA polymerase (RdRP), in the absence of other viral proteins, can profoundly reconfigure mammalian innate antiviral immunity by exposing the normally membrane-sequestered RdRP activity to sustained innate immune detection. RdRP-transgenic mice have life-long, quantitatively dramatic upregulation of 80 interferon-stimulated genes (ISGs) and show profound resistance to normally lethal viral challenge. Multiple crosses with defined knockout mice (Rag1, Mda5, Mavs, Ifnar1, Ifngr1, and Tlr3) established that the mechanism operates via MDA5 and MAVS and is fully independent of the adaptive immune system. Human cell models recapitulated the key features with striking fidelity, with the RdRP inducing an analogous ISG network and a strict block to HIV-1 infection. This RdRP-mediated antiviral mechanism does not depend on secondary structure within the RdRP mRNA but operates at the protein level and requires RdRP catalysis. Importantly, despite lifelong massive ISG elevations, RdRP mice are entirely healthy, with normal longevity. Our data reveal that a powerfully augmented MDA5-mediated activation state can be a well-tolerated mammalian innate immune system configuration. These results provide a foundation for augmenting innate immunity to achieve broad-spectrum antiviral protection.

  5. Innate Immune Cells in Liver Inflammation

    Directory of Open Access Journals (Sweden)

    Evaggelia Liaskou

    2012-01-01

    Full Text Available Innate immune system is the first line of defence against invading pathogens that is critical for the overall survival of the host. Human liver is characterised by a dual blood supply, with 80% of blood entering through the portal vein carrying nutrients and bacterial endotoxin from the gastrointestinal tract. The liver is thus constantly exposed to antigenic loads. Therefore, pathogenic microorganism must be efficiently eliminated whilst harmless antigens derived from the gastrointestinal tract need to be tolerized in the liver. In order to achieve this, the liver innate immune system is equipped with multiple cellular components; monocytes, macrophages, granulocytes, natural killer cells, and dendritic cells which coordinate to exert tolerogenic environment at the same time detect, respond, and eliminate invading pathogens, infected or transformed self to mount immunity. This paper will discuss the innate immune cells that take part in human liver inflammation, and their roles in both resolution of inflammation and tissue repair.

  6. Innate predator recognition in giant pandas.

    Science.gov (United States)

    Du, Yiping; Huang, Yan; Zhang, Hemin; Li, Desheng; Yang, Bo; Wei, Ming; Zhou, Yingmin; Liu, Yang

    2012-02-01

    Innate predator recognition confers a survival advantage to prey animals. We investigate whether giant pandas exhibit innate predator recognition. We analyzed behavioral responses of 56 naive adult captive giant pandas (Ailuropoda melanoleuca), to urine from predators and non-predators and water control. Giant pandas performed more chemosensory investigation and displayed flehmen behaviors more frequently in response to predator urine compared to both non-predator urine and water control. Subjects also displayed certain defensive behaviors, as indicated by vigilance, and in certain cases, fleeing behaviors. Our results suggest that there is an innate component to predator recognition in captive giant pandas, although such recognition was only slight to moderate. These results have implications that may be applicable to the conservation and reintroduction of this endangered species.

  7. 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.

  8. Bacterial subversion of host innate immune pathways.

    Science.gov (United States)

    Baxt, Leigh A; Garza-Mayers, Anna Cristina; Goldberg, Marcia B

    2013-05-10

    The pathogenesis of infection is a continuously evolving battle between the human host and the infecting microbe. The past decade has brought a burst of insights into the molecular mechanisms of innate immune responses to bacterial pathogens. In parallel, multiple specific mechanisms by which microorganisms subvert these host responses have been uncovered. This Review highlights recently characterized mechanisms by which bacterial pathogens avoid killing by innate host responses, including autophagy pathways and a proinflammatory cytokine transcriptional response, and by the manipulation of vesicular trafficking to avoid the toxicity of lysosomal enzymes.

  9. [Innate Immune Evasion Mechanisms of Pseudorabies Virus].

    Science.gov (United States)

    Liu, Yaozong; Rui, Ping; Ma, Rui; Ma, Zengjun

    2015-11-01

    Pseudorabies is an economically important disease in a variety ot animals caused by pseudorabies virus. Since 2011, pseudorabies outbreaks occurred in many regions of China. Related researches on this virus become a hot topic in virology and veterinary. One of the difficulties for pseudorabies prevention and control is innate immune evasion. Explorations on this issue are conducive to the development of vaccine and drugs. Therefore, this review summarized the recent research progress on the mechanisms of pseudorabies virus innate immune evasion. Theoretical direction was provided on effetive prevention and control of pseudorabies owing to this review.

  10. Ultrasound guided supraclavicular block.

    LENUS (Irish Health Repository)

    Hanumanthaiah, Deepak

    2013-09-01

    Ultrasound guided regional anaesthesia is becoming increasingly popular. The supraclavicular block has been transformed by ultrasound guidance into a potentially safe superficial block. We reviewed the techniques of performing supraclavicular block with special focus on ultrasound guidance.

  11. The biology of innate lymphoid cells

    NARCIS (Netherlands)

    Artis, David; Spits, Hergen

    2015-01-01

    The innate immune system is composed of a diverse array of evolutionarily ancient haematopoietic cell types, including dendritic cells, monocytes, macrophages and granulocytes. These cell populations collaborate with each other, with the adaptive immune system and with non-haematopoietic cells to

  12. Adrenergic regulation of innate immunity: a review

    Directory of Open Access Journals (Sweden)

    Angela eScanzano

    2015-08-01

    Full Text Available The sympathetic nervous system has a major role in the brain-immune cross-talk, but few information exist on the sympathoadrenergic regulation of innate immune system.The aim of this review is to summarize available knowledge regarding the sympathetic modulation of the innate immune response, providing a rational background for the possible repurposing of adrenergic drugs as immunomodulating agents.The cells of immune system express adrenoceptors (AR, which represent the target for noradrenaline and adrenaline. In human neutrophils, adrenaline and noradrenaline inhibit migration, CD11b/CD18 expression, and oxidative metabolism, possibly through β-AR, although the role of α1- and α2-AR requires further investigation. Natural Killer express β-AR, which are usually inhibitory. Monocytes express β-AR and their activation is usually antiinflammatory. On murine Dentritic cells (DC, β-AR mediate sympathetic influence on DC-T cells interactions. In human DC β2-AR may affect Th1/2 differentiation of CD4+ T cells. In microglia and in astrocytes, β2-AR dysregulation may contribute to neuroinflammation in autoimmune and neurodegenerative disease.In conclusion, extensive evidence supports a critical role for adrenergic mechanisms in the regulation of innate immunity, in peripheral tissues as well as in the CNS. Sympathoadrenergic pathways in the innate immune system may represent novel antiinflammatory and immunomodulating targets with significant therapeutic potential.

  13. Innate Immunity to Mucosal Candida Infections

    Directory of Open Access Journals (Sweden)

    Akash Verma

    2017-10-01

    Full Text Available Mucosal epithelial tissues are exposed to high numbers of microbes, including commensal fungi, and are able to distinguish between those that are avirulent and those that cause disease. Epithelial cells have evolved multiple mechanisms to defend against colonization and invasion by Candida species. The interplay between mucosal epithelial tissues and immune cells is key for control and clearance of fungal infections. Our understanding of the mucosal innate host defense system has expanded recently with new studies bringing to light the importance of epithelial cell responses, innate T cells, neutrophils, and other phagocytes during Candida infections. Epithelial tissues release cytokines, host defense peptides, and alarmins during Candida invasion that act in concert to limit fungal proliferation and recruit immune effector cells. The innate T cell/IL-17 axis and recruitment of neutrophils are of central importance in controlling mucosal fungal infections. Here, we review current knowledge of the innate immunity at sites of mucosal Candida infection, with a focus on infections caused by C. albicans.

  14. Is there an innate need for children

    NARCIS (Netherlands)

    R. Veenhoven (Ruut)

    1974-01-01

    textabstractABSTRACT It is commonly assumed that we have an innate need for children, in particular, that women have a 'mother instinct'. This belief lives in the general public as well as among scientists. In this paper that theory is criticized on two grounds: Firstly, it is argued that the theory

  15. Monotheism versus an innate bias towards mentalizing.

    Science.gov (United States)

    Costello, Fintan John

    2016-01-01

    Norenzayan et al.'s account for the spread of monotheistic "Big God" religions sees these religions originating as by-products of innate cognitive biases. These biases produce polytheistic rather than monotheistic systems, however, and so do not explain the origin of monotheism. Accounts where monotheism arises from polytheism (for political reasons, for example) appear better able to explain the spread of monotheism.

  16. Innate lymphoid cells in inflammation and immunity

    NARCIS (Netherlands)

    McKenzie, Andrew N. J.; Spits, Hergen; Eberl, Gerard

    2014-01-01

    Innate lymphoid cells (ILCs) were first described as playing important roles in the development of lymphoid tissues and more recently in the initiation of inflammation at barrier surfaces in response to infection or tissue damage. It has now become apparent that ILCs play more complex roles

  17. Biliary Innate Immunity: Function and Modulation

    Directory of Open Access Journals (Sweden)

    Kenichi Harada

    2010-01-01

    Full Text Available Biliary innate immunity is involved in the pathogenesis of cholangiopathies in patients with primary biliary cirrhosis (PBC and biliary atresia. Biliary epithelial cells possess an innate immune system consisting of the Toll-like receptor (TLR family and recognize pathogen-associated molecular patterns (PAMPs. Tolerance to bacterial PAMPs such as lipopolysaccharides is also important to maintain homeostasis in the biliary tree, but tolerance to double-stranded RNA (dsRNA is not found. In PBC, CD4-positive Th17 cells characterized by the secretion of IL-17 are implicated in the chronic inflammation of bile ducts and the presence of Th17 cells around bile ducts is causally associated with the biliary innate immune responses to PAMPs. Moreover, a negative regulator of intracellular TLR signaling, peroxisome proliferator-activated receptor-γ (PPARγ, is involved in the pathogenesis of cholangitis. Immunosuppression using PPARγ ligands may help to attenuate the bile duct damage in PBC patients. In biliary atresia characterized by a progressive, inflammatory, and sclerosing cholangiopathy, dsRNA viruses are speculated to be an etiological agent and to directly induce enhanced biliary apoptosis via the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL. Moreover, the epithelial-mesenchymal transition (EMT of biliary epithelial cells is also evoked by the biliary innate immune response to dsRNA.

  18. The biology of human innate lymphoid cells

    NARCIS (Netherlands)

    Bernink, J.H.J.

    2016-01-01

    In this thesis I performed studies to investigate the contribution of human innate lymphoid cells (ILCs) in maintaining the mucosal homeostasis, initiating and/or propagating inflammatory responses, but also - when not properly regulated - how these cells contribute to immunopathology. First I

  19. Innate Immunity and the 2011 Nobel Prize

    Indian Academy of Sciences (India)

    IAS Admin

    recurring infections in affected children. Also, this coating may lead to the activation of the complement pathway so as to lyse these microbes. ..... of blood cells from the horse shoe crab, Limulus polyphemus, which coagulate in the presence of very small amounts of LPS. This is a good example to illustrate the innate ...

  20. Innate Immune Response to Burkholderia mallei

    Science.gov (United States)

    2017-02-16

    vaccination and therapeutic approaches are necessary for complete protection against B. mallei. Keywords: Innate Immune response, Burkholderia mallei...immune signaling, cellular immunity, vaccine . TR-17-034 DISTRIBUTION STATEMENT A: Approved for public release; distribution is unlimited. UNCLASSIFIED...Currently, no licensed vaccines are available for either disease, and medical therapeutic options are limited. Both B. pseudomallei and B. mallei

  1. Improving microphage innate immunity by modulating protein ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Improving microphage innate immunity by modulating protein tyrosine phosphatases: The complete mouse and human PTPomes. Diseases that result from an infection are most often resolved by cells that use an immune response to clear foreign agents. These cells include macrophages, which are the predominant type of ...

  2. Innate Immunity and the 2011 Nobel Prize

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 17; Issue 10. Innate Immunity and the 2011 Nobel Prize. Mukta Deobagkar Lele Chetana Bhaskarla Rajkumar Dhanaraju Manikandan Ponnusamy Dipankar Nandi. General Article Volume 17 Issue 10 October 2012 pp 974-995 ...

  3. Innate immunity and the new forward genetics.

    Science.gov (United States)

    Beutler, Bruce

    2016-12-01

    As it is a hard-wired system for responses to microbes, innate immunity is particularly susceptible to classical genetic analysis. Mutations led the way to the discovery of many of the molecular elements of innate immune sensing and signaling pathways. In turn, the need for a faster way to find the molecular causes of mutation-induced phenotypes triggered a huge transformation in forward genetics. During the 1980s and 1990s, many heritable phenotypes were ascribed to mutations through positional cloning. In mice, this required three steps. First, a genetic mapping step was used to show that a given phenotype emanated from a circumscribed region of the genome. Second, a physical mapping step was undertaken, in which all of the region was cloned and its gene content determined. Finally, a concerted search for the mutation was performed. Such projects usually lasted for several years, but could produce breakthroughs in our understanding of biological processes. Publication of the annotated mouse genome sequence in 2002 made physical mapping unnecessary. More recently we devised a new technology for automated genetic mapping, which eliminated both genetic mapping and the search for mutations among candidate genes. The cause of phenotype can now be determined instantaneously. We have created more than 100,000 coding/splicing mutations. And by screening for defects of innate and adaptive immunity we have discovered many "new" proteins needed for innate immune function. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Host Genetics: Fine-Tuning Innate Signaling

    OpenAIRE

    Fellay, Jacques; Goldstein, David B.

    2007-01-01

    A polymorphism modulating innate immunity signal transduction has recently been shown to influence human susceptibility to many different infections, providing one more indication of the potential of host genetics to reveal physiological pathways and mechanisms that influence resistance to infectious diseases.

  5. History of Innate Immunity in Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Patrick eMcGeer

    2011-12-01

    Full Text Available The foundations of innate immunity in neurodegenerative disorders were first laid by Hortega in 1919. He identified and named microglia, recognizing them as cells of mesodermal origin. Van Furth in 1969 elaborated the monocyte phagocytic system with microglia as the brain representatives. Validation of these concepts did not occur until 1987 when HLA-DR was identified on activated microglia in a spectrum of neurological disorders. HLA-DR had already been established as a definitive marker of immunocompetent cells of mesodermal origin. It was soon determined that the observed inflammatory reaction was an innate immune response. A rapid expansion of the field took place as other markers of an innate immune response were found that were made by neurons, astrocytes, oligodendroglia and endothelial cells. The molecules included complement proteins and their regulators, inflammatory cytokines, chemokines, acute phase reactants, prostaglandins, proteases, protease inhibitors, coagulation factors, fibrinolytic factors, anaphylotoxins, integrins, free radical generators, and other unidentified neurotoxins. The Nimmerjahn movies demonstrated that resting microglia were constantly active, sampling the surround and responding rapidly to brain damage. Ways of reducing the neurotoxic innate immune response and stimulating a healing response continue to be sought as a means for ameliorating the pathology in a spectrum of chronic degenerative disorders.

  6. Impaired innate immunity in Crohn's disease

    NARCIS (Netherlands)

    Comalada, Monica; Peppelenbosch, Maikel P.

    The aetiology of Crohn's disease - a chronic intestinal disorder that involves an immune response against the commensal bacterial flora - remains fiercely debated. Two hypotheses exist: (i) those who think that the disease is caused by genetic defects that produce exaggerated innate responses to the

  7. Langerhans cells in innate defense against pathogens

    NARCIS (Netherlands)

    de Jong, Marein A. W. P.; Geijtenbeek, Teunis B. H.

    2010-01-01

    Langerhans cells (LCs) are at the frontline in defense against mucosal infections because they line the mucosal tissues and are ideally situated to intercept pathogens. Recent data suggest that LCs have an innate anti-HIV-1 function. LCs express the LC-specific C-type lectin Langerin that

  8. Innate host defense against intracellular pathogens

    NARCIS (Netherlands)

    Vaart, Michiel van der

    2013-01-01

    This thesis focuses on the recognition of pathogenic bacteria and the defense mechanisms that are activated during the innate immune response to infection. Detection of pathogens, such as bacteria, viruses, and parasites, depends on receptors that bind to evolutionary conserved structures on their

  9. Innate immune responses to environmental allergens

    NARCIS (Netherlands)

    Kauffman, HF

    Aero-allergens, including plant pollens, house dust mite particles, fungal spores, and mycelium fragments, are continuously inhaled and deposited on the airway mucosa. These particles and their soluble components actively interact with innate recognition systems present in the mucosal layer (e.g.,

  10. Homogeneous bilateral block shifts

    Indian Academy of Sciences (India)

    Douglas class were classified in [3]; they are unilateral block shifts of arbitrary block size (i.e. dim H(n) can be anything). However, no examples of irreducible homogeneous bilateral block shifts of block size larger than 1 were known until now.

  11. Innate cell communication kick-starts pathogen-specific immunity.

    Science.gov (United States)

    Rivera, Amariliz; Siracusa, Mark C; Yap, George S; Gause, William C

    2016-04-01

    Innate cells are responsible for the rapid recognition of infection and mediate essential mechanisms of pathogen elimination, and also facilitate adaptive immune responses. We review here the numerous intricate interactions among innate cells that initiate protective immunity. The efficient eradication of pathogens depends on the coordinated actions of multiple cells, including innate cells and epithelial cells. Rather than acting as isolated effector cells, innate cells are in constant communication with other responding cells of the immune system, locally and distally. These interactions are critically important for the efficient control of primary infections as well for the development of 'trained' innate cells that facilitate the rapid elimination of homologous or heterologous infections.

  12. Recognition of Viral RNA by Pattern Recognition Receptors in the Induction of Innate Immunity and Excessive Inflammation During Respiratory Viral Infections.

    Science.gov (United States)

    Okamoto, Masaaki; Tsukamoto, Hirotake; Kouwaki, Takahisa; Seya, Tsukasa; Oshiumi, Hiroyuki

    The innate immune system is the first line of defense against virus infection that triggers the expression of type I interferon (IFN) and proinflammatory cytokines. Pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns, resulting in the induction of innate immune responses. Viral RNA in endosomes is recognized by Toll-like receptors, and cytoplasmic viral RNA is recognized by RIG-I-like receptors. The host innate immune response is critical for protection against virus infection. However, it has been postulated that an excessive inflammatory response in the lung caused by the innate immune response is harmful to the host and is a cause of lethality during influenza A virus infection. Although the deletion of genes encoding PRRs or proinflammatory cytokines does not improve the mortality of mice infected with influenza A virus, a partial block of the innate immune response is successful in decreasing the mortality rate of mice without a loss of protection against virus infection. In addition, morbidity and mortality rates are influenced by other factors. For example, secondary bacterial infection increases the mortality rate in patients with influenza A virus and in animal models of the disease, and environmental factors, such as cigarette smoke and fine particles, also affect the innate immune response. In this review, we summarize recent findings related to the role of PRRs in innate immune response during respiratory viral infection.

  13. Skin innate immune response to flaviviral infection.

    Science.gov (United States)

    Garcia, Magali; Wehbe, Michel; Lévêque, Nicolas; Bodet, Charles

    2017-06-01

    Skin is a complex organ and the largest interface of the human body exposed to numerous stress and pathogens. Skin is composed of different cell types that together perform essential functions such as pathogen sensing, barrier maintenance and immunity, at once providing the first line of defense against microbial infections and ensuring skin homeostasis. Being inoculated directly through the epidermis and the dermis during a vector blood meal, emerging Dengue, Zika and West Nile mosquito-borne viruses lead to the initiation of the innate immune response in resident skin cells and to the activation of dendritic cells, which migrate to the draining lymph node to elicit an adaptive response. This literature review aims to describe the inflammatory response and the innate immune signalization pathways involved in human skin cells during Dengue, Zika and West Nile virus infections.

  14. Revisiting the innate preference for consonance.

    Science.gov (United States)

    Plantinga, Judy; Trehub, Sandra E

    2014-02-01

    The origin of the Western preference for consonance remains unresolved, with some suggesting that the preference is innate. In Experiments 1 and 2 of the present study, 6-month-old infants heard six different consonant/dissonant pairs of stimuli, including those tested in previous research. In contrast to the findings of others, infants in the present study failed to listen longer to consonant stimuli. After 3 minutes of exposure to consonant or dissonant stimuli in Experiment 3, 6-month-old infants listened longer to the familiar stimulus, whether consonant or dissonant. Our findings are inconsistent with innate preferences for consonant stimuli. Instead, the effect of short-term exposure is consistent with the view that familiarity underlies the origin of the Western preference for consonant intervals. PsycINFO Database Record (c) 2014 APA, all rights reserved.

  15. Regulation of intestinal homeostasis by innate immune cells.

    Science.gov (United States)

    Kayama, Hisako; Nishimura, Junichi; Takeda, Kiyoshi

    2013-12-01

    The intestinal immune system has an ability to distinguish between the microbiota and pathogenic bacteria, and then activate pro-inflammatory pathways against pathogens for host defense while remaining unresponsive to the microbiota and dietary antigens. In the intestine, abnormal activation of innate immunity causes development of several inflammatory disorders such as inflammatory bowel diseases (IBD). Thus, activity of innate immunity is finely regulated in the intestine. To date, multiple innate immune cells have been shown to maintain gut homeostasis by preventing inadequate adaptive immune responses in the murine intestine. Additionally, several innate immune subsets, which promote Th1 and Th17 responses and are implicated in the pathogenesis of IBD, have recently been identified in the human intestinal mucosa. The demonstration of both murine and human intestinal innate immune subsets contributing to regulation of adaptive immunity emphasizes the conserved innate immune functions across species and might promote development of the intestinal innate immunity-based clinical therapy.

  16. Innate immunity in Sjögren's syndrome.

    Science.gov (United States)

    Kiripolsky, Jeremy; McCabe, Liam G; Kramer, Jill M

    2017-09-01

    Sjögren's syndrome (SS) is an autoimmune disease of exocrine tissue that primarily affects women. Although patients typically experience xerostomia and xerophthalmia, numerous systemic disease manifestations are seen. Innate immune hyperactivity is integral to many autoimmune diseases, including SS. Results from SS mouse models suggest that innate immune dysregulation drives disease and this is a seminal event in SS pathogenesis. Findings in SS patients corroborate those in mouse models, as innate immune cells and pathways are dysregulated both in exocrine tissue and in peripheral blood. We will review the role of the innate immune system in SS pathogenesis. We will discuss the etiology of SS with an emphasis on innate immune dysfunction. Moreover, we will review the innate cells that mediate inflammation in SS, the pathways implicated in disease, and the potential mechanisms governing their dysregulation. Finally, we will discuss emerging therapeutic approaches to target dysregulated innate immune signaling in SS. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Innate Immune Activation in Intestinal Homeostasis

    OpenAIRE

    Harrison, Oliver J.; Maloy, Kevin J.

    2011-01-01

    Loss of intestinal immune regulation leading to aberrant immune responses to the commensal microbiota are believed to precipitate the chronic inflammation observed in the gastrointestinal tract of patients with inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis. Innate immune receptors that recognize conserved components derived from the microbiota are widely expressed by both epithelial cells and leucocytes of the gastrointestinal tract and play a key role in host prot...

  18. Innate and intrinsic antiviral immunity in skin.

    Science.gov (United States)

    Kawamura, Tatsuyoshi; Ogawa, Youichi; Aoki, Rui; Shimada, Shinji

    2014-09-01

    As the body's most exposed interface with the environment, the skin is constantly challenged by potentially pathogenic microbes, including viruses. To sense the invading viruses, various types of cells resident in the skin express many different pattern-recognition receptors (PRRs) such as C-type lectin receptors (CLRs), Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and cytosolic DNA sensors, that can detect the pathogen-associated molecular patterns (PAMPs) of the viruses. The detection of viral PAMPs initiates two major innate immune signaling cascades: the first involves the activation of the downstream transcription factors, such as interferon regulatory factors (IRFs), nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1), which cooperate to induce the transcription of type I interferons and pro-inflammatory cytokines. The second signaling pathway involves the caspase-1-mediated processing of IL-1β and IL-18 through the formation of an inflammasome complex. Cutaneous innate immunity including the production of the innate cytokines constitutes the first line of host defence that limits the virus dissemination from the skin, and also plays an important role in the activation of adaptive immune response, which represents the second line of defence. More recently, the third immunity "intrinsic immunity" has emerged, that provides an immediate and direct antiviral defense mediated by host intrinsic restriction factors. This review focuses on the recent advances regarding the antiviral immune systems, highlighting the innate and intrinsic immunity against the viral infections in the skin, and describes how viral components are recognized by cutaneous immune systems. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  19. Characteristic of innate lymphoid cells (ILC

    Directory of Open Access Journals (Sweden)

    Mateusz Adamiak

    2014-12-01

    Full Text Available Innate lymphoid cells (ILC is a newly described family of immune cells that are part of the natural immunity which is important not only during infections caused by microorganisms, but also in the formation of lymphoid tissue, tissue remodeling after damage due to injury and homeostasis tissue stromal cells. Family ILC cells form NK cells (natural killer and lymphoid tissue inducer T cells (LTi, which, although they have different functions, are evolutionarily related. NK cells are producing mainly IFN-γ, whereas LTi cells as NKR+LTi like, IL-17 and/or IL-22, which suggests that the last two cells, can also represent the innate versions of helper T cell - TH17 and TH22. Third population of ILC is formed by cells with characteristics such as NK cells and LTi (ILC22 - which are named NK22 cells, natural cytotoxicity receptor 22 (NCR22 cells or NK receptor-positive (LTi NKR+ LTi cells. Fourth population of ILC cells are ILC17 - producing IL-17, while the fifth is formed by natural helper type 2 T cells (nTH2, nuocyte, innate type 2 helper cells (IH2 and multi-potent progenitor type 2 cells (MPPtype2. Cells of the last population synthesize IL-5 and IL-13. It is assumed that an extraordinary functional diversity of ILC family, resembles T cells, probably because they are under the control of the corresponding transcription factors - as direct regulation factors, such as the family of lymphocytes T.

  20. Bacterial RNAs activate innate immunity in Arabidopsis.

    Science.gov (United States)

    Lee, Boyoung; Park, Yong-Soon; Lee, Soohyun; Song, Geun Cheol; Ryu, Choong-Min

    2016-01-01

    The common molecular patterns of microbes play a critical role in the regulation of plant innate immunity. However, little is known about the role of nucleic acids in this process in plants. We pre-infiltrated Arabidopsis leaves with total RNAs from Pseudomonas syringae pv. tomato DC3000 (Pto DC3000) and subsequently inoculated these plants with the same bacterial cells. Total Pto DC3000 RNAs pre-infiltrated into Arabidopsis leaves elicited plant immune responses against Pto DC3000. However, sheared RNAs and RNase A application failed to induce immunity, suggesting that intact bacterial RNAs function in plant innate immunity. This notion was supported by the positive regulation of superoxide anion levels, callose deposition, two mitogen-activated protein kinases and defense-related genes observed in bacterial RNA-pre-treated leaves. Intriguingly, the Pto DC3000 population was not compromised in known pattern recognition receptor mutants for chitin, flagellin and elongation factor-Tu (EF-Tu). Plant defense-related mutant analyses further revealed that bacterial RNA-elicited innate immunity was normally required for salicylic and jasmonic acid signaling. Notably, among total RNAs, the abundant bacterial RNA species 16S and 23S ribosomal RNAs were the major determinants of this response. Our findings provide evidence that bacterial RNA serves as a microbe-associated molecular pattern in plants. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

  1. Distinct mechanisms of the newborn innate immunity.

    Science.gov (United States)

    Kumar, S Kingsley Manoj; Bhat, B Vishnu

    2016-05-01

    The ontogeny of immunity during early life is of high importance as it shapes the immune system for the entire course of life. The microbiome and the environment contribute to the development of immunity in newborns. As immune responses in newborns are predominantly less experienced they are increasingly susceptible to infections. Though the immune cells in newborns are in 'naïve' state, they have been shown to mount adult-like responses in several circumstances. The innate immunity plays a vital role in providing protection during the neonatal period. Various stimulants have been shown to enhance the potential and functioning of the innate immune cells in newborns. They are biased against the production of pro-inflammatory cytokines and this makes them susceptible to wide variety of intracellular pathogens. The adaptive immunity requires prior antigenic experience which is very limited in newborns. This review discusses in detail the characteristics of innate immunity in newborns and the underlying developmental and functional mechanisms involved in the immune response. A better understanding of the immunological milieu in newborns could help the medical fraternity to find novel methods for prevention and treatment of infection in newborns. Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  2. Heme on innate immunity and inflammation

    Directory of Open Access Journals (Sweden)

    Fabianno Ferreira Dutra

    2014-05-01

    Full Text Available Heme is an essential molecule expressed ubiquitously all through our tissues. Heme plays major functions in cellular physiology and metabolism as the prostetic group of diverse proteins. Once released from cells and from hemeproteins free heme causes oxidative damage and inflammation, thus acting as a prototypic damage-associated molecular pattern. In this context, free heme is a critical component of the pathological process of sterile and infectious hemolytic conditions including malaria, hemolytic anemias, ischemia-reperfusion and hemorrhage. The plasma scavanger proteins hemopexin and albumin reduce heme toxicity and are responsible for transporting free heme to intracellular compartments where it is catabolized by heme-oxygenase enzymes. Upon hemolysis or severe cellular damage the serum capacity to scavange heme may saturate and increase free heme to sufficient amounts to cause tissue damage in various organs. The mechanism by which heme causes reactive oxygen generation, activation of cells of the innate immune system and cell death are not fully understood. Although heme can directly promote lipid peroxidation by its iron atom, heme can also induce ROS generation and production of inflammatory mediators through the activation of selective signaling pathways. Heme activates innate immune cells such as macrophages and neutrophils through activation of innate immune receptors. The importance of these events has been demonstrated in infectious and non-infectious diseases models. In this review we will discuss the mechanisms behind heme-induced citotoxicity and inflammation and the consequences of these events on different tissues and diseases.

  3. Training innate immunity: the changing concept of immunological memory in innate host defence.

    Science.gov (United States)

    Netea, Mihai G

    2013-08-01

    The inability of innate immunity to build an immunological memory is considered a main difference with adaptive immunity. This concept has been challenged by studies in plants, invertebrates and mammals. Recently, a paradigm shift in our understanding host defence has been triggered by the mounting evidence for innate immune memory, leading to increased responses to secondary infections. Important differences between the cell populations and the molecular mechanisms exist between the adaptive traits of innate host defence on the one hand and immunological memory of adaptive immunity on the other hand. The lasting state of enhanced innate immunity termed 'trained immunity' is mediated by prototypical innate immune cells such as natural killer cells and monocytes/macrophages. It provides protection against reinfection in a T/B-cell-independent manner, with both specific mechanisms and nonspecific epigenetic reprogramming mediating these effects. This concept represents a paradigm change in immunity, and its putative role in resistance to reinfection may represent the next step in the design of future vaccines. © 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.

  4. Activation of the Innate Immune Receptors: Guardians of the Micro Galaxy : Activation and Functions of the Innate Immune Receptors.

    Science.gov (United States)

    De Nardo, Dominic

    2017-01-01

    The families of innate immune receptors are the frontline responders to danger. These superheroes of the host immune systems populate innate immune cells, surveying the extracellular environment and the intracellular endolysosomal compartments and cytosol for exogenous and endogenous danger signals. As a collective the innate immune receptors recognise a wide array of stimuli, and in response they initiate specific signalling pathways leading to activation of transcriptional or proteolytic pathways and the production of inflammatory molecules to destroy foreign pathogens and/or resolve tissue injury. In this review, I will give an overview of the innate immune system and the activation and effector functions of the families of receptors it comprises. Current key concepts will be described throughout, including innate immune memory, formation of innate immune receptor signalosomes, inflammasome formation and pyroptosis, methods of extrinsic cell communication and examples of receptor cooperation. Finally, several open questions and future directions in the field of innate immunity will be presented and discussed.

  5. Post-Translational Modification Control of Innate Immunity.

    Science.gov (United States)

    Liu, Juan; Qian, Cheng; Cao, Xuetao

    2016-07-19

    A coordinated balance between the positive and negative regulation of pattern-recognition receptor (PRR)-initiated innate inflammatory responses is required to ensure the most favorable outcome for the host. Post-translational modifications (PTMs) of innate sensors and downstream signaling molecules influence their activity and function by inducing their covalent linkage to new functional groups. PTMs including phosphorylation and polyubiquitination have been shown to potently regulate innate inflammatory responses through the activation, cellular translocation, and interaction of innate receptors, adaptors, and downstream signaling molecules in response to infectious and dangerous signals. Other PTMs such as methylation, acetylation, SUMOylation, and succinylation are increasingly implicated in the regulation of innate immunity and inflammation. In this review, we focus on the roles of PTMs in controlling PRR-triggered innate immunity and inflammatory responses. The emerging roles of PTMs in the pathogenesis and potential treatment of infectious and inflammatory immune diseases are also discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. [The role of the innate immune system in atopic dermatitis].

    Science.gov (United States)

    Volz, T; Kaesler, S; Skabytska, Y; Biedermann, T

    2015-02-01

    The mechanisms how the innate immune system detects microbes and mounts a rapid immune response have been more and more elucidated in the past years. Subsequently it has been shown that innate immunity also shapes adaptive immune responses and determines their quality that can be either inflammatory or tolerogenic. As atopic dermatitis is characterized by disturbances of innate and adaptive immune responses, colonization with pathogens and defects in skin barrier function, insight into mechanisms of innate immunity has helped to understand the vicious circle of ongoing skin inflammation seen in atopic dermatitis patients. Elucidating general mechanisms of the innate immune system and its functions in atopic dermatitis paves the way for developing new therapies. Especially the novel insights into the human microbiome and potential functional consequences make the innate immune system a very fundamental and promising target. As a result atopic dermatitis manifestations can be attenuated or even resolved. These currently developed strategies will be introduced in the current review.

  7. Homogeneous bilateral block shifts

    Indian Academy of Sciences (India)

    A new 3-parameter family of homogeneous 2-by-2 block shifts is described. These are the first examples of irreducible homogeneous bilateral block shifts of block size larger than 1. Author Affiliations. Adam Korányi1. Department of Mathematics, The Graduate Center, City University of New York, New York, NY 10016, USA ...

  8. Virus-associated activation of innate immunity induces rapid disruption of Peyer's patches in mice.

    Science.gov (United States)

    Heidegger, Simon; Anz, David; Stephan, Nicolas; Bohn, Bernadette; Herbst, Tina; Fendler, Wolfgang Peter; Suhartha, Nina; Sandholzer, Nadja; Kobold, Sebastian; Hotz, Christian; Eisenächer, Katharina; Radtke-Schuller, Susanne; Endres, Stefan; Bourquin, Carole

    2013-10-10

    Early in the course of infection, detection of pathogen-associated molecular patterns by innate immune receptors can shape the subsequent adaptive immune response. Here we investigate the influence of virus-associated innate immune activation on lymphocyte distribution in secondary lymphoid organs. We show for the first time that virus infection of mice induces rapid disruption of the Peyer's patches but not of other secondary lymphoid organs. The observed effect was not dependent on an active infectious process, but due to innate immune activation and could be mimicked by virus-associated molecular patterns such as the synthetic double-stranded RNA poly(I:C). Profound histomorphologic changes in Peyer's patches were associated with depletion of organ cellularity, most prominent among the B-cell subset. We demonstrate that the disruption is entirely dependent on type I interferon (IFN). At the cellular level, we show that virus-associated immune activation by IFN-α blocks B-cell trafficking to the Peyer's patches by downregulating expression of the homing molecule α4β7-integrin. In summary, our data identify a mechanism that results in type I IFN-dependent rapid but reversible disruption of intestinal lymphoid organs during systemic viral immune activation. We propose that such rerouted lymphocyte trafficking may impact the development of B-cell immunity to systemic viral pathogens.

  9. Lloviu virus VP24 and VP35 proteins function as innate immune antagonists in human and bat cells

    International Nuclear Information System (INIS)

    Feagins, Alicia R.; Basler, Christopher F.

    2015-01-01

    Lloviu virus (LLOV) is a new member of the filovirus family that also includes Ebola virus (EBOV) and Marburg virus (MARV). LLOV has not been cultured; however, its genomic RNA sequence indicates the coding capacity to produce homologs of the EBOV and MARV VP24, VP35, and VP40 proteins. EBOV and MARV VP35 proteins inhibit interferon (IFN)-alpha/beta production and EBOV VP35 blocks activation of the antiviral kinase PKR. The EBOV VP24 and MARV VP40 proteins inhibit IFN signaling, albeit by different mechanisms. Here we demonstrate that LLOV VP35 suppresses Sendai virus induced IFN regulatory factor 3 (IRF3) phosphorylation, IFN-α/β production, and PKR phosphorylation. Additionally, LLOV VP24 blocks tyrosine phosphorylated STAT1 binding to karyopherin alpha 5 (KPNA5), STAT1 nuclear accumulation, and IFN-induced gene expression. LLOV VP40 lacks detectable IFN antagonist function. These activities parallel EBOV IFN inhibitory functions. EBOV and LLOV VP35 and VP24 proteins also inhibit IFN responses in bat cells. These data suggest that LLOV infection will block innate immune responses in a manner similar to EBOV. - Highlights: • Lloviu virus (LLOV) is a new member of the filovirus family. • LLOV VP35 blocks IRF3 phosphorylation, IFN-α/β production and PKR phosphorylation. • LLOV VP24 inhibits IFN responses by targeting phospho-STAT1 KPNA interaction. • Infection by LLOV may block innate immune responses in a manner similar to EBOV.

  10. Lloviu virus VP24 and VP35 proteins function as innate immune antagonists in human and bat cells

    Energy Technology Data Exchange (ETDEWEB)

    Feagins, Alicia R.; Basler, Christopher F., E-mail: chris.basler@mssm.edu

    2015-11-15

    Lloviu virus (LLOV) is a new member of the filovirus family that also includes Ebola virus (EBOV) and Marburg virus (MARV). LLOV has not been cultured; however, its genomic RNA sequence indicates the coding capacity to produce homologs of the EBOV and MARV VP24, VP35, and VP40 proteins. EBOV and MARV VP35 proteins inhibit interferon (IFN)-alpha/beta production and EBOV VP35 blocks activation of the antiviral kinase PKR. The EBOV VP24 and MARV VP40 proteins inhibit IFN signaling, albeit by different mechanisms. Here we demonstrate that LLOV VP35 suppresses Sendai virus induced IFN regulatory factor 3 (IRF3) phosphorylation, IFN-α/β production, and PKR phosphorylation. Additionally, LLOV VP24 blocks tyrosine phosphorylated STAT1 binding to karyopherin alpha 5 (KPNA5), STAT1 nuclear accumulation, and IFN-induced gene expression. LLOV VP40 lacks detectable IFN antagonist function. These activities parallel EBOV IFN inhibitory functions. EBOV and LLOV VP35 and VP24 proteins also inhibit IFN responses in bat cells. These data suggest that LLOV infection will block innate immune responses in a manner similar to EBOV. - Highlights: • Lloviu virus (LLOV) is a new member of the filovirus family. • LLOV VP35 blocks IRF3 phosphorylation, IFN-α/β production and PKR phosphorylation. • LLOV VP24 inhibits IFN responses by targeting phospho-STAT1 KPNA interaction. • Infection by LLOV may block innate immune responses in a manner similar to EBOV.

  11. Tweaking Innate Immunity: The Promise of Innate Immunologicals as Anti-Infectives

    Directory of Open Access Journals (Sweden)

    Kenneth L Rosenthal

    2006-01-01

    Full Text Available New and exciting insights into the importance of the innate immune system are revolutionizing our understanding of immune defense against infections, pathogenesis, and the treatment and prevention of infectious diseases. The innate immune system uses multiple families of germline-encoded pattern recognition receptors (PRRs to detect infection and trigger a variety of antimicrobial defense mechanisms. PRRs are evolutionarily highly conserved and serve to detect infection by recognizing pathogen-associated molecular patterns that are unique to microorganisms and essential for their survival. Toll-like receptors (TLRs are transmembrane signalling receptors that activate gene expression programs that result in the production of proinflammatory cytokines and chemokines, type I interferons and antimicrobial factors. Furthermore, TLR activation facilitates and guides activation of adaptive immune responses through the activation of dendritic cells. TLRs are localized on the cell surface and in endosomal/lysosomal compartments, where they detect bacterial and viral infections. In contrast, nucleotide-binding oligomerization domain proteins and RNA helicases are located in the cell cytoplasm, where they serve as intracellular PRRs to detect cytoplasmic infections, particularly viruses. Due to their ability to enhance innate immune responses, novel strategies to use ligands, synthetic agonists or antagonists of PRRs (also known as 'innate immunologicals' can be used as stand-alone agents to provide immediate protection or treatment against bacterial, viral or parasitic infections. Furthermore, the newly appreciated importance of innate immunity in initiating and shaping adaptive immune responses is contributing to our understanding of vaccine adjuvants and promises to lead to improved next-generation vaccines.

  12. Candida innate immunity at the mucosa.

    Science.gov (United States)

    Richardson, Jonathan P; Moyes, David L; Ho, Jemima; Naglik, Julian R

    2018-03-08

    The tremendous diversity in microbial species that colonise the mucosal surfaces of the human body is only now beginning to be fully appreciated. Distinguishing between the behaviour of commensal microbes and harmful pathogens that reside at mucosal sites in the body is a complex, and exquisitely fine-tuned process central to mucosal health. The fungal pathobiont Candida albicans is frequently isolated from mucosal surfaces with an asymptomatic carriage rate of approximately 60% in the human population. While normally a benign member of the microbiota, overgrowth of C. albicans often results in localised mucosal infection causing morbidity in otherwise healthy individuals, and invasive infection that often causes death in the absence of effective immune defence. C. albicans triggers numerous innate immune responses at mucosal surfaces, and detection of C. albicans hyphae in particular, stimulates the production of antimicrobial peptides, danger-associated molecular patterns and cytokines that function to reduce fungal burdens during infection. This review will summarise our current understanding of innate immune responses to C. albicans at mucosal surfaces. Copyright © 2018. Published by Elsevier Ltd.

  13. Fish innate immunity against intestinal helminths.

    Science.gov (United States)

    Dezfuli, B S; Bosi, G; DePasquale, J A; Manera, M; Giari, L

    2016-03-01

    Most individual fish in farmed and wild populations are infected with parasites. Upon dissection of fish, helminths from gut are often easily visible. Enteric helminths include several species of digeneans, cestodes, acanthocephalans and nematodes. Some insights into biology, morphology and histopathological effects of the main fish enteric helminths taxa will be described here. The immune system of fish, as that of other vertebrates, can be subdivided into specific and aspecific types, which in vivo act in concert with each other and indeed are interdependent in many ways. Beyond the small number of well-described models that exist, research focusing on innate immunity in fish against parasitic infections is lacking. Enteric helminths frequently cause inflammation of the digestive tract, resulting in a series of chemical and morphological changes in the affected tissues and inducing leukocyte migration to the site of infection. This review provides an overview on the aspecific defence mechanisms of fish intestine against helminths. Emphasis will be placed on the immune cellular response involving mast cells, neutrophils, macrophages, rodlet cells and mucous cells against enteric helminths. Given the relative importance of innate immunity in fish, and the magnitude of economic loss in aquaculture as a consequence of disease, this area deserves considerable attention and support. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Innate immunity orchestrates adipose tissue homeostasis.

    Science.gov (United States)

    Lin, Yi-Wei; Wei, Li-Na

    2017-06-23

    Obesity is strongly associated with multiple diseases including insulin resistance, type 2 diabetes, cardiovascular diseases, fatty liver disease, neurodegenerative diseases and cancers, etc. Adipose tissue (AT), mainly brown AT (BAT) and white AT (WAT), is an important metabolic and endocrine organ that maintains whole-body homeostasis. BAT contributes to non-shivering thermogenesis in a cold environment; WAT stores energy and produces adipokines that fine-tune metabolic and inflammatory responses. Obesity is often characterized by over-expansion and inflammation of WAT where inflammatory cells/mediators are abundant, especially pro-inflammatory (M1) macrophages, resulting in chronic low-grade inflammation and leading to insulin resistance and metabolic complications. Macrophages constitute the major component of innate immunity and can be activated as a M1 or M2 (anti-inflammatory) phenotype in response to environmental stimuli. Polarized M1 macrophage causes AT inflammation, whereas polarized M2 macrophage promotes WAT remodeling into the BAT phenotype, also known as WAT browning/beiging, which enhances insulin sensitivity and metabolic health. This review will discuss the regulation of AT homeostasis in relation to innate immunity.

  15. Innate Immunity Evasion by Dengue Virus

    Directory of Open Access Journals (Sweden)

    Ana Fernandez-Sesma

    2012-03-01

    Full Text Available For viruses to productively infect their hosts, they must evade or inhibit important elements of the innate immune system, namely the type I interferon (IFN response, which negatively influences the subsequent development of antigen-specific adaptive immunity against those viruses. Dengue virus (DENV can inhibit both type I IFN production and signaling in susceptible human cells, including dendritic cells (DCs. The NS2B3 protease complex of DENV functions as an antagonist of type I IFN production, and its proteolytic activity is necessary for this function. DENV also encodes proteins that antagonize type I IFN signaling, including NS2A, NS4A, NS4B and NS5 by targeting different components of this signaling pathway, such as STATs. Importantly, the ability of the NS5 protein to bind and degrade STAT2 contributes to the limited host tropism of DENV to humans and non-human primates. In this review, we will evaluate the contribution of innate immunity evasion by DENV to the pathogenesis and host tropism of this virus.

  16. Innate immunity evasion by Dengue virus.

    Science.gov (United States)

    Morrison, Juliet; Aguirre, Sebastian; Fernandez-Sesma, Ana

    2012-03-01

    For viruses to productively infect their hosts, they must evade or inhibit important elements of the innate immune system, namely the type I interferon (IFN) response, which negatively influences the subsequent development of antigen-specific adaptive immunity against those viruses. Dengue virus (DENV) can inhibit both type I IFN production and signaling in susceptible human cells, including dendritic cells (DCs). The NS2B3 protease complex of DENV functions as an antagonist of type I IFN production, and its proteolytic activity is necessary for this function. DENV also encodes proteins that antagonize type I IFN signaling, including NS2A, NS4A, NS4B and NS5 by targeting different components of this signaling pathway, such as STATs. Importantly, the ability of the NS5 protein to bind and degrade STAT2 contributes to the limited host tropism of DENV to humans and non-human primates. In this review, we will evaluate the contribution of innate immunity evasion by DENV to the pathogenesis and host tropism of this virus.

  17. Evasion of the Innate Immune Type I Interferon System by Monkeypox Virus.

    Science.gov (United States)

    Arndt, William D; Cotsmire, Samantha; Trainor, Kelly; Harrington, Heather; Hauns, Kevin; Kibler, Karen V; Huynh, Trung P; Jacobs, Bertram L

    2015-10-01

    The vaccinia virus (VACV) E3 protein has been shown to be important for blocking activation of the cellular innate immune system and allowing viral replication to occur unhindered. Mutation or deletion of E3L severely affects viral host range and pathogenesis. While the monkeypox virus (MPXV) genome encodes a homologue of the VACV E3 protein, encoded by the F3L gene, the MPXV gene is predicted to encode a protein with a truncation of 37 N-terminal amino acids. VACV with a genome encoding a similarly truncated E3L protein (VACV-E3LΔ37N) has been shown to be attenuated in mouse models, and infection with VACV-E3LΔ37N has been shown to lead to activation of the host antiviral protein kinase R pathway. In this report, we present data demonstrating that, despite containing a truncated E3 homologue, MPXV phenotypically resembles a wild-type (wt) VACV rather than VACV-E3LΔ37N. Thus, MPXV appears to contain a gene or genes that can suppress the phenotypes associated with an N-terminal truncation in E3. The suppression maps to sequences outside F3L, suggesting that the suppression is extragenic in nature. Thus, MPXV appears to have evolved mechanisms to minimize the effects of partial inactivation of its E3 homologue. Poxviruses have evolved to have many mechanisms to evade host antiviral innate immunity; these mechanisms may allow these viruses to cause disease. Within the family of poxviruses, variola virus (which causes smallpox) is the most pathogenic, while monkeypox virus is intermediate in pathogenicity between vaccinia virus and variola virus. Understanding the mechanisms of monkeypox virus innate immune evasion will help us to understand the evolution of poxvirus innate immune evasion capabilities, providing a better understanding of how poxviruses cause disease. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  18. Blocked Randomization with Randomly Selected Block Sizes

    Directory of Open Access Journals (Sweden)

    Jimmy Efird

    2010-12-01

    Full Text Available When planning a randomized clinical trial, careful consideration must be given to how participants are selected for various arms of a study. Selection and accidental bias may occur when participants are not assigned to study groups with equal probability. A simple random allocation scheme is a process by which each participant has equal likelihood of being assigned to treatment versus referent groups. However, by chance an unequal number of individuals may be assigned to each arm of the study and thus decrease the power to detect statistically significant differences between groups. Block randomization is a commonly used technique in clinical trial design to reduce bias and achieve balance in the allocation of participants to treatment arms, especially when the sample size is small. This method increases the probability that each arm will contain an equal number of individuals by sequencing participant assignments by block. Yet still, the allocation process may be predictable, for example, when the investigator is not blind and the block size is fixed. This paper provides an overview of blocked randomization and illustrates how to avoid selection bias by using random block sizes.

  19. Blocked randomization with randomly selected block sizes.

    Science.gov (United States)

    Efird, Jimmy

    2011-01-01

    When planning a randomized clinical trial, careful consideration must be given to how participants are selected for various arms of a study. Selection and accidental bias may occur when participants are not assigned to study groups with equal probability. A simple random allocation scheme is a process by which each participant has equal likelihood of being assigned to treatment versus referent groups. However, by chance an unequal number of individuals may be assigned to each arm of the study and thus decrease the power to detect statistically significant differences between groups. Block randomization is a commonly used technique in clinical trial design to reduce bias and achieve balance in the allocation of participants to treatment arms, especially when the sample size is small. This method increases the probability that each arm will contain an equal number of individuals by sequencing participant assignments by block. Yet still, the allocation process may be predictable, for example, when the investigator is not blind and the block size is fixed. This paper provides an overview of blocked randomization and illustrates how to avoid selection bias by using random block sizes.

  20. Oral innate immunity in HIV infection in HAART era.

    Science.gov (United States)

    Nittayananta, Wipawee; Tao, Renchuan; Jiang, Lanlan; Peng, Yuanyuan; Huang, Yuxiao

    2016-01-01

    Oral innate immunity, an important component in host defense and immune surveillance in the oral cavity, plays a crucial role in the regulation of oral health. As part of the innate immune system, epithelial cells lining oral mucosal surfaces not only provide a physical barrier but also produce different antimicrobial peptides, including human β-defensins (hBDs), secretory leukocyte protease inhibitor (SLPI), and various cytokines. These innate immune mediators help in maintaining oral homeostasis. When they are impaired either by local or systemic causes, various oral infections and malignancies may be developed. Human immunodeficiency virus (HIV) infection and other co-infections appear to have both direct and indirect effects on systemic and local innate immunity leading to the development of oral opportunistic infections and malignancies. Highly active antiretroviral therapy (HAART), the standard treatment of HIV infection, contributed to a global reduction of HIV-associated oral lesions. However, prolonged use of HAART may lead to adverse effects on the oral innate immunity resulting in the relapse of oral lesions. This review article focused on the roles of oral innate immunity in HIV infection in HAART era. The following five key questions were addressed: (i) What are the roles of oral innate immunity in health and disease?, (ii) What are the effects of HIV infection on oral innate immunity?, (iii) What are the roles of oral innate immunity against other co-infections?, (iv) What are the effects of HAART on oral innate immunity?, and (v) Is oral innate immunity enhanced by HAART? © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. 31 CFR 595.301 - Blocked account; blocked property.

    Science.gov (United States)

    2010-07-01

    ... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY TERRORISM SANCTIONS REGULATIONS General Definitions § 595.301 Blocked account; blocked property. The terms blocked account and blocked...

  2. Unfolded protein response (UPR) signaling regulates arsenic trioxide-mediated macrophage innate immune function disruption

    Energy Technology Data Exchange (ETDEWEB)

    Srivastava, Ritesh K.; Li, Changzhao; Chaudhary, Sandeep C. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL (United States); Ballestas, Mary E. [Department of Pediatrics Infectious Disease, Children' s of Alabama, School of Medicine, University of Alabama at Birmingham, AL (United States); Elmets, Craig A. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL (United States); Robbins, David J. [Department of Surgery, Molecular Oncology Program, Miller School of Medicine, University of Miami, Miami (United States); Matalon, Sadis [Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL (United States); Deshane, Jessy S. [Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL (United States); Afaq, Farrukh [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL (United States); Bickers, David R. [Department of Dermatology, Columbia University Medical Center, New York (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL (United States)

    2013-11-01

    Arsenic exposure is known to disrupt innate immune functions in humans and in experimental animals. In this study, we provide a mechanism by which arsenic trioxide (ATO) disrupts macrophage functions. ATO treatment of murine macrophage cells diminished internalization of FITC-labeled latex beads, impaired clearance of phagocytosed fluorescent bacteria and reduced secretion of pro-inflammatory cytokines. These impairments in macrophage functions are associated with ATO-induced unfolded protein response (UPR) signaling pathway characterized by the enhancement in proteins such as GRP78, p-PERK, p-eIF2α, ATF4 and CHOP. The expression of these proteins is altered both at transcriptional and translational levels. Pretreatment with chemical chaperon, 4-phenylbutyric acid (PBA) attenuated the ATO-induced activation in UPR signaling and afforded protection against ATO-induced disruption of macrophage functions. This treatment also reduced ATO-mediated reactive oxygen species (ROS) generation. Interestingly, treatment with antioxidant N-acetylcysteine (NAC) prior to ATO exposure, not only reduced ROS production and UPR signaling but also improved macrophage functions. These data demonstrate that UPR signaling and ROS generation are interdependent and are involved in the arsenic-induced pathobiology of macrophage. These data also provide a novel strategy to block the ATO-dependent impairment in innate immune responses. - Highlights: • Inorganic arsenic to humans and experimental animals disrupt innate immune responses. • The mechanism underlying arsenic impaired macrophage functions involves UPR signaling. • Chemical chaperon attenuates arsenic-mediated macrophage function impairment. • Antioxidant, NAC blocks impairment in arsenic-treated macrophage functions.

  3. Unfolded protein response (UPR) signaling regulates arsenic trioxide-mediated macrophage innate immune function disruption

    International Nuclear Information System (INIS)

    Srivastava, Ritesh K.; Li, Changzhao; Chaudhary, Sandeep C.; Ballestas, Mary E.; Elmets, Craig A.; Robbins, David J.; Matalon, Sadis; Deshane, Jessy S.; Afaq, Farrukh; Bickers, David R.; Athar, Mohammad

    2013-01-01

    Arsenic exposure is known to disrupt innate immune functions in humans and in experimental animals. In this study, we provide a mechanism by which arsenic trioxide (ATO) disrupts macrophage functions. ATO treatment of murine macrophage cells diminished internalization of FITC-labeled latex beads, impaired clearance of phagocytosed fluorescent bacteria and reduced secretion of pro-inflammatory cytokines. These impairments in macrophage functions are associated with ATO-induced unfolded protein response (UPR) signaling pathway characterized by the enhancement in proteins such as GRP78, p-PERK, p-eIF2α, ATF4 and CHOP. The expression of these proteins is altered both at transcriptional and translational levels. Pretreatment with chemical chaperon, 4-phenylbutyric acid (PBA) attenuated the ATO-induced activation in UPR signaling and afforded protection against ATO-induced disruption of macrophage functions. This treatment also reduced ATO-mediated reactive oxygen species (ROS) generation. Interestingly, treatment with antioxidant N-acetylcysteine (NAC) prior to ATO exposure, not only reduced ROS production and UPR signaling but also improved macrophage functions. These data demonstrate that UPR signaling and ROS generation are interdependent and are involved in the arsenic-induced pathobiology of macrophage. These data also provide a novel strategy to block the ATO-dependent impairment in innate immune responses. - Highlights: • Inorganic arsenic to humans and experimental animals disrupt innate immune responses. • The mechanism underlying arsenic impaired macrophage functions involves UPR signaling. • Chemical chaperon attenuates arsenic-mediated macrophage function impairment. • Antioxidant, NAC blocks impairment in arsenic-treated macrophage functions

  4. Hemin activation of innate cellular response blocks human immunodeficiency virus type-1-induced osteoclastogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Takeda, Kazuyo [Microscopy and Imaging Core Facility, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD (United States); Adhikari, Rewati [Division of Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD (United States); Yamada, Kenneth M. [National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Dhawan, Subhash, E-mail: subhash.dhawan@fda.hhs.gov [Division of Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD (United States)

    2015-08-14

    The normal skeletal developmental and homeostatic process termed osteoclastogenesis is exacerbated in numerous pathological conditions and causes excess bone loss. In cancer and HIV-1-infected patients, this disruption of homeostasis results in osteopenia and eventual osteoporesis. Counteracting the factors responsible for these metabolic disorders remains a challenge for preventing or minimizing this co-morbidity associated with these diseases. In this report, we demonstrate that a hemin-induced host protection mechanism not only suppresses HIV-1 associated osteoclastogenesis, but it also exhibits anti-osteoclastogenic activity for non-infected cells. Since the mode of action of hemin is both physiological and pharmacological through induction of heme oxygenase-1 (HO-1), an endogenous host protective response to an FDA-licensed therapeutic used to treat another disease, our study suggests an approach to developing novel, safe and effective therapeutic strategies for treating bone disorders, because hemin administration in humans has previously met required FDA safety standards. - Highlights: • HIV-1 infection induced osteoclastogenesis in primary human macrophages. • Heme oxygenase-1 (HO-1) induction inhibited HIV-1-induced osteoclastogenesis in macrophages. • HO-1 induction suppressed RANKL-enhanced osteoclastogenesis in HIV-1-infected macrophages. • This inverse relationship between HO-1 and HIV-1 pathogenesis may define a novel host defense response against HIV-1 infection.

  5. Innate resistance to avian influenza: Of MHC's and Mx proteins

    Science.gov (United States)

    Avian influenza (AI) is an economically important virus of poultry that has significant impact on global trade. Recently, increased attention to animal genomics has been applied to enhance innate resistance to infectious diseases in poultry. Two known contributors to innate resistance are the host m...

  6. Innate immunological function of TH2 cells in vivo

    Science.gov (United States)

    Th2 cells produce IL-13 when stimulated by papain or house dust mites (HDM) and induce eosinophilic inflammation. This innate response of cells of the adaptive immune system is dependent on IL-33-, not T cell receptor-, based stimulation. While type 2 innate lymphoid cells (ILC2s) are the dominant ...

  7. Cell-autonomous stress responses in innate immunity.

    Science.gov (United States)

    Moretti, Julien; Blander, J Magarian

    2017-01-01

    The innate immune response of phagocytes to microbes has long been known to depend on the core signaling cascades downstream of pattern recognition receptors (PRRs), which lead to expression and production of inflammatory cytokines that counteract infection and induce adaptive immunity. Cell-autonomous responses have recently emerged as important mechanisms of innate immunity. Either IFN-inducible or constitutive, these processes aim to guarantee cell homeostasis but have also been shown to modulate innate immune response to microbes and production of inflammatory cytokines. Among these constitutive cell-autonomous responses, autophagy is prominent and its role in innate immunity has been well characterized. Other stress responses, such as metabolic stress, the ER stress/unfolded protein response, mitochondrial stress, or the DNA damage response, seem to also be involved in innate immunity, although the precise mechanisms by which they regulate the innate immune response are not yet defined. Of importance, these distinct constitutive cell-autonomous responses appear to be interconnected and can also be modulated by microbes and PRRs, which add further complexity to the interplay between innate immune signaling and cell-autonomous responses in the mediation of an efficient innate immune response. © Society for Leukocyte Biology.

  8. Modulation of the innate immune responses in the striped ...

    African Journals Online (AJOL)

    Thus, most of the innate non-specific immune responses are inducible though they are constitutive of fish immune system exhibiting a basal level of activity even in the absence of pathogen challenge. Keywords: Aeromonas hydrophila, Experimental challenge, Innate immune response, Striped snakehead murrel ...

  9. Innatism, Concept Formation, Concept Mastery and Formal Education

    Science.gov (United States)

    Winch, Christopher

    2015-01-01

    This article will consider the claim that the possession of concepts is innate rather than learned. Innatism about concept learning is explained through consideration of the work of Fodor and Chomsky. First, an account of concept formation is developed. Second the argument against the claim that concepts are learned through the construction of a…

  10. Generalized Block Failure

    DEFF Research Database (Denmark)

    Jönsson, Jeppe

    2015-01-01

    Block tearing is considered in several codes as a pure block tension or a pure block shear failure mechanism. However in many situations the load acts eccentrically and involves the transfer of a substantial moment in combination with the shear force and perhaps a normal force. A literature study...... shows that no readily available tests with a well-defined substantial eccentricity have been performed. This paper presents theoretical and experimental work leading towards generalized block failure capacity methods. Simple combination of normal force, shear force and moment stress distributions along...

  11. Innate immune response development in nestling tree swallows

    Science.gov (United States)

    Stambaugh, T.; Houdek, B.J.; Lombardo, M.P.; Thorpe, P.A.; Caldwell, Hahn D.

    2011-01-01

    We tracked the development of innate immunity in nestling Tree Swallows (Tachycineta bicolor) and compared it to that of adults using blood drawn from nestlings during days 6, 12, and 18 of the ???20-day nestling period and from adults. Innate immunity was characterized using an in vitro assay of the ability of whole blood to kill Escherichia coli. The ability of whole blood to kill E. coli increased as nestlings matured. Neither this component of innate immunity nor right wing chord length on day18 were as developed as in adults indicating that development of the innate immune system and growth both continued after fledging. Narrow sense heritability analyses suggest that females with strong immune responses produced nestlings with strong immune responses. These data suggest nestling Tree Swallows allocated sufficient energy to support rapid growth to enable fledging by day 18, but that further development of innate immunity occurred post-fledging. ?? 2011 by the Wilson Ornithological Society.

  12. Are innate immune signaling pathways in plants and animals conserved?

    Science.gov (United States)

    Ausubel, Frederick M

    2005-10-01

    Although adaptive immunity is unique to vertebrates, the innate immune response seems to have ancient origins. Common features of innate immunity in vertebrates, invertebrate animals and plants include defined receptors for microbe-associated molecules, conserved mitogen-associated protein kinase signaling cascades and the production of antimicrobial peptides. It is commonly reported that these similarities in innate immunity represent a process of divergent evolution from an ancient unicellular eukaryote that pre-dated the divergence of the plant and animal kingdoms. However, at present, data suggest that the seemingly analogous regulatory modules used in plant and animal innate immunity are a consequence of convergent evolution and reflect inherent constraints on how an innate immune system can be constructed.

  13. Innate cell communication kick-starts pathogen-specific immunity

    Science.gov (United States)

    Rivera, Amariliz; Siracusa, Mark C.; Yap, George S.; Gause, William C.

    2016-01-01

    Innate cells are responsible for the rapid recognition of infection and mediate essential mechanisms of pathogen elimination, and also facilitate adaptive immune responses. We review here the numerous intricate interactions among innate cells that initiate protective immunity. The efficient eradication of pathogens depends on the coordinated actions of multiple cells, including innate cells and epithelial cells. Rather than acting as isolated effector cells, innate cells are in constant communication with other responding cells of the immune system, locally and distally. These interactions are critically important for the efficient control of primary infections as well for the development of ‘trained’ innate cells that facilitate the rapid elimination of homologous or heterologous infections. PMID:27002843

  14. Cellular Innate Immunity: An Old Game with New Players.

    Science.gov (United States)

    Gasteiger, Georg; D'Osualdo, Andrea; Schubert, David A; Weber, Alexander; Bruscia, Emanuela M; Hartl, Dominik

    2017-01-01

    Innate immunity is a rapidly evolving field with novel cell types and molecular pathways being discovered and paradigms changing continuously. Innate and adaptive immune responses are traditionally viewed as separate from each other, but emerging evidence suggests that they overlap and mutually interact. Recently discovered cell types, particularly innate lymphoid cells and myeloid-derived suppressor cells, are gaining increasing attention. Here, we summarize and highlight current concepts in the field, focusing on innate immune cells as well as the inflammasome and DNA sensing which appear to be critical for the activation and orchestration of innate immunity, and may provide novel therapeutic opportunities for treating autoimmune, autoinflammatory, and infectious diseases. © 2016 S. Karger AG, Basel.

  15. Innate sexuality determines the mechanisms of telomere maintenance.

    Science.gov (United States)

    Tasaka, Kenta; Yokoyama, Naoki; Nodono, Hanae; Hoshi, Motonori; Matsumoto, Midori

    2013-01-01

    Recently, telomere length has been shown to be differentially regulated in asexually and sexually reproducing planarians. In addition, it was found that asexual worms maintain telomere length somatically during reproduction by fission or when regeneration is induced by amputation, whereas sexual worms only achieve telomere elongation through sexual reproduction. We have established an experimental bioassay system to induce switching from asexual to sexual reproduction in planarians, that is, sexualization. In this study, the relationship between the reproductive mode and telomere maintenance was investigated using innate asexually reproducing worms, innate sexually reproducing worms, and experimentally sexualized worms. Here, we show that innate asexual planarians maintain telomere length during cell division and that innate sexual planarians exhibit telomere shortening. However, experimental sexualized worms maintain telomere length during cell division. These results indicate that innate sexuality is linked to the mechanism of telomere maintenance.

  16. MAP Kinase Cascades in Plant Innate Immunity

    Directory of Open Access Journals (Sweden)

    Magnus Wohlfahrt Rasmussen

    2012-07-01

    Full Text Available Plant mitogen-activated protein kinase (MAPK cascades generally transduce extracellular stimuli into cellular responses. These stimuli include the perception of pathogen-associated molecular patterns (PAMPs by host transmembrane pattern recognition receptors (PRRs which trigger MAPK-dependent innate immune responses. In the model Arabidopsis, molecular genetic evidence implicates a number of MAPK cascade components in PAMP signaling, and in responses to immunity-related phytohormones such as ethylene, jasmonate and salicylate. In a few cases, cascade components have been directly linked to the transcription of target genes or to the regulation of phytohormone synthesis. Thus MAPKs are obvious targets for bacterial effector proteins and are likely guardees of resistance (R proteins, which mediate defense signaling in response to the action of effectors, or effector-triggered immunity (ETI. This mini-review discusses recent progress in this field with a focus on the Arabidopsis MAPKs MPK3, 4, 6 and 11 in their apparent pathways.

  17. Ocular Surface as Barrier of Innate Immunity

    Science.gov (United States)

    Bolaños-Jiménez, Rodrigo; Navas, Alejandro; López-Lizárraga, Erika Paulina; de Ribot, Francesc March; Peña, Alexandra; Graue-Hernández, Enrique O; Garfias, Yonathan

    2015-01-01

    Sight is one of the most important senses that human beings possess. The ocular system is a complex structure equipped with mechanisms that prevent or limit damage caused by physical, chemical, infectious and environmental factors. These mechanisms include a series of anatomical, cellular and humoral factors that have been a matter of study. The cornea is not only the most powerful and important lens of the optical system, but also, it has been involved in many other physiological and pathological processes apart from its refractive nature; the morphological and histological properties of the cornea have been thoroughly studied for the last fifty years; drawing attention in its molecular characteristics of immune response. This paper will review the anatomical and physiological aspects of the cornea, conjunctiva and lacrimal apparatus, as well as the innate immunity at the ocular surface. PMID:26161163

  18. Interactions between Innate Immunity, Microbiota, and Probiotics.

    Science.gov (United States)

    Giorgetti, GianMarco; Brandimarte, Giovanni; Fabiocchi, Federica; Ricci, Salvatore; Flamini, Paolo; Sandri, Giancarlo; Trotta, Maria Cristina; Elisei, Walter; Penna, Antonio; Lecca, Piera Giuseppina; Picchio, Marcello; Tursi, Antonio

    2015-01-01

    The term "microbiota" means genetic inheritance associated with microbiota, which is about 100 times larger than the guest. The tolerance of the resident bacterial flora is an important key element of immune cell function. A key role in the interaction between the host and the microbiota is played by Paneth cell, which is able to synthesize and secrete proteins and antimicrobial peptides, such as α/β defensins, cathelicidin, 14 β-glycosidases, C-type lectins, and ribonuclease, in response to various stimuli. Recent studies found probiotics able to preserve intestinal homeostasis by downmodulating the immune response and inducing the development of T regulatory cells. Specific probiotic strain, as well as probiotic-driven metabolic products called "postbiotics," has been recently recognized and it is able to influence innate immunity. New therapeutic approaches based on probiotics are now available, and further treatments based on postbiotics will come in the future.

  19. Deciphering the Innate Lymphoid Cell Transcriptional Program

    Directory of Open Access Journals (Sweden)

    Cyril Seillet

    2016-10-01

    Full Text Available Innate lymphoid cells (ILCs are enriched at mucosal surfaces, where they provide immune surveillance. All ILC subsets develop from a common progenitor that gives rise to pre-committed progenitors for each of the ILC lineages. Currently, the temporal control of gene expression that guides the emergence of these progenitors is poorly understood. We used global transcriptional mapping to analyze gene expression in different ILC progenitors. We identified PD-1 to be specifically expressed in PLZF+ ILCp and revealed that the timing and order of expression of the transcription factors NFIL3, ID2, and TCF-1 was critical. Importantly, induction of ILC lineage commitment required only transient expression of NFIL3 prior to ID2 and TCF-1 expression. These findings highlight the importance of the temporal program that permits commitment of progenitors to the ILC lineage, and they expand our understanding of the core transcriptional program by identifying potential regulators of ILC development.

  20. Innate immune evasion strategies of influenza viruses.

    Science.gov (United States)

    Hale, Benjamin G; Albrecht, Randy A; García-Sastre, Adolfo

    2010-01-01

    Influenza viruses are globally important human respiratory pathogens. These viruses cause seasonal epidemics and occasional worldwide pandemics, both of which can vary significantly in disease severity. The virulence of a particular influenza virus strain is partly determined by its success in circumventing the host immune response. This article briefly reviews the innate mechanisms that host cells have evolved to resist virus infection, and outlines the plethora of strategies that influenza viruses have developed in order to counteract such powerful defences. The molecular details of this virus-host interplay are summarized, and the ways in which research in this area is being applied to the rational design of protective vaccines and novel antivirals are discussed.

  1. Innate immune defences in the human endometrium

    Directory of Open Access Journals (Sweden)

    Kelly Rodney W

    2003-11-01

    Full Text Available Abstract The human endometrium is an important site of innate immune defence, giving protection against uterine infection. Such protection is critical to successful implantation and pregnancy. Infection is a major cause of preterm birth and can also cause infertility and ectopic pregnancy. Natural anti-microbial peptides are key mediators of the innate immune system. These peptides, between them, have anti-bacterial, anti-fungal and anti-viral activity and are expressed at epithelial surfaces throughout the female genital tract. Two families of natural anti-microbials, the defensins and the whey acidic protein (WAP motif proteins, appear to be prominent in endometrium. The human endometrial epithelium expresses beta-defensins 1–4 and the WAP motif protein, secretory leukocyte protease inhibitor. Each beta-defensin has a different expression profile in relation to the stage of the menstrual cycle, providing potential protection throughout the cycle. Secretory leukocyte protease inhibitor is expressed during the secretory phase of the cycle and has a range of possible roles including anti-protease and anti-microbial activity as well as having effects on epithelial cell growth. The leukocyte populations in the endometrium are also a source of anti-microbial production. Neutrophils are a particularly rich source of alpha-defensins, lactoferrin, lysozyme and the WAP motif protein, elafin. The presence of neutrophils during menstruation will enhance anti-microbial protection at a time when the epithelial barrier is disrupted. Several other anti-microbials including the natural killer cell product, granulysin, are likely to have a role in endometrium. The sequential production of natural anti-microbial peptides by the endometrium throughout the menstrual cycle and at other sites in the female genital tract will offer protection from many pathogens, including those that are sexually transmitted.

  2. Pulmonary contusion primes systemic innate immunity responses.

    Science.gov (United States)

    Hoth, J Jason; Martin, R S; Yoza, Barbara K; Wells, Jonathan D; Meredith, J W; McCall, Charles E

    2009-07-01

    Traumatic injury may result in an exaggerated response to subsequent immune stimuli such as nosocomial infection. This "second hit" phenomenon and molecular mechanism(s) of immune priming by traumatic lung injury, specifically, pulmonary contusion, remain unknown. We used an animal model of pulmonary contusion to determine whether the injury resulted in priming of the innate immune response and to test the hypothesis that resuscitation fluids could attenuate the primed response to a second hit. Male, 8 to 9 weeks, C57/BL6 mice with a pulmonary contusion were challenged by a second hit of intratracheal administration of the Toll-like receptor 4 agonist, lipopolysaccharide (LPS, 50 microg) 24 hours after injury (injury + LPS). Other experimental groups were injury + vehicle or LPS alone. A separate group was injured and resuscitated by 4 cc/kg of hypertonic saline (HTS) or Lactated Ringer's (LR) resuscitation before LPS challenge. Mice were killed 4 hours after LPS challenge and blood, bronchoalveolar lavage, and tissue were isolated and analyzed. Data were analyzed using one-way analysis of variance with Bonferroni multiple comparison posttest for significant differences (*p < or = 0.05). Injury + LPS showed immune priming observed by lung injury histology and increased bronchoalveolar lavage neutrophilia, lung myeloperoxidase and serum IL-6, CXCL1, and MIP-2 levels when compared with injury + vehicle or LPS alone. After injury, resuscitation with HTS, but not Lactated Ringer's was more effective in attenuating the primed response to a second hit. Pulmonary contusion primes innate immunity for an exaggerated response to a second hit with the Toll-like receptor 4 agonist, LPS. We observed synergistic increases in inflammatory mediator expression in the blood and a more severe lung injury in injured animals challenged with LPS. This priming effect was reduced when HTS was used to resuscitate the animal after lung contusion.

  3. Alzheimer's disease: Innate immunity gone awry?

    Science.gov (United States)

    VanItallie, Theodore B

    2017-04-01

    Inflammation is an immune activity designed to protect the host from pathogens and noxious agents. In its low-intensity form, presence of an inflammatory process must be inferred from appropriate biomarkers. Occult neuroinflammation is not just secondary to Alzheimer's disease (AD) but may contribute to its pathogenesis and promote its progression. A leaky blood-brain barrier (BBB) has been observed in early AD and may play a role in its initiation and development. Studies of the temporal evolution of AD's biomarkers have shown that, in AD, the brain's amyloid burden correlates poorly with cognitive decline. In contrast, cognitive deficits in AD correlate well with synapse loss. Oligomeric forms of amyloid-beta (oAβs) can be synaptotoxic and evidence of their deposition inside synaptic terminals of cognition-associated neurons explains early memory loss in AD better than formation of extracellular Aβ plaques. Among innate immune cells that reside in the brain, microglia sense danger signals represented by proteins like oAβ and become activated by neuronal damage such as that caused by bacterial endotoxins. The resulting reactive microgliosis has been implicated in generating the chronic form of microglial activation believed to promote AD's development. Genome-wide association studies (GWASs) have yielded data from patients with sporadic AD indicating that its causes include genetic variation in the innate immune system. Recent preclinical studies have reported that β-hydroxybutyrate (βOHB) may protect the brain from the adverse effects of both the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome and the deacetylation of histone. Consequently, there is an urgent need for clinical investigations designed to test whether an orally administered βOHB preparation, such as a ketone ester, can have a similar beneficial effect in human subjects. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Vibrio cholerae T3SS effector VopE modulates mitochondrial dynamics and innate immune signaling by targeting Miro GTPases.

    Science.gov (United States)

    Suzuki, Masato; Danilchanka, Olga; Mekalanos, John J

    2014-11-12

    The cellular surveillance-activated detoxification and defenses (cSADD) theory postulates the presence of host surveillance mechanisms that monitor the integrity of common cellular processes and components targeted by pathogen effectors. Being organelles essential for multiple cellular processes, including innate immune responses, mitochondria represent an attractive target for pathogens. We describe a Vibrio cholerae Type 3 secretion system effector VopE that localizes to mitochondria during infection and acts as a specific GTPase-activating protein to interfere with the function of mitochondrial Rho GTPases Miro1 and Miro2. Miro GTPases modulate mitochondrial dynamics and interfering with this functionality effectively blocks innate immune responses that presumably require mitochondria as signaling platforms. Our data indicate that interference with mitochondrial dynamics may be an unappreciated strategy that pathogens use to block host innate immune responses that would otherwise control these bacterial infections. VopE might represent a bacterial effector that targets the cSADD surveillance response. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Human Milk Hyaluronan Enhances Innate Defense of the Intestinal Epithelium*

    Science.gov (United States)

    Hill, David R.; Rho, Hyunjin K.; Kessler, Sean P.; Amin, Ripal; Homer, Craig R.; McDonald, Christine; Cowman, Mary K.; de la Motte, Carol A.

    2013-01-01

    Breast-feeding is associated with enhanced protection from gastrointestinal disease in infants, mediated in part by an array of bioactive glycan components in milk that act through molecular mechanisms to inhibit enteric pathogen infection. Human milk contains hyaluronan (HA), a glycosaminoglycan polymer found in virtually all mammalian tissues. We have shown that synthetic HA of a specific size range promotes expression of antimicrobial peptides in intestinal epithelium. We hypothesize that hyaluronan from human milk also enhances innate antimicrobial defense. Here we define the concentration of HA in human milk during the first 6 months postpartum. Importantly, HA isolated from milk has a biological function. Treatment of HT-29 colonic epithelial cells with human milk HA at physiologic concentrations results in time- and dose-dependent induction of the antimicrobial peptide human β-defensin 2 and is abrogated by digestion of milk HA with a specific hyaluronidase. Milk HA induction of human β-defensin 2 expression is also reduced in the presence of a CD44-blocking antibody and is associated with a specific increase in ERK1/2 phosphorylation, suggesting a role for the HA receptor CD44. Furthermore, oral administration of human milk-derived HA to adult, wild-type mice results in induction of the murine Hβ D2 ortholog in intestinal mucosa and is dependent upon both TLR4 and CD44 in vivo. Finally, treatment of cultured colonic epithelial cells with human milk HA enhances resistance to infection by the enteric pathogen Salmonella typhimurium. Together, our observations suggest that maternally provided HA stimulates protective antimicrobial defense in the newborn. PMID:23950179

  6. Homogeneous bilateral block shifts

    Indian Academy of Sciences (India)

    Homogeneous bilateral block shifts. ADAM KORÁNYI. Department of Mathematics, The Graduate Center, City University of New York,. New York, NY 10016, USA. E-mail: Adam.Koranyi@lehman.cuny.edu. MS received 18 January 2013. Abstract. A new 3-parameter family of homogeneous 2-by-2 block shifts is described.

  7. Related Drupal Nodes Block

    NARCIS (Netherlands)

    Van der Vegt, Wim

    2010-01-01

    Related Drupal Nodes Block This module exposes a block that uses Latent Semantic Analysis (Lsa) internally to suggest three nodes that are relevant to the node a user is viewing. This module performs three tasks. 1) It periodically indexes a Drupal site and generates a Lsa Term Document Matrix.

  8. Control rod blocking monitor

    International Nuclear Information System (INIS)

    Suzuki, Shigeru.

    1993-01-01

    The number of times for setting up a control rod blocking monitor of a BWR type power plant is remarkably reduced to mitigate operator's burden. In the control rod blocking monitor, trip levels, as a judging standard upon outputting control rod blocking inhibition signals, are set up stepwise depending on the power level around control rods put to blocking control. The present invention comprises an allowance judging means capable of setting up trip levels for each of power levels corresponding to a plurality of control rods at once if the power levels are within the set up allowable range. With such a constitution, the set up allowable range is determined previously in the allowance judging means. Accordingly, when a gang blocking is conducted to control rods, if power levels around the control rods are increased at once into the set up allowable range, the trip levels for each of the control rods are set up at once. (I.S.)

  9. Pentraxins in innate immunity: lessons from PTX3.

    Science.gov (United States)

    Deban, Livija; Jaillon, Sebastien; Garlanda, Cecilia; Bottazzi, Barbara; Mantovani, Alberto

    2011-01-01

    The innate immune system constitutes the first line of defence against microorganisms and plays a primordial role in the activation and regulation of adaptive immunity. The innate immune system is composed of a cellular arm and a humoral arm. Components of the humoral arm include members of the complement cascade and soluble pattern recognition molecules (PRMs). These fluid-phase PRMs represent the functional ancestors of antibodies and play a crucial role in the discrimination between self, non-self and modified-self. Moreover, evidence has been presented that these soluble PRMs participate in the regulation of inflammatory responses and interact with the cellular arm of the innate immune system. Pentraxins consist of a set of multimeric soluble proteins and represent the prototypic components of humoral innate immunity. Based on the primary structure of the protomer, pentraxins are divided into two groups: short pentraxins and long pentraxins. The short pentraxins C-reactive protein and serum amyloid P-component are produced by the liver and represent the main acute phase proteins in human and mouse, respectively. The long pentraxin PTX3 is produced by innate immunity cells (e.g. PMN, macrophages, dendritic cells), interacts with several ligands and plays an essential role in innate immunity, tuning inflammation and matrix deposition. PTX3 provides a paradigm for the mode of action of humoral innate immunity.

  10. Predictability of blocking

    International Nuclear Information System (INIS)

    Tosi, E.; Ruti, P.; Tibaldi, S.; D'Andrea, F.

    1994-01-01

    Tibaldi and Molteni (1990, hereafter referred to as TM) had previously investigated operational blocking predictability by the ECMWF model and the possible relationships between model systematic error and blocking in the winter season of the Northern Hemisphere, using seven years of ECMWF operational archives of analyses and day 1 to 10 forecasts. They showed that fewer blocking episodes than in the real atmosphere were generally simulated by the model, and that this deficiency increased with increasing forecast time. As a consequence of this, a major contribution to the systematic error in the winter season was shown to derive from the inability of the model to properly forecast blocking. In this study, the analysis performed in TM for the first seven winter seasons of the ECMWF operational model is extended to the subsequent five winters, during which model development, reflecting both resolution increases and parametrisation modifications, continued unabated. In addition the objective blocking index developed by TM has been applied to the observed data to study the natural low frequency variability of blocking. The ability to simulate blocking of some climate models has also been tested

  11. Innate lymphoid cells, possible interaction with microbiota.

    Science.gov (United States)

    Moro, Kazuyo; Koyasu, Shigeo

    2015-01-01

    Recent studies have identified novel lymphocyte subsets named innate lymphoid cells (ILCs) lacking antigen-specific receptors. ILCs are present in a wide variety of epithelial compartments and occupy an intermediate position between acquired immune cells and myeloid cells. ILCs are now classified into three groups: group 1 ILC, group 2 ILC, and group 3 ILC based on their cytokine production patterns that correspond to the helper T cell subsets Th1, Th2, and Th17, respectively. ILCs play important roles in protection against various invading microbes including multicellular parasites, and in the maintenance of homeostasis and repair of epithelial layers. Excessive activation of ILCs, however, leads to various inflammatory disease conditions. ILCs have thus attracted interests of many researchers in the fields of infectious immunity, inflammatory diseases, and allergic diseases. Because epithelial cells sense alterations in environmental cues, it is important to understand the functional interaction between epithelial cells, ILCs, and environmental factors such as commensal microbiota. We discuss in this review developmental pathways of ILCs, their functions, and contribution of commensal microbiota to the differentiation and function of ILCs.

  12. 31 CFR 594.301 - Blocked account; blocked property.

    Science.gov (United States)

    2010-07-01

    ... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY GLOBAL TERRORISM SANCTIONS REGULATIONS General Definitions § 594.301 Blocked account; blocked property. The terms blocked account and...

  13. Bundle Branch Block

    Science.gov (United States)

    ... 2015. Bundle branch block Symptoms & causes Diagnosis & treatment Advertisement Mayo Clinic does not endorse companies or products. ... a Job Site Map About This Site Twitter Facebook Google YouTube Pinterest Mayo Clinic is a not- ...

  14. Blocked Urethral Valves

    Science.gov (United States)

    ... the penis. Rarely, small membranes form across the urethra in boys early in pregnancy, and they can block the flow of urine out of the bladder. These membranes are called posterior urethral valves and can have life-threatening consequences ...

  15. Optoelectronics using block copolymers.

    Energy Technology Data Exchange (ETDEWEB)

    Botiz, I.; Darling, S. B.; Center for Nanoscale Materials

    2010-05-01

    Block copolymers, either as semiconductors themselves or as structure directors, are emerging as a promising class of materials for understanding and controlling processes associated with both photovoltaic energy conversion and light emitting devices.

  16. Trained immunity: a memory for innate host defense

    NARCIS (Netherlands)

    Netea, M.G.; Quintin, J.; Meer, J.W.M. van der

    2011-01-01

    Immune responses in vertebrates are classically divided into innate and adaptive, with only the latter being able to build up immunological memory. However, although lacking adaptive immune responses, plants and invertebrates are protected against reinfection with pathogens, and invertebrates even

  17. The Innate Immune-Related Genes in Catfish

    Science.gov (United States)

    Gao, Lei; He, Chongbo; Liu, Xueguang; Su, Hao; Gao, Xianggang; Li, Yunfeng; Liu, Weidong

    2012-01-01

    Catfish is one of the most important aquaculture species in America (as well as in Asia and Africa). In recent years, the production of catfish has suffered massive financial losses due to pathogen spread and breakouts. Innate immunity plays a crucial role in increasing resistance to pathogenic organisms and has generated increasing interest in the past few years. This review summarizes the current understanding of innate immune-related genes in catfish, including pattern recognition receptors, antimicrobial peptides, complements, lectins, cytokines, transferrin and gene expression profiling using microarrays and next generation sequencing technologies. This review will benefit the understanding of innate immune system in catfish and further efforts in studying the innate immune-related genes in fish. PMID:23203058

  18. Neural regulation of innate and adaptive immunity in the gut

    NARCIS (Netherlands)

    Dhawan, S.

    2017-01-01

    This thesis investigates the role of neurotransmitters acetylcholine (ACh) and norepinephrine (NE), in modulating the innate and adaptive immune function in the intestine, during physiological and pathophysiological conditions. Furthermore, this thesis attempts to advance our current understanding

  19. RNA-virus proteases counteracting host innate immunity.

    Science.gov (United States)

    Lei, Jian; Hilgenfeld, Rolf

    2017-10-01

    Virus invasion triggers host immune responses, in particular, innate immune responses. Pathogen-associated molecular patterns of viruses (such as dsRNA, ssRNA, or viral proteins) released during virus replication are detected by the corresponding pattern-recognition receptors of the host, and innate immune responses are induced. Through production of type-I and type-III interferons as well as various other cytokines, the host innate immune system forms the frontline to protect host cells and inhibit virus infection. Not surprisingly, viruses have evolved diverse strategies to counter this antiviral system. In this review, we discuss the multiple strategies used by proteases of positive-sense single-stranded RNA viruses of the families Picornaviridae, Coronaviridae, and Flaviviridae, when counteracting host innate immune responses. © 2017 Federation of European Biochemical Societies.

  20. Effects of engineered nanoparticles on the innate immune system.

    Science.gov (United States)

    Liu, Yuanchang; Hardie, Joseph; Zhang, Xianzhi; Rotello, Vincent M

    2017-12-01

    Engineered nanoparticles (NPs) have broad applications in industry and nanomedicine. When NPs enter the body, interactions with the immune system are unavoidable. The innate immune system, a non-specific first line of defense against potential threats to the host, immediately interacts with introduced NPs and generates complicated immune responses. Depending on their physicochemical properties, NPs can interact with cells and proteins to stimulate or suppress the innate immune response, and similarly activate or avoid the complement system. NPs size, shape, hydrophobicity and surface modification are the main factors that influence the interactions between NPs and the innate immune system. In this review, we will focus on recent reports about the relationship between the physicochemical properties of NPs and their innate immune response, and their applications in immunotherapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Role of Aging on Innate Responses to Viral Infections

    OpenAIRE

    Goldstein, Daniel R.

    2011-01-01

    Older people exhibit increased morbidity and mortality after viral infections than younger people. Additionally, vaccines are less protective in older people than in younger people. As the immune system is critical for host defense to viral infections and for vaccine efficacy, the implications are that aging negatively affects immunity. The immune system is broadly categorized into adaptive and innate systems. The innate immune system acts as a first line of defense to pathogen invasion. In t...

  2. Innate immune functions of microglia isolated from human glioma patients

    Directory of Open Access Journals (Sweden)

    Grimm Elizabeth

    2006-03-01

    Full Text Available Abstract Background Innate immunity is considered the first line of host defense and microglia presumably play a critical role in mediating potent innate immune responses to traumatic and infectious challenges in the human brain. Fundamental impairments of the adaptive immune system in glioma patients have been investigated; however, it is unknown whether microglia are capable of innate immunity and subsequent adaptive anti-tumor immune responses within the immunosuppressive tumor micro-environment of human glioma patients. We therefore undertook a novel characterization of the innate immune phenotype and function of freshly isolated human glioma-infiltrating microglia (GIM. Methods GIM were isolated by sequential Percoll purification from patient tumors immediately after surgical resection. Flow cytometry, phagocytosis and tumor cytotoxicity assays were used to analyze the phenotype and function of these cells. Results GIM expressed significant levels of Toll-like receptors (TLRs, however they do not secrete any of the cytokines (IL-1β, IL-6, TNF-α critical in developing effective innate immune responses. Similar to innate macrophage functions, GIM can mediate phagocytosis and non-MHC restricted cytotoxicity. However, they were statistically less able to mediate tumor cytotoxicity compared to microglia isolated from normal brain. In addition, the expression of Fas ligand (FasL was low to absent, indicating that apoptosis of the incoming lymphocyte population may not be a predominant mode of immunosuppression by microglia. Conclusion We show for the first time that despite the immunosuppressive environment of human gliomas, GIM are capable of innate immune responses such as phagocytosis, cytotoxicity and TLR expression but yet are not competent in secreting key cytokines. Further understanding of these innate immune functions could play a critical role in understanding and developing effective immunotherapies to malignant human gliomas.

  3. Regulation of Intestinal Homeostasis by Innate Immune Cells

    OpenAIRE

    Kayama, Hisako; Nishimura, Junichi; Takeda, Kiyoshi

    2013-01-01

    The intestinal immune system has an ability to distinguish between the microbiota and pathogenic bacteria, and then activate pro-inflammatory pathways against pathogens for host defense while remaining unresponsive to the microbiota and dietary antigens. In the intestine, abnormal activation of innate immunity causes development of several inflammatory disorders such as inflammatory bowel diseases (IBD). Thus, activity of innate immunity is finely regulated in the intestine. To date, multiple...

  4. Interplay between Candida albicans and the Mammalian Innate Host Defense

    Science.gov (United States)

    Cheng, Shih-Chin; Joosten, Leo A. B.; Kullberg, Bart-Jan

    2012-01-01

    Candida albicans is both the most common fungal commensal microorganism in healthy individuals and the major fungal pathogen causing high mortality in at-risk populations, especially immunocompromised patients. In this review, we summarize the interplay between the host innate system and C. albicans, ranging from how the host recognizes, responds, and clears C. albicans infection to how C. albicans evades, dampens, and escapes from host innate immunity. PMID:22252867

  5. Innateness and culture in the evolution of language

    OpenAIRE

    Kirby, Simon; Dowman, Mike; Griffiths, Thomas L.

    2007-01-01

    Human language arises from biological evolution, individual learning, and cultural transmission, but the interaction of these three processes has not been widely studied. We set out a formal framework for analyzing cultural transmission, which allows us to investigate how innate learning biases are related to universal properties of language. We show that cultural transmission can magnify weak biases into strong linguistic universals, undermining one of the arguments for strong innate constra...

  6. 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....

  7. Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production

    OpenAIRE

    Zhang, Junjie; Zhu, Lining; Feng, Pinghui

    2014-01-01

    In response to a viral infection, the host innate immune response is activated to up-regulate gene expression and production of antiviral cytokines. Conversely, viruses have evolved intricate strategies to evade and exploit host immune signaling for survival and propagation. Viral immune evasion, entailing host defense and viral evasion, provides one of the most fascinating and dynamic interfaces to discern the host-virus interaction. These studies advance our understanding in innate immune r...

  8. Sepsis syndromes: understanding the role of innate and acquired immunity.

    Science.gov (United States)

    Oberholzer, A; Oberholzer, C; Moldawer, L L

    2001-08-01

    An intact innate and acquired immune response are essential for defeating systemic microbial infections. Recognition molecules, inflammatory cells, and the cytokines they produce are the principal means for host tissues to recognize invading microbes and to initiate intercellular communication between the innate and acquired immune systems. However, activation of host innate immunity may also occur in the absence of microbial recognition, through expression of internal "danger" signals produced by tissue ischemia and necrosis. When activation of the innate immune system is severe enough, the host response itself can propel the patient into a systemic inflammatory response syndrome (SIRS), or even multiple system organ failure (MSOF) and shock. Although most patients survive the initial SIRS insult, these patients remain at increased risk of developing secondary or opportunistic infections because of the frequent onset of a compensatory anti-inflammatory response syndrome (CARS). The initial activation of the innate immune response often leads to macrophage deactivation, T-cell anergy, and the rapid apoptotic loss of lymphoid tissues, which all contribute to the development of this CARS syndrome and its associated morbidity and mortality. Initial efforts to treat the septic patient with anticytokine therapies directed at the SIRS response have been disappointing, and therapeutic efforts to modify the immune response during sepsis syndromes will require a more thorough understanding of the innate and acquired immune responses and the increased apoptosis in the lymphoid tissue.

  9. Stress Hyperglycemia, Insulin Treatment, and Innate Immune Cells

    Directory of Open Access Journals (Sweden)

    Fangming Xiu

    2014-01-01

    Full Text Available Hyperglycemia (HG and insulin resistance are the hallmarks of a profoundly altered metabolism in critical illness resulting from the release of cortisol, catecholamines, and cytokines, as well as glucagon and growth hormone. Recent studies have proposed a fundamental role of the immune system towards the development of insulin resistance in traumatic patients. A comprehensive review of published literatures on the effects of hyperglycemia and insulin on innate immunity in critical illness was conducted. This review explored the interaction between the innate immune system and trauma-induced hypermetabolism, while providing greater insight into unraveling the relationship between innate immune cells and hyperglycemia. Critical illness substantially disturbs glucose metabolism resulting in a state of hyperglycemia. Alterations in glucose and insulin regulation affect the immune function of cellular components comprising the innate immunity system. Innate immune system dysfunction via hyperglycemia is associated with a higher morbidity and mortality in critical illness. Along with others, we hypothesize that reduction in morbidity and mortality observed in patients receiving insulin treatment is partially due to its effect on the attenuation of the immune response. However, there still remains substantial controversy regarding moderate versus intensive insulin treatment. Future studies need to determine the integrated effects of HG and insulin on the regulation of innate immunity in order to provide more effective insulin treatment regimen for these patients.

  10. Acquired and innate immunity to polyaromatic hydrocarbons

    International Nuclear Information System (INIS)

    Yusuf, Nabiha; Timares, Laura; Seibert, Megan D.; Xu Hui; Elmets, Craig A.

    2007-01-01

    Polyaromatic hydrocarbons are ubiquitous environmental pollutants that are potent mutagens and carcinogens. Researchers have taken advantage of these properties to investigate the mechanisms by which chemicals cause cancer of the skin and other organs. When applied to the skin of mice, several carcinogenic polyaromatic hydrocarbons have also been shown to interact with the immune system, stimulating immune responses and resulting in the development of antigen-specific T-cell-mediated immunity. Development of cell-mediated immunity is strain-specific and is governed by Ah receptor genes and by genes located within the major histocompatibility complex. CD8 + T cells are effector cells in the response, whereas CD4 + T cells down-regulate immunity. Development of an immune response appears to have a protective effect since strains of mice that develop a cell-mediated immune response to carcinogenic polyaromatic hydrocarbons are less likely to develop tumors when subjected to a polyaromatic hydrocarbon skin carcinogenesis protocol than mice that fail to develop an immune response. With respect to innate immunity, TLR4-deficient C3H/HeJ mice are more susceptible to polyaromatic hydrogen skin tumorigenesis than C3H/HeN mice in which TLR4 is normal. These findings support the hypothesis that immune responses, through their interactions with chemical carcinogens, play an active role in the prevention of chemical skin carcinogenesis during the earliest stages. Efforts to augment immune responses to the chemicals that cause tumors may be a productive approach to the prevention of tumors caused by these agents

  11. Dengue Virus Targets the Adaptor Protein MITA to Subvert Host Innate Immunity

    Science.gov (United States)

    Yu, Chia-Yi; Chang, Tsung-Hsien; Liang, Jian-Jong; Chiang, Ruei-Lin; Lee, Yi-Ling; Liao, Ching-Len; Lin, Yi-Ling

    2012-01-01

    Dengue is one of the most important arboviral diseases caused by infection of four serotypes of dengue virus (DEN). We found that activation of interferon regulatory factor 3 (IRF3) triggered by viral infection and by foreign DNA and RNA stimulation was blocked by DEN-encoded NS2B3 through a protease-dependent mechanism. The key adaptor protein in type I interferon pathway, human mediator of IRF3 activation (MITA) but not the murine homologue MPYS, was cleaved in cells infected with DEN-1 or DEN-2 and with expression of the enzymatically active protease NS2B3. The cleavage site of MITA was mapped to LRR↓96G and the function of MITA was suppressed by dengue protease. DEN replication was reduced with overexpression of MPYS but not with MITA, while DEN replication was enhanced by MPYS knockdown, indicating an antiviral role of MITA/MPYS against DEN infection. The involvement of MITA in DEN-triggered innate immune response was evidenced by reduction of IRF3 activation and IFN induction in cells with MITA knockdown upon DEN-2 infection. NS2B3 physically interacted with MITA, and the interaction and cleavage of MITA could be further enhanced by poly(dA:dT) stimulation. Thus, we identified MITA as a novel host target of DEN protease and provide the molecular mechanism of how DEN subverts the host innate immunity. PMID:22761576

  12. Dengue virus targets the adaptor protein MITA to subvert host innate immunity.

    Science.gov (United States)

    Yu, Chia-Yi; Chang, Tsung-Hsien; Liang, Jian-Jong; Chiang, Ruei-Lin; Lee, Yi-Ling; Liao, Ching-Len; Lin, Yi-Ling

    2012-01-01

    Dengue is one of the most important arboviral diseases caused by infection of four serotypes of dengue virus (DEN). We found that activation of interferon regulatory factor 3 (IRF3) triggered by viral infection and by foreign DNA and RNA stimulation was blocked by DEN-encoded NS2B3 through a protease-dependent mechanism. The key adaptor protein in type I interferon pathway, human mediator of IRF3 activation (MITA) but not the murine homologue MPYS, was cleaved in cells infected with DEN-1 or DEN-2 and with expression of the enzymatically active protease NS2B3. The cleavage site of MITA was mapped to LRR↓(96)G and the function of MITA was suppressed by dengue protease. DEN replication was reduced with overexpression of MPYS but not with MITA, while DEN replication was enhanced by MPYS knockdown, indicating an antiviral role of MITA/MPYS against DEN infection. The involvement of MITA in DEN-triggered innate immune response was evidenced by reduction of IRF3 activation and IFN induction in cells with MITA knockdown upon DEN-2 infection. NS2B3 physically interacted with MITA, and the interaction and cleavage of MITA could be further enhanced by poly(dA:dT) stimulation. Thus, we identified MITA as a novel host target of DEN protease and provide the molecular mechanism of how DEN subverts the host innate immunity.

  13. Dengue virus targets the adaptor protein MITA to subvert host innate immunity.

    Directory of Open Access Journals (Sweden)

    Chia-Yi Yu

    Full Text Available Dengue is one of the most important arboviral diseases caused by infection of four serotypes of dengue virus (DEN. We found that activation of interferon regulatory factor 3 (IRF3 triggered by viral infection and by foreign DNA and RNA stimulation was blocked by DEN-encoded NS2B3 through a protease-dependent mechanism. The key adaptor protein in type I interferon pathway, human mediator of IRF3 activation (MITA but not the murine homologue MPYS, was cleaved in cells infected with DEN-1 or DEN-2 and with expression of the enzymatically active protease NS2B3. The cleavage site of MITA was mapped to LRR↓(96G and the function of MITA was suppressed by dengue protease. DEN replication was reduced with overexpression of MPYS but not with MITA, while DEN replication was enhanced by MPYS knockdown, indicating an antiviral role of MITA/MPYS against DEN infection. The involvement of MITA in DEN-triggered innate immune response was evidenced by reduction of IRF3 activation and IFN induction in cells with MITA knockdown upon DEN-2 infection. NS2B3 physically interacted with MITA, and the interaction and cleavage of MITA could be further enhanced by poly(dA:dT stimulation. Thus, we identified MITA as a novel host target of DEN protease and provide the molecular mechanism of how DEN subverts the host innate immunity.

  14. 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.

  15. Inhibition of antiviral innate immunity by birnavirus VP3 protein via blockage of viral double-stranded RNA binding to the host cytoplasmic RNA detector MDA5.

    Science.gov (United States)

    Ye, Chengjin; Jia, Lu; Sun, Yanting; Hu, Boli; Wang, Lun; Lu, Xingmeng; Zhou, Jiyong

    2014-10-01

    Chicken MDA5 (chMDA5), the sole known pattern recognition receptor for cytoplasmic viral RNA in chickens, initiates type I interferon (IFN) production. Infectious bursal disease virus (IBDV) evades host innate immunity, but the mechanism is unclear. We report here that IBDV inhibited antiviral innate immunity via the chMDA5-dependent signaling pathway. IBDV infection did not induce efficient type I interferon (IFN) production but antagonized the antiviral activity of beta interferon (IFN-β) in DF-1 cells pretreated with IFN-α/β. Dual-luciferase assays and inducible expression systems demonstrated that IBDV protein VP3 significantly inhibited IFN-β expression stimulated by naked IBDV genomic double-stranded RNA (dsRNA). The VP3 protein competed strongly with chMDA5 to bind IBDV genomic dsRNA in vitro and in vivo, and VP3 from other birnaviruses also bound dsRNA. Site-directed mutagenesis confirmed that deletion of the VP3 dsRNA binding domain restored IFN-β expression. Our data demonstrate that VP3 inhibits antiviral innate immunity by blocking binding of viral genomic dsRNA to MDA5. MDA5, a known pattern recognition receptor and cytoplasmic viral RNA sensor, plays a critical role in host antiviral innate immunity. Many pathogens escape or inhibit the host antiviral immune response, but the mechanisms involved are unclear for most pathogens. We report here that birnaviruses inhibit host antiviral innate immunity via the MDA5-dependent signaling pathway. The antiviral innate immune system involving IFN-β did not function effectively during birnavirus infection, and the viral protein VP3 significantly inhibited IFN-β expression stimulated by naked viral genomic dsRNA. We also show that VP3 blocks MDA5 binding to viral genomic dsRNA in vitro and in vivo. Our data reveal that birnavirus-encoded viral protein VP3 is an inhibitor of the antiviral innate immune response and inhibits the antiviral innate immune response via the MDA5-dependent signaling pathway

  16. Right bundle branch block

    DEFF Research Database (Denmark)

    Bussink, Barbara E; Holst, Anders Gaarsdal; Jespersen, Lasse

    2013-01-01

    AimsTo determine the prevalence, predictors of newly acquired, and the prognostic value of right bundle branch block (RBBB) and incomplete RBBB (IRBBB) on a resting 12-lead electrocardiogram in men and women from the general population.Methods and resultsWe followed 18 441 participants included.......5%/2.3% in women, P Right bundle branch block was associated with significantly...... increased all-cause and cardiovascular mortality in both genders with age-adjusted hazard ratios (HR) of 1.31 [95% confidence interval (CI), 1.11-1.54] and 1.87 (95% CI, 1.48-2.36) in the gender pooled analysis with little attenuation after multiple adjustment. Right bundle branch block was associated...

  17. Early life innate immune signatures of persistent food allergy.

    Science.gov (United States)

    Neeland, Melanie R; Koplin, Jennifer J; Dang, Thanh D; Dharmage, Shyamali C; Tang, Mimi L; Prescott, Susan L; Saffery, Richard; Martino, David J; Allen, Katrina J

    2017-11-14

    Food allergy naturally resolves in a proportion of food-allergic children without intervention; however the underlying mechanisms governing the persistence or resolution of food allergy in childhood are not understood. This study aimed to define the innate immune profiles associated with egg allergy at age 1 year, determine the phenotypic changes that occur with the development of natural tolerance in childhood, and explore the relationship between early life innate immune function and serum vitamin D. This study used longitudinally collected PBMC samples from a population-based cohort of challenge-confirmed egg-allergic infants with either persistent or transient egg allergy outcomes in childhood to phenotype and quantify the functional innate immune response associated with clinical phenotypes of egg allergy. We show that infants with persistent egg allergy exhibit a unique innate immune signature, characterized by increased numbers of circulating monocytes and dendritic cells that produce more inflammatory cytokines both at baseline and following endotoxin exposure when compared with infants with transient egg allergy. Follow-up analysis revealed that this unique innate immune signature continues into childhood in those with persistent egg allergy and that increased serum vitamin D levels correlate with changes in innate immune profiles observed in children who developed natural tolerance to egg. Early life innate immune dysfunction may represent a key immunological driver and predictor of persistent food allergy in childhood. Serum vitamin D may play an immune-modulatory role in the development of natural tolerance. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  18. HIV-1 evades innate immune recognition through specific cofactor recruitment

    Science.gov (United States)

    Rasaiyaah, Jane; Tan, Choon Ping; Fletcher, Adam J.; Price, Amanda J.; Blondeau, Caroline; Hilditch, Laura; Jacques, David A.; Selwood, David L.; James, Leo C.; Noursadeghi, Mahdad; Towers, Greg J.

    2013-11-01

    Human immunodeficiency virus (HIV)-1 is able to replicate in primary human macrophages without stimulating innate immunity despite reverse transcription of genomic RNA into double-stranded DNA, an activity that might be expected to trigger innate pattern recognition receptors. We reasoned that if correctly orchestrated HIV-1 uncoating and nuclear entry is important for evasion of innate sensors then manipulation of specific interactions between HIV-1 capsid and host factors that putatively regulate these processes should trigger pattern recognition receptors and stimulate type 1 interferon (IFN) secretion. Here we show that HIV-1 capsid mutants N74D and P90A, which are impaired for interaction with cofactors cleavage and polyadenylation specificity factor subunit 6 (CPSF6) and cyclophilins (Nup358 and CypA), respectively, cannot replicate in primary human monocyte-derived macrophages because they trigger innate sensors leading to nuclear translocation of NF-κB and IRF3, the production of soluble type 1 IFN and induction of an antiviral state. Depletion of CPSF6 with short hairpin RNA expression allows wild-type virus to trigger innate sensors and IFN production. In each case, suppressed replication is rescued by IFN-receptor blockade, demonstrating a role for IFN in restriction. IFN production is dependent on viral reverse transcription but not integration, indicating that a viral reverse transcription product comprises the HIV-1 pathogen-associated molecular pattern. Finally, we show that we can pharmacologically induce wild-type HIV-1 infection to stimulate IFN secretion and an antiviral state using a non-immunosuppressive cyclosporine analogue. We conclude that HIV-1 has evolved to use CPSF6 and cyclophilins to cloak its replication, allowing evasion of innate immune sensors and induction of a cell-autonomous innate immune response in primary human macrophages.

  19. DMPD: Innate immunity minireview series: making biochemical sense of nucleic acidsensors that trigger antiviral innate immunity. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17395579 Innate immunity minireview series: making biochemical sense of nucleic aci...007 Mar 29. (.png) (.svg) (.html) (.csml) Show Innate immunity minireview series: making biochemical sense o...itle Innate immunity minireview series: making biochemical sense of nucleic acidsensors that trigger antivir

  20. E-Block: A Tangible Programming Tool with Graphical Blocks

    OpenAIRE

    Danli Wang; Yang Zhang; Shengyong Chen

    2013-01-01

    This paper designs a tangible programming tool, E-Block, for children aged 5 to 9 to experience the preliminary understanding of programming by building blocks. With embedded artificial intelligence, the tool defines the programming blocks with the sensors as the input and enables children to write programs to complete the tasks in the computer. The symbol on the programming block's surface is used to help children understanding the function of each block. The sequence information is transfer...

  1. Innate immune recognition of double-stranded RNA triggers increased expression of NKG2D ligands after virus infection.

    Science.gov (United States)

    Esteso, Gloria; Guerra, Susana; Valés-Gómez, Mar; Reyburn, Hugh T

    2017-12-15

    Self/non-self-discrimination by the innate immune system relies on germline-encoded, non-rearranging receptors expressed by innate immune cells recognizing conserved pathogen-associated molecular patterns. The natural killer group 2D (NKG2D) receptor is a potent immune-activating receptor that binds human genome-encoded ligands, whose expression is negligible in normal tissues, but increased in stress and disease conditions for reasons that are incompletely understood. Here it is not clear how the immune system reconciles receptor binding of self-proteins with self/non-self-discrimination to avoid autoreactivity. We now report that increased expression of NKG2D ligands after virus infection depends on interferon response factors activated by the detection of viral double-stranded RNA by pattern-recognition receptors (RIG-I/MDA-5) and that NKG2D ligand up-regulation can be blocked by the expression of viral dsRNA-binding proteins. Thus, innate immunity-mediated recognition of viral nucleic acids triggers the infected cell to release interferon for NK cell recruitment and to express NKG2D ligands to become more visible to the immune system. Finally, the observation that NKG2D-ligand induction is a consequence of signaling by pattern-recognition receptors that have been selected over evolutionary time to be highly pathogen-specific explains how the risks of autoreactivity in this system are minimized. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. Herpes simplex virus 1 infection dampens the immediate early antiviral innate immunity signaling from peroxisomes by tegument protein VP16.

    Science.gov (United States)

    Zheng, Chunfu; Su, Chenhe

    2017-02-21

    Herpes simplex virus 1 (HSV-1) is an archetypal member of the alphaherpesvirus subfamily with a large genome encoding over 80 proteins, many of which play a critical role in virus-host interactions and immune modulation. Upon viral infections, the host cells activate innate immune responses to restrict their replications. Peroxisomes, which have long been defined to regulate metabolic activities, are reported to be important signaling platforms for antiviral innate immunity. It has been verified that signaling from peroxisomal MAVS (MAVS-Pex) triggers a rapid interferon (IFN) independent IFN-stimulated genes (ISGs) production against invading pathogens. However, little is known about the interaction between DNA viruses such as HSV-1 and the MAVS-Pex mediated signaling. HSV-1 could activate the MAVS-Pex signaling pathway at a low multiplicity of infection (MOI), while infection at a high MOI dampens MAVS-Pex induced immediately early ISGs production. A high-throughput screen assay reveals that HSV-1 tegument protein VP16 inhibits the immediate early ISGs expression downstream of MAVS-Pex signaling. Moreover, the expression of ISGs was recovered when VP16 was knockdown with its specific short hairpin RNA. HSV-1 blocks MAVS-Pex mediated early ISGs production through VP16 to dampen the immediate early antiviral innate immunity signaling from peroxisomes.

  3. The human cytomegalovirus tegument protein pp65 (pUL83): a key player in innate immune evasion.

    Science.gov (United States)

    Biolatti, Matteo; Dell'Oste, Valentina; De Andrea, Marco; Landolfo, Santo

    2018-01-31

    The germline encoded proteins serving as "pattern recognition receptors" (PRRs) constitute the earliest step in the innate immune response by recognizing the "pathogen-associated molecular patterns" (PAMPs) that comprise microbe nucleic acids and proteins usually absent from healthy hosts. Upon detection of exogenous nucleic acid two different innate immunity signaling cascades are activated. The first culminates in the production of chemokines, cytokines, and type I interferons (IFN-I), while the second leads to inflammasome complex formation. Human cytomegalovirus (HCMV), a member of the -herpesvirus subfamily, is a wide spread pathogen that infects a vast majority of the world's population. The virion has an icosahedral capsid that contains a linear dsDNA genome of approximately 240 kb, surrounded by an outer lipid envelope and a proteinaceous tegument containing several viral proteins. Despite the numerous and multifaceted antiviral effects of IFNs and cytokines, HCMV is able to invade, multiply, and establish persistent infection in healthy human hosts. To achieve this goal the virus has developed different strategies to block the IFN-I response and to alter the physiological outcomes of the IFN-inducible genes. This article focuses on HCMV tegument pp65 by reviewing its mechanisms of action in favoring virus evasion from the host innate immune response.

  4. Contaminated soil concrete blocks

    NARCIS (Netherlands)

    de Korte, A.C.J.; Brouwers, Jos; Limbachiya, Mukesh C.; Kew, Hsein Y.

    2009-01-01

    According to Dutch law the contaminated soil needs to be remediated or immobilised. The main focus in this article is the design of concrete blocks, containing contaminated soil, that are suitable for large production, financial feasible and meets all technical and environmental requirements. In

  5. Making Block Grants Accountable.

    Science.gov (United States)

    Chelimsky, Eleanor

    Methods of accountability are presented in considering the Reagan administration plan to consolidate 84 federal health, education and social service grants into six block grant areas and to cut overall funding. After matching aspects of public criticism with proposal objectives, a rationale is developed for building elements of accountability into…

  6. Linoleum Block Printing Revisited.

    Science.gov (United States)

    Chetelat, Frank J.

    1980-01-01

    The author discusses practical considerations of teaching linoleum block printing in the elementary grades (tool use, materials, motivation) and outlines a sequence of design concepts in this area for the primary, intermediate and junior high grades. A short list of books and audiovisual aids is appended. (SJL)

  7. Effects of Block Scheduling

    Directory of Open Access Journals (Sweden)

    William R. Veal

    1999-09-01

    Full Text Available This study examined the effects of a tri-schedule on the academic achievement of students in a high school. The tri-schedule consists of traditional, 4x4 block, and hybrid schedules running at the same time in the same high school. Effectiveness of the schedules was determined from the state mandated test of basic skills in reading, language, and mathematics. Students who were in a particular schedule their freshman year were tested at the beginning of their sophomore year. A statistical ANCOVA test was performed using the schedule types as independent variables and cognitive skill index and GPA as covariates. For reading and language, there was no statistically significant difference in test results. There was a statistical difference mathematics-computation. Block mathematics is an ideal format for obtaining more credits in mathematics, but the block format does little for mathematics achievement and conceptual understanding. The results have content specific implications for schools, administrations, and school boards who are considering block scheduling adoption.

  8. Coding with Blockly

    CERN Document Server

    Lovett, Amber

    2017-01-01

    "Blockly is a fun, graphical programming language designed to get kids interested in creating their own computer programs. Through simple text written to foster creativity and problem solving, students will the art of innovation. Large, colorful images show students how to complete activities. Additional tools, including a glossary and an index, help students learn new vocabulary and locate information."-- Provided by publisher.

  9. Probiotic Modulation of Innate Cell Pathogen Sensing and Signaling Events

    Directory of Open Access Journals (Sweden)

    Amy Llewellyn

    2017-10-01

    Full Text Available There is a growing body of evidence documenting probiotic bacteria to have a beneficial effect to the host through their ability to modulate the mucosal immune system. Many probiotic bacteria can be considered to act as either immune activators or immune suppressors, which have appreciable influence on homeostasis, inflammatory- and suppressive-immunopathology. What is becoming apparent is the ability of these probiotics to modulate innate immune responses via direct or indirect effects on the signaling pathways that drive these activatory or suppressive/tolerogenic mechanisms. This review will focus on the immunomodulatory role of probiotics on signaling pathways in innate immune cells: from positive to negative regulation associated with innate immune cells driving gut mucosal functionality. Research investigations have shown probiotics to modulate innate functionality in many ways including, receptor antagonism, receptor expression, binding to and expression of adaptor proteins, expression of negative regulatory signal molecules, induction of micro-RNAs, endotoxin tolerisation and finally, the secretion of immunomodulatory proteins, lipids and metabolites. The detailed understanding of the immunomodulatory signaling effects of probiotic strains will facilitate strain-specific selective manipulation of innate cell signal mechanisms in the modulation of mucosal adjuvanticity, immune deviation and tolerisation in both healthy subjects and patients with inflammatory and suppressive pathology.

  10. Postnatal Innate Immune Development: From Birth to Adulthood

    Directory of Open Access Journals (Sweden)

    Anastasia Georgountzou

    2017-08-01

    Full Text Available It is well established that adaptive immune responses are deficient in early life, contributing to increased mortality and morbidity. The developmental trajectories of different components of innate immunity are only recently being explored. Individual molecules, cells, or pathways of innate recognition and signaling, within different compartments/anatomical sites, demonstrate variable maturation patterns. Despite some discrepancies among published data, valuable information is emerging, showing that the developmental pattern of cytokine responses during early life is age and toll-like receptor specific, and may be modified by genetic and environmental factors. Interestingly, specific environmental exposures have been linked both to innate function modifications and the occurrence of chronic inflammatory disorders, such as respiratory allergies. As these conditions are on the rise, our knowledge on innate immune development and its modulating factors needs to be expanded. Improved understanding of the sequence of events associated with disease onset and persistence will lead toward meaningful interventions. This review describes the state-of-the-art on normal postnatal innate immune ontogeny and highlights research areas that are currently explored or should be further addressed.

  11. Convergence of the innate and adaptive immunity during human aging

    Directory of Open Access Journals (Sweden)

    Branca Isabel Pereira

    2016-11-01

    Full Text Available Aging is associated with profound changes in the human immune system, a phenomenon referred to as immunosenescence. This complex immune remodeling affects the adaptive immune system and the CD8+ T cell compartment in particular, leading to the accumulation of terminally differentiated T cells, which can rapidly exert their effector functions at the expenses of a limited proliferative potential. In this review we will discuss evidence suggesting that senescent αβCD8+ T cells acquire the hallmarks of innate-like T cells and use recently acquired NK cell receptors as an alternative mechanism to mediate rapid effector functions. These cells concomitantly lose expression of co-stimulatory receptors and exhibit decreased TCR signaling suggesting a functional shift away from antigen specific activation. The convergence of innate and adaptive features in senescent T cells challenges the classic division between innate and adaptive immune systems. Innate-like T cells are particularly important for stress and tumor surveillance and we propose a new role for these cells in aging, where the acquisition of innate-like functions may represent a beneficial adaptation to an increased burden of malignancy with age, although it may also pose a higher risk of autoimmune disorders.

  12. Infectious Agents as Stimuli of Trained Innate Immunity.

    Science.gov (United States)

    Rusek, Paulina; Wala, Mateusz; Druszczyńska, Magdalena; Fol, Marek

    2018-02-03

    The discoveries made over the past few years have modified the current immunological paradigm. It turns out that innate immunity cells can mount some kind of immunological memory, similar to that observed in the acquired immunity and corresponding to the defense mechanisms of lower organisms, which increases their resistance to reinfection. This phenomenon is termed trained innate immunity. It is based on epigenetic changes in innate immune cells (monocytes/macrophages, NK cells) after their stimulation with various infectious or non-infectious agents. Many infectious stimuli, including bacterial or fungal cells and their components (LPS, β-glucan, chitin) as well as viruses or even parasites are considered potent inducers of innate immune memory. Epigenetic cell reprogramming occurring at the heart of the phenomenon may provide a useful basis for designing novel prophylactic and therapeutic strategies to prevent and protect against multiple diseases. In this article, we present the current state of art on trained innate immunity occurring as a result of infectious agent induction. Additionally, we discuss the mechanisms of cell reprogramming and the implications for immune response stimulation/manipulation.

  13. Trained immunity: A smart way to enhance innate immune defence.

    Science.gov (United States)

    van der Meer, Jos W M; Joosten, Leo A B; Riksen, Niels; Netea, Mihai G

    2015-11-01

    The innate arm of the immune system is generally viewed as primitive and non-specific and - in contrast to the adaptive immune arm - not to possess memory. However in plants and invertebrate animals that lack adaptive immunity, innate immunity will exhibit a prolonged enhanced functional state after adequate priming. A similar enhancement of function of the innate immunity has occasionally been described in vertebrates, including humans. Over the past few years we have studied this phenomenon in greater detail and we have coined the term 'Trained (innate) immunity' (TI). TI can be induced by a variety of stimuli, of which we have studied BCG and β-glucan in greater detail. The non-specific protective effects of BCG that have been observed in vaccination studies in the literature are probably due to TI. Monocytes and macrophages are among the main cells of the innate immune arm that can be trained. We have discovered that both BCG (via NOD2 signalling) and β-glucan (via dectin-1) induce epigenetic reprogramming, in particular stable changes in histone trimethylation at H3K4. These epigenetic changes lead to cellular activation, enhanced cytokine production and a change in the metabolic state of the cell with a shift from oxidative phosphorylation to aerobic glycolysis. TI is not only important for host defence and vaccine responses, but most probably also for diseases like atherosclerosis. Modulation of TI is a promising area for new treatments. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. [Masquerading bundle branch block].

    Science.gov (United States)

    Kukla, Piotr; Baranchuk, Adrian; Jastrzębski, Marek; Bryniarski, Leszek

    2014-01-01

    We here describe a surface 12-lead electrocardiogram (ECG) of a 72-year-old female with a prior history of breast cancer and chemotherapy-induced cardiomyopathy. An echocardiogram revealed left ventricular dysfunction, ejection fraction of 23%, with mild enlarged left ventricle. The 12-lead ECG showed atrial fibrillation with a mean heart rate of about 100 bpm, QRS duration 160 ms, QT interval 400 ms, right bundle branch block (RBBB) and left anterior fascicular block (LAFB). The combination of RBBB features in the precordial leads and LAFB features in the limb leads is known as ''masquerading bundle branch block''. In most cases of RBBB and LAFB, the QRS axis deviation is located between - 80 to -120 degrees. Rarely, when predominant left ventricular forces are present, the QRS axis deviation is near about -90 degrees, turning the pattern into an atypical form. In a situation of RBBB associated with LAFB, the S wave can be absent or very small in lead I. Such a situation is the result of not only purely LAFB but also with left ventricular hypertrophy and/or focal block due to scar (extensive anterior myocardial infarction) or fibrosis (cardiomyopathy). Sometimes, this specific ECG pattern is mistaken for LBBB. RBBB with LAFB may imitate LBBB either in the limb leads (known as 'standard masquerading' - absence of S wave in lead I), or in the precordial leads (called 'precordial masquerading' - absence of S wave in leads V₅ and V₆). Our ECG showed both these types of masquerading bundle branch block - absence of S wave in lead I and in leads V₅ and V₆.

  15. Novel adaptive and innate immunity targets in hypertension.

    Science.gov (United States)

    Abais-Battad, Justine M; Dasinger, John Henry; Fehrenbach, Daniel J; Mattson, David L

    2017-06-01

    Hypertension is a worldwide epidemic and global health concern as it is a major risk factor for the development of cardiovascular diseases. A relationship between the immune system and its contributing role to the pathogenesis of hypertension has been long established, but substantial advancements within the last few years have dissected specific causal molecular mechanisms. This review will briefly examine these recent studies exploring the involvement of either innate or adaptive immunity pathways. Such pathways to be discussed include innate immunity factors such as antigen presenting cells and pattern recognition receptors, adaptive immune elements including T and B lymphocytes, and more specifically, the emerging role of T regulatory cells, as well as the potential of cytokines and chemokines to serve as signaling messengers connecting innate and adaptive immunity. Together, we summarize these studies to provide new perspective for what will hopefully lead to more targeted approaches to manipulate the immune system as hypertensive therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Retinoic Acid and Its Role in Modulating Intestinal Innate Immunity.

    Science.gov (United States)

    Czarnewski, Paulo; Das, Srustidhar; Parigi, Sara M; Villablanca, Eduardo J

    2017-01-13

    Vitamin A (VA) is amongst the most well characterized food-derived nutrients with diverse immune modulatory roles. Deficiency in dietary VA has not only been associated with immune dysfunctions in the gut, but also with several systemic immune disorders. In particular, VA metabolite all-trans retinoic acid ( at RA) has been shown to be crucial in inducing gut tropism in lymphocytes and modulating T helper differentiation. In addition to the widely recognized role in adaptive immunity, increasing evidence identifies at RA as an important modulator of innate immune cells, such as tolerogenic dendritic cells (DCs) and innate lymphoid cells (ILCs). Here, we focus on the role of retinoic acid in differentiation, trafficking and the functions of innate immune cells in health and inflammation associated disorders. Lastly, we discuss the potential involvement of at RA during the plausible crosstalk between DCs and ILCs.

  17. Innate Lung Defense during Invasive Aspergillosis: New Mechanisms.

    Science.gov (United States)

    Garth, Jaleesa M; Steele, Chad

    2017-01-01

    Invasive aspergillosis (IA) is one of the most difficult to treat and, consequently, one of the most lethal fungal infections known to man. Continued use of immunosuppressive agents during chemotherapy and organ transplantation often leads to the development of neutropenia, the primary risk factor for IA. However, IA is also becoming more appreciated in chronic diseases associated with corticosteroid therapy. The innate immune response to Aspergillus fumigatus, the primary agent in IA, plays a pivotal role in the recognition and elimination of organisms from the pulmonary system. This review highlights recent findings about innate host defense mechanisms, including novel aspects of innate cellular immunity and pathogen recognition, and the inflammatory mediators that control infection with A. fumigatus. © 2017 S. Karger AG, Basel.

  18. Analysis of innate defences against Plasmodium falciparum in immunodeficient mice

    Directory of Open Access Journals (Sweden)

    Van Rooijen Nico

    2010-07-01

    Full Text Available Abstract Background Mice with genetic deficiencies in adaptive immunity are used for the grafting of human cells or pathogens, to study human diseases, however, the innate immune responses to xenografts in these mice has received little attention. Using the NOD/SCID Plasmodium falciparum mouse model an analysis of innate defences responsible for the substantial control of P. falciparum which remains in such mice, was performed. Methods NOD/SCID mice undergoing an immunomodulatory protocol that includes, clodronate-loaded liposomes to deplete macrophages and an anti-polymorphonuclear leukocytes antibody, were grafted with human red blood cells and P. falciparum. The systematic and kinetic analysis of the remaining innate immune responses included the number and phenotype of peripheral blood leukocytes as well as inflammatory cytokines/chemokines released in periphery. The innate responses towards the murine parasite Plasmodium yoelii were used as a control. Results Results show that 1 P. falciparum induces a strong inflammation characterized by an increase in circulating leukocytes and the release of inflammatory cytokines; 2 in contrast, the rodent parasite P. yoelii, induces a far more moderate inflammation; 3 human red blood cells and the anti-inflammatory agents employed induce low-grade inflammation; and 4 macrophages seem to bear the most critical function in controlling P. falciparum survival in those mice, whereas polymorphonuclear and NK cells have only a minor role. Conclusions Despite the use of an immunomodulatory treatment, immunodeficient NOD/SCID mice are still able to mount substantial innate responses that seem to be correlated with parasite clearance. Those results bring new insights on the ability of innate immunity from immunodeficient mice to control xenografts of cells of human origin and human pathogens.

  19. Interplay of innate lymphoid cells and the microbiota.

    Science.gov (United States)

    Britanova, Liudmila; Diefenbach, Andreas

    2017-09-01

    Innate lymphoid cells (ILC) are a recently identified group of innate lymphocytes that are preferentially located at barrier surfaces. Barrier surfaces are in direct contact with complex microbial ecosystems, collectively referred to as the microbiota. It is now believed that the interplay of the microbiota with host components (i.e. epithelial cells and immune cells) promotes host fitness by regulating organ homeostasis, metabolism, and host defense against pathogens. In this review, we will give an overview of this multifaceted interplay between ILC and components of the microbiota. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Interactions between the intestinal microbiota and innate lymphoid cells.

    Science.gov (United States)

    Chen, Vincent L; Kasper, Dennis L

    2014-01-01

    The mammalian intestine must manage to contain 100 trillion intestinal bacteria without inducing inappropriate immune responses to these microorganisms. The effects of the immune system on intestinal microorganisms are numerous and well-characterized, and recent research has determined that the microbiota influences the intestinal immune system as well. In this review, we first discuss the intestinal immune system and its role in containing and maintaining tolerance to commensal organisms. We next introduce a category of immune cells, the innate lymphoid cells, and describe their classification and function in intestinal immunology. Finally, we discuss the effects of the intestinal microbiota on innate lymphoid cells.

  1. Soluble Host Defense Lectins in Innate Immunity to Influenza Virus

    Science.gov (United States)

    Ng, Wy Ching; Tate, Michelle D.; Brooks, Andrew G.; Reading, Patrick C.

    2012-01-01

    Host defenses against viral infections depend on a complex interplay of innate (nonspecific) and adaptive (specific) components. In the early stages of infection, innate mechanisms represent the main line of host defense, acting to limit the spread of virus in host tissues prior to the induction of the adaptive immune response. Serum and lung fluids contain a range of lectins capable of recognizing and destroying influenza A viruses (IAV). Herein, we review the mechanisms by which soluble endogenous lectins mediate anti-IAV activity, including their role in modulating IAV-induced inflammation and disease and their potential as prophylactic and/or therapeutic treatments during severe IAV-induced disease. PMID:22665991

  2. SUPERFICIAL CERVICAL PLEXUS BLOCK

    Directory of Open Access Journals (Sweden)

    Komang Mega Puspadisari

    2014-01-01

    Full Text Available Superficial cervical plexus block is one of the regional anesthesia in  neck were limited to thesuperficial fascia. Anesthesia is used to relieve pain caused either during or after the surgery iscompleted. This technique can be done by landmark or with ultrasound guiding. The midpointof posterior border of the Sternocleidomastoid was identified and the prosedure done on thatplace or on the level of cartilage cricoid.

  3. Change Around the Block?

    Science.gov (United States)

    Berlin, Joey

    2017-04-01

    Proponents of a block grant or per-capita cap trumpet them as vehicles for the federal government to give the states a capped amount of funding for Medicaid that legislatures would effectively distribute how they see fit. Questions abound as to what capped Medicaid funding would look like, and what effect it would have on the current Medicaid-eligible population, covered services, and physician payments.

  4. Managing access block.

    Science.gov (United States)

    Cameron, Peter; Scown, Paul; Campbell, Donald

    2002-01-01

    There is pessimism regarding the ability of the Acute Health Sector to manage access block for emergency and elective patients. Melbourne Health suffered an acute bed crisis in 2001 resulting in record ambulance diversions and emergency department (ED) delays. We conducted an observational study to reduce access block for emergency patients whilst maintaining elective throughput at Melbourne Health. This involved a clinician-led taskforce using previously proven principles for organisational change to implement 51 actions to improve patient access over a three-month period. The primary outcome measures were ambulance diversion, emergency patients waiting more than 12 hours for an inpatient bed, elective throughput and theatre cancellations. Despite a reduction in multi-day bed numbers all primary objectives were met, ambulance diversion decreased to minimal levels, 12-hour waits decreased by 40% and elective throughput was maintained. Theatre cancellations were also minimised. We conclude that access block can be improved by clinician-led implementation of proven process improvements over a short time frame. The ability to sustain change over the longer term requires further study.

  5. Rotavirus nonstructural protein 1 antagonizes innate immune response by interacting with retinoic acid inducible gene I

    Directory of Open Access Journals (Sweden)

    Qin Lan

    2011-12-01

    Full Text Available Abstract Background The nonstructural protein 1 (NSP1 of rotavirus has been reported to block interferon (IFN signaling by mediating proteasome-dependent degradation of IFN-regulatory factors (IRFs and (or the β-transducin repeat containing protein (β-TrCP. However, in addition to these targets, NSP1 may subvert innate immune responses via other mechanisms. Results The NSP1 of rotavirus OSU strain as well as the IRF3 binding domain truncated NSP1 of rotavirus SA11 strain are unable to degrade IRFs, but can still inhibit host IFN response, indicating that NSP1 may target alternative host factor(s other than IRFs. Overexpression of NSP1 can block IFN-β promoter activation induced by the retinoic acid inducible gene I (RIG-I, but does not inhibit IFN-β activation induced by the mitochondrial antiviral-signaling protein (MAVS, indicating that NSP1 may target RIG-I. Immunoprecipitation experiments show that NSP1 interacts with RIG-I independent of IRF3 binding domain. In addition, NSP1 induces down-regulation of RIG-I in a proteasome-independent way. Conclusions Our findings demonstrate that inhibition of RIG-I mediated type I IFN responses by NSP1 may contribute to the immune evasion of rotavirus.

  6. Memorizing innate instructions requires a sufficiently specific adaptive immune system

    NARCIS (Netherlands)

    Borghans, J.A.M.; Boer, R.J. de

    2002-01-01

    During its primary encounter with a pathogen, the immune system has to decide which type of immune response is most appropriate. Based on signals from the innate immune system and the immunological context in which the pathogen is presented, responding lymphocytes will adopt a particular phenotype,

  7. Pattern Recognition Receptors in Innate Immunity, Host Defense, and Immunopathology

    Science.gov (United States)

    Suresh, Rahul; Mosser, David M.

    2013-01-01

    Infection by pathogenic microbes initiates a set of complex interactions between the pathogen and the host mediated by pattern recognition receptors. Innate immune responses play direct roles in host defense during the early stages of infection, and they also exert a profound influence on the generation of the adaptive immune responses that ensue.…

  8. Innate immunity and the role of defensins in otitis media.

    Science.gov (United States)

    Underwood, Mark; Bakaletz, Lauren

    2011-12-01

    Otitis media is the most common pediatric disease in developed countries and a significant cause of morbidity and hearing loss in developing countries. The innate immune system is essential to protecting the middle ear from infection. Defensins, broad-spectrum cationic antimicrobial peptides, have been implicated in prevention of and the early response to acute otitis media; however, the mechanisms by which defensins and other antimicrobial molecules mediate this protection have not been completely elucidated. In both animal otitis media models and human middle ear epithelial cell culture models, β-defensins are highly induced and effectively kill the common pathogens associated with otitis media. We review the importance of innate immunity in protecting the middle ear and recent advances in understanding the roles of defensins and other antimicrobial molecules in the prevention and treatment of otitis media. The extremely high prevalence of otitis media, in spite of sophisticated innate and adaptive immune systems, is a vexing problem for clinicians and scientists. We therefore also review mechanisms by which bacteria evade innate immune defenses.

  9. Mitochondrial DNA in the regulation of innate immune responses

    Directory of Open Access Journals (Sweden)

    Chunju Fang

    2015-10-01

    Full Text Available Abstract Mitochondrion is known as the energy factory of the cell, which is also a unique mammalian organelle and considered to be evolved from aerobic prokaryotes more than a billion years ago. Mitochondrial DNA, similar to that of its bacterial ancestor’s, consists of a circular loop and contains significant number of unmethylated DNA as CpG islands. The innate immune system plays an important role in the mammalian immune response. Recent research has demonstrated that mitochondrial DNA (mtDNA activates several innate immune pathways involving TLR9, NLRP3 and STING signaling, which contributes to the signaling platforms and results in effector responses. In addition to facilitating antibacterial immunity and regulating antiviral signaling, mounting evidence suggests that mtDNA contributes to inflammatory diseases following cellular damage and stress. Therefore, in addition to its well-appreciated roles in cellular metabolism and energy production, mtDNA appears to function as a key member in the innate immune system. Here, we highlight the emerging roles of mtDNA in innate immunity.

  10. MAMPs/PAMPs - elicitors of innate immunity in plants

    DEFF Research Database (Denmark)

    Erbs, Gitte; Newman, Mari-Anne

    2009-01-01

    Patterns (MAMPs or PAMPs), are recognised by the plant innate immune systems Pattern Recognition Receptors (PRRs). General bacterial elicitors, like lipopolysaccharides (LPS), flagellin (Flg), elongation factor Tu (EF-Tu), cold shock protein (CSP), peptidoglycan (PGN) and the enzyme superoxide dismutase...

  11. Man's nature: innate determinants of response to natural environments

    Science.gov (United States)

    B. L. Driver; Peter Greene

    1977-01-01

    Man's sensory mechanisms evolved by natural selection in natural settings and humans survived as a species not so much by the "club in the hand" but by the "plan in the head." That plan or ability enabled man to remember, interpret, and predict environmental events. Humans have an innate capacity (but not necessarily a developed ability) to...

  12. HIV infection: focus on the innate immune cells.

    Science.gov (United States)

    Espíndola, Milena S; Soares, Luana S; Galvão-Lima, Leonardo J; Zambuzi, Fabiana A; Cacemiro, Maira C; Brauer, Verônica S; Frantz, Fabiani G

    2016-12-01

    Innate immune cells play a critical role during the onset of HIV infection and remain active until the final events that characterize AIDS. The viral impact on innate immune cell response may be a result of direct infection or indirect modulation, and each cell type responds in a specific manner to HIV. During HIV infection, the immune system works in a dynamic way, where innate and adaptive cells contribute with each other stimulating their function and modulating phenotypes and consequently infection resolution. Understanding the alterations in the cell populations induced by the virus is pivotal and can help to combat HIV at the time of infection and above all, to prevent the establishment of viral reservoirs. In this review, we will describe the frequency and the subtypes of infected cells such as of monocytes, DCs, neutrophils, eosinophils, mast cells/basophils, NK cells, NKT cells and γδ T cells, and we discuss the possibility of cell-targeting strategies. Our aim is to consolidate the existing knowledge of the interaction between HIV and cells that constitute the innate immune response.

  13. Hypoxia, innate immunity and infection in the lung.

    LENUS (Irish Health Repository)

    Schaible, Bettina

    2012-02-01

    The mucosal surface of the lung is the key interface between the external atmosphere and the bloodstream. Normally, this well oxygenated tissue is maintained in state of sterility by a number of innate immune processes. These include a physical and dynamic mucus barrier, the production of microbiocidal peptides and the expression of specific pattern recognition receptors on alveolar epithelial cells and resident macrophages and dendritic cells which recognise microbial structures and initiate innate immune responses which promote the clearance of potentially infectious agents. In a range of diseases, the mucosal surface of the lung experiences decreased oxygen tension leading to localised areas of prominent hypoxia which can impact upon innate immune and subsequent infectious and inflammatory processes. Under these conditions, the lung is generally more susceptible to infection and subsequent inflammation. In the current review, we will discuss recent data pertaining to the role of hypoxia in regulating both host and pathogen in the lung during pulmonary disease and how this contributes to innate immunity, infection and inflammation.

  14. Experimental evidence for innate predator recognition in the Seychelles warbler

    NARCIS (Netherlands)

    Veen, Thor; Richardson, David S.; Blaakmeer, Karen; Komdeur, Jan

    2000-01-01

    Nest predation is a major determinant of fitness in birds and costly nest defence behaviours have evolved in order to reduce nest predation. Some avian studies have suggested that predator recognition is innate whereas others hate stressed the importance: of learning. However, none of these studies

  15. Neural regulation of innate and adaptive immunity in the gut

    OpenAIRE

    Dhawan, S.

    2017-01-01

    This thesis investigates the role of neurotransmitters acetylcholine (ACh) and norepinephrine (NE), in modulating the innate and adaptive immune function in the intestine, during physiological and pathophysiological conditions. Furthermore, this thesis attempts to advance our current understanding of the gut-brain immune axis, also known as the cholinergic anti-inflammatory pathway, coined largely due to the cholinergic nature of the vagus nerve.

  16. Breakdown of the innate immune system by bacterial proteases

    NARCIS (Netherlands)

    Laarman, A.J.

    2011-01-01

    Bacteria have developed many strategies to circumvent our immune system to survive and colonize human tissues. One of these strategies is by secreting proteases that specifically target the innate immune system. Aureolysin is a metalloprotease from Staphylococcus aureus which target the main

  17. Lipoprotein Lipase Maintains Microglial Innate Immunity in Obesity

    NARCIS (Netherlands)

    Gao, Yuanqing; Vidal-Itriago, Andrés; Kalsbeek, Martin J; Layritz, Clarita; García-Cáceres, Cristina; Tom, Robby Zachariah; Eichmann, Thomas O; Vaz, Frédéric M; Houtkooper, Riekelt H; van der Wel, Nicole; Verhoeven, Arthur J; Yan, Jie; Kalsbeek, A.; Eckel, Robert H; Hofmann, Susanna M; Yi, Chun-Xia

    2017-01-01

    Consumption of a hypercaloric diet upregulates microglial innate immune reactivity along with a higher expression of lipoprotein lipase (Lpl) within the reactive microglia in the mouse brain. Here, we show that knockdown of the Lpl gene specifically in microglia resulted in deficient microglial

  18. Role of innate immunity in the pathogenesis of otitis media.

    Science.gov (United States)

    Mittal, Rahul; Kodiyan, Joyson; Gerring, Robert; Mathee, Kalai; Li, Jian-Dong; Grati, M'hamed; Liu, Xue Zhong

    2014-12-01

    Otitis media (OM) is a public health problem in both developed and developing countries. It is the leading cause of hearing loss and represents a significant healthcare burden. In some cases, acute OM progresses to chronic suppurative OM (CSOM), characterized by effusion and discharge, despite antimicrobial therapy. The emergence of antibiotic resistance and potential ototoxicity of antibiotics has created an urgent need to design non-conventional therapeutic strategies against OM based on modern insights into its pathophysiology. In this article, we review the role of innate immunity as it pertains to OM and discuss recent advances in understanding the role of innate immune cells in protecting the middle ear. We also discuss the mechanisms utilized by pathogens to subvert innate immunity and thereby overcome defensive responses. A better knowledge about bacterial virulence and host resistance promises to reveal novel targets to design effective treatment strategies against OM. The identification and characterization of small natural compounds that can boost innate immunity may provide new avenues for the treatment of OM. There is also a need to design novel methods for targeted delivery of these compounds into the middle ear, allowing higher therapeutic doses and minimizing systemic side effects. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  19. Role of innate immunity in the pathogenesis of otitis media

    Science.gov (United States)

    Mittal, Rahul; Kodiyan, Joyson; Gerring, Robert; Mathee, Kalai; Li, Jian-Dong; Grati, M’hamed; Liu, Xue Zhong

    2015-01-01

    Summary Otitis media (OM) is a public health problem in both developed and developing countries. It is the leading cause of hearing loss and represents a significant healthcare burden. In some cases, acute OM progresses to chronic suppurative OM (CSOM), characterized by effusion and discharge, despite antimicrobial therapy. The emergence of antibiotic resistance and potential ototoxicity of antibiotics has created an urgent need to design non-conventional therapeutic strategies against OM based on modern insights into its pathophysiology. In this article, we review the role of innate immunity as it pertains to OM and discuss recent advances in understanding the role of innate immune cells in protecting the middle ear. We also discuss the mechanisms utilized by pathogens to subvert innate immunity and thereby overcome defensive responses. A better knowledge about bacterial virulence and host resistance promises to reveal novel targets to design effective treatment strategies against OM. The identification and characterization of small natural compounds that can boost innate immunity may provide new avenues for the treatment of OM. There is also a need to design novel methods for targeted delivery of these compounds into the middle ear, allowing higher therapeutic doses and minimizing systemic side effects. PMID:25447732

  20. Innate lymphoid cells and parasites: Ancient foes with shared history.

    Science.gov (United States)

    Neill, D R; Fallon, P G

    2018-02-01

    This special issue of Parasite Immunology charts the rapid advances made in our understanding of the myriad interactions between innate lymphoid cells and parasites and how these interactions have shaped our evolutionary history. Here, we provide an overview of the issue and highlight key findings from studies in mice and man. © 2017 The Authors. Parasite Immunology Published by John Wiley & Sons Ltd.

  1. Cell-specific innate immunity in lung infection and inflammation

    NARCIS (Netherlands)

    Anas, A.A.

    2017-01-01

    Pneumonia and asthma affect millions of adults and children annually and are responsible for a significant amount of morbidity and mortality worldwide. Our airways are continuously exposed to pathogens and allergens inhaled through air that can potentially cause these serious illnesses. The innate

  2. The immunobiology of Campylobacter jejuni: Innate immunity and autoimmune diseases.

    Science.gov (United States)

    Phongsisay, Vongsavanh

    2016-04-01

    The Gram-negative bacterium Campylobacter jejuni causes gastroenteritis and Guillain-Barré syndrome in humans. Recent advances in the immunobiology of C. jejuni have been made. This review summarizes C. jejuni-binding innate receptors and highlights the role of innate immunity in autoimmune diseases. This human pathogen produces a variety of glycoconjugates, including human ganglioside-like determinants and multiple activators of Toll-like receptors (TLRs). Furthermore, C. jejuni targets MyD88, NLRP3 inflammasome, TIR-domain-containing adapter-inducing interferon-β (TRIF), sialic acid-binding immunoglobulin-like lectins (Siglecs), macrophage galactose-type lectin (MGL), and immunoglobulin-like receptors (TREM2, LMIR5/CD300b). The roles of these innate receptors and signaling molecules have been extensively studied. MyD88-mediated TLR activation or inflammasome-dependent IL-1β secretion is essential for autoimmune induction. TRIF mediates the production of type I interferons that promote humoral immune responses and immunoglobulin class-switching. Siglec-1 and Siglec-7 interact directly with gangliosides. Siglec-1 activation enhances phagocytosis and inflammatory responses. MGL internalizes GalNAc-containing glycoconjugates. TREM2 is well-known for its role in phagocytosis. LMIR5 recognizes C. jejuni components and endogenous sulfoglycolipids. Several lines of evidence from animal models of autoimmune diseases suggest that simultaneous activation of innate immunity in the presence of autoreactive lymphocytes or antigen mimicry may link C. jejuni to immunopathology. Copyright © 2015 Elsevier GmbH. All rights reserved.

  3. Innate, adaptive and regulatory responses in schistosomiasis: Relationship to allergy

    NARCIS (Netherlands)

    Hartgers, F.C.; Smits, H.H.; Kleij, D. van der; Yazdanbakhsh, M.

    2006-01-01

    Helminth infections have profound effects on the immune system. Here, recent insights in the molecular interactions between schistosomes and the host are described with respect to adaptive but also with respect to innate immune responses. Furthermore, the different mechanisms of immune

  4. Innate immune responses in central nervous system inflammation

    DEFF Research Database (Denmark)

    Finsen, Bente; Owens, Trevor

    2011-01-01

    In autoimmune diseases of the central nervous system (CNS), innate glial cell responses play a key role in determining the outcome of leukocyte infiltration. Access of leukocytes is controlled via complex interactions with glial components of the blood-brain barrier that include angiotensin II...

  5. Dental metal-induced innate reactivity in keratinocytes

    NARCIS (Netherlands)

    Rachmawati, D.; Buskermolen, J.K.; Scheper, R.J.; Gibbs, S.; von Blomberg, B.M.E.; van Hoogstraten, I.M.W.

    2015-01-01

    Gold, nickel, copper and mercury, i.e. four metals frequently used in dental applications, were explored for their capacity to induce innate immune activation in keratinocytes (KC). Due to their anatomical location the latter epithelial cells are key in primary local irritative responses of skin and

  6. Mycobacteria and innate cells: critical encounter for immunogenicity

    Indian Academy of Sciences (India)

    Protective immunity against mycobacterial infections such as Mycobacterium tuberculosis is mediated by interactions between specific T cells and activated macrophages. To date, many aspects of mycobacterial immunity have shown that innate cells are the key elements that substantially influence the subsequent adaptive ...

  7. Glycoconjugates as elicitors or suppressors of plant innate immunity

    DEFF Research Database (Denmark)

    Silipo, Alba; Erbs, Gitte; Shinya, Tomonori

    2010-01-01

    Innate immunity is the first line of defense against invading microorganisms in vertebrates and the only line of defense in invertebrates and plants. Bacterial glyco-conjugates, such as lipopolysaccharides (LPS) from the outer membrane of Gram-negative bacteria and peptidoglycan (PGN) from the ce...

  8. Paving block study : final report.

    Science.gov (United States)

    1971-10-01

    The Louisiana Department of Highways has conducted field tests with an experimental revetment consisting of cellular concrete revetment blocks used in conjunction with plastic filter cloth and/or vegetation such as grass or vines. The precast blocks ...

  9. Habitat Blocks and Wildlife Corridors

    Data.gov (United States)

    Vermont Center for Geographic Information — Habitat blocks are areas of contiguous forest and other natural habitats that are unfragmented by roads, development, or agriculture. Vermonts habitat blocks are...

  10. Demographic Data - MDC_Block

    Data.gov (United States)

    NSGIC Local Govt | GIS Inventory — A polygon feature class of Miami-Dade Census 2000 Blocks. Census blocks are areas bounded on all sides by visible and/or invisible features shown on a map prepared...

  11. Anthrax Lethal Toxin Impairs Innate Immune Functions of Alveolar Macrophages and Facilitates Bacillus anthracis Survival

    National Research Council Canada - National Science Library

    Ribot, Wilson J; Panchal, Rekha G; Brittingham, Katherine C; Ruthel, Gordon; Kenny, Tara A; Lane, Douglas; Curry, Bob; Hoover, Timothy A; Friedlander, Arthur M; Bavari, Sina

    2006-01-01

    Alveolar macrophages (AM) are very important for pulmonary innate immune responses against invading inhaled pathogens because they directly kill the organisms and initiate a cascade of innate and adaptive immune responses...

  12. DMPD: Innate immune responses during infection. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15576198 Innate immune responses during infection. Ulevitch RJ, Mathison JC, da Sil...ses during infection. PubmedID 15576198 Title Innate immune responses during infection. Authors Ulevitch RJ, Math

  13. Blocking the Hawking radiation

    DEFF Research Database (Denmark)

    Autzen, M.; Kouvaris, C.

    2014-01-01

    grows after its formation (and eventually destroys the star) instead of evaporating. The fate of the black hole is dictated by the two opposite mechanics, i.e., accretion of nuclear matter from the center of the star and Hawking radiation that tends to decrease the mass of the black hole. We study how...... the assumptions for the accretion rate can in fact affect the critical mass beyond which a black hole always grows. We also study to what extent degenerate nuclear matter can impede Hawking radiation due to the fact that emitted particles can be Pauli blocked at the core of the star....

  14. Vitamin D signaling in intestinal innate immunity and homeostasis.

    Science.gov (United States)

    Dimitrov, Vassil; White, John H

    2017-09-15

    The lumen of the gut hosts a plethora of microorganisms that participate in food assimilation, inactivation of harmful particles and in vitamin synthesis. On the other hand, enteric flora, a number of food antigens, and toxins are capable of triggering immune responses causing inflammation, which, when unresolved, may lead to chronic conditions such as inflammatory bowel disease (IBD). It is important, therefore, to contain the gut bacteria within the lumen, control microbial load and composition, as well as ensure adequate innate and adaptive immune responses to pathogenic threats. There is growing evidence that vitamin D signaling has impacts on all these aspects of intestinal physiology, contributing to healthy enteric homeostasis. VD was first discovered as the curative agent for nutritional rickets, and its classical actions are associated with calcium absorption and bone health. However, vitamin D exhibits a number of extra-skeletal effects, particularly in innate immunity. Notably, it stimulates production of pattern recognition receptors, anti-microbial peptides, and cytokines, which are at the forefront of innate immune responses. They play a role in sensing the microbiota, in preventing excessive bacterial overgrowth, and complement the actions of vitamin D signaling in enhancing intestinal barrier function. Vitamin D also favours tolerogenic rather than inflammogenic T cell differentiation and function. Compromised innate immune function and overactive adaptive immunity, as well as defective intestinal barrier function, have been associated with IBD. Importantly, observational and intervention studies support a beneficial role of vitamin D supplementation in patients with Crohn's disease, a form of IBD. This review summarizes the effects of vitamin D signaling on barrier integrity and innate and adaptive immunity in the gut, as well as on microbial load and composition. Collectively, studies to date reveal that vitamin D signaling has widespread effects

  15. Mitochondria as Molecular Platforms Integrating Multiple Innate Immune Signalings.

    Science.gov (United States)

    Monlun, Marie; Hyernard, Caroline; Blanco, Patrick; Lartigue, Lydia; Faustin, Benjamin

    2017-01-06

    The immune system of vertebrates confers protective mechanisms to the host through the sensing of stress-induced agents expressed during infection or cell stress. Among them, the first line of host defense composed of the innate immune sensing of these agents by pattern recognition receptors enables downstream adaptive immunity to be primed, mediating the body's appropriate response to clear infection and tissue damage. Mitochondria are «bacteria within» that allowed the emergence of functional eukaryotic cells by positioning themselves as the cell powerhouse and an initiator of cell death programs. It is striking to consider that such ancestral bacteria, which had to evade host defense at some point to develop evolutionary endosymbiosis, have become instrumental for the modern eukaryotic cell in alerting the immune system against various insults including infection by other pathogens. Mitochondria have indeed become critical regulators of innate immune responses to both pathogens and cell stress. They host numerous modulators, which play a direct role into the assembly of innate sensing machineries that trigger host immune response in both sterile and non-sterile conditions. Several lines of evidence indicate the existence of a complex molecular interplay between mechanisms involved in inflammation and metabolism. Mitochondrial function seems to participate in innate immunity at various stages as diverse as the transcriptional regulation of inflammatory cytokines and chemokines and their maturation by inflammasomes. Here, we review the mechanisms by which mitochondria orchestrate innate immune responses at different levels by promoting a cellular metabolic reprogramming and the cytosolic immune signaling cascades. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Innate immune interferon responses to human immunodeficiency virus-1 infection.

    Science.gov (United States)

    Hughes, Rose; Towers, Greg; Noursadeghi, Mahdad

    2012-07-01

    Type I interferon (IFN) responses represent the canonical host innate immune response to viruses, which serves to upregulate expression of antiviral restriction factors and augment adaptive immune defences. There is clear evidence for type I IFN activity in both acute and chronic HIV-1 infection in vivo, and plasmacytoid dendritic cells have been identified as one important source for these responses, through innate immune detection of viral RNA by Toll-like receptor 7. In addition, new insights into the molecular mechanisms that trigger induction of type I IFNs suggest innate immune receptors for viral DNA may also mediate these responses. It is widely recognised that HIV-1 restriction factors share the characteristic of IFN-inducible expression, and that the virus has evolved to counteract these antiviral mechanisms. However, in some target cells, such as macrophages, IFN can still effectively restrict virus. In this context, HIV-1 shows the ability to evade innate immune recognition and thereby avoid induction of type I IFN in order to successfully establish productive infection. The relative importance of evasion of innate immune detection and evasion of IFN-inducible restriction in the natural history of HIV-1 infection is not known, and the data suggest that type I IFN responses may play a role in both viral control and in the immunopathogenesis of progressive disease. Further study of the relationship between HIV-1 infection and type I IFN responses is required to unravel these issues and inform the development of novel therapeutics or vaccine strategies. Copyright © 2012 John Wiley & Sons, Ltd.

  17. How Artists Overcome Creative Blocks.

    Science.gov (United States)

    Hirst, Barbara

    1992-01-01

    Six practicing artists were interviewed about how they overcome creative blocks. Their responses indicated that feelings of self-doubt, fear, and depression accompany blocks but that relaxing and working on new directions and playing ideas off a supportive person helped to overcome such blocks. (DB)

  18. Block Scheduling in High Schools.

    Science.gov (United States)

    Irmsher, Karen

    1996-01-01

    Block Scheduling has been considered a cure for a lengthy list of educational problems. This report reviews the literature on block schedules and describes some Oregon high schools that have integrated block scheduling. Major disadvantages included resistance to change and requirements that teachers change their teaching strategies. There is…

  19. Abdominal wall blocks in adults

    DEFF Research Database (Denmark)

    Neimann, Jens Dupont Børglum; Gögenür, Ismail; Bendtsen, Thomas F.

    2016-01-01

    Purpose of review Abdominal wall blocks in adults have evolved much during the last decade; that is, particularly with the introduction of ultrasound-guided (USG) blocks. This review highlights recent advances of block techniques within this field and proposes directions for future research.  Rec...

  20. DMPD: Innate immune response to viral infection. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18694646 Innate immune response to viral infection. Koyama S, Ishii KJ, Coban C, Ak...ira S. Cytokine. 2008 Sep;43(3):336-41. Epub 2008 Aug 9. (.png) (.svg) (.html) (.csml) Show Innate immune response to viral infection.... PubmedID 18694646 Title Innate immune response to viral infection. Authors Koyama

  1. DMPD: Innate immune recognition of, and regulation by, DNA. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16979939 Innate immune recognition of, and regulation by, DNA. Ishii KJ, Akira S. T...rends Immunol. 2006 Nov;27(11):525-32. Epub 2006 Sep 18. (.png) (.svg) (.html) (.csml) Show Innate immune reco...gnition of, and regulation by, DNA. PubmedID 16979939 Title Innate immune recognition of, and regulation b

  2. Unravelling the nature of non-specific effects of vaccines-A challenge for innate immunologists

    DEFF Research Database (Denmark)

    Jensen, Kristoffer Jarlov; Benn, Christine Stabell; van Crevel, Reinout

    2016-01-01

    ) of vaccines, including heterologous T-cell reactivity and innate immune memory or 'trained innate immunity', which involves epigenetic reprogramming of innate immune cells. Here, we review the epidemiological evidence for NSE as well as human, animal and in vitro immunological data that could explain...

  3. DMPD: Innate immune responses: crosstalk of signaling and regulation of genetranscription. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16753195 Innate immune responses: crosstalk of signaling and regulation of genetran...l) (.csml) Show Innate immune responses: crosstalk of signaling and regulation of genetranscription. PubmedI...D 16753195 Title Innate immune responses: crosstalk of signaling and regulation o

  4. Toll-like receptors are part of the innate immune defense system of sponges (demospongiae: Porifera).

    Science.gov (United States)

    Wiens, Matthias; Korzhev, Michael; Perovic-Ottstadt, Sanja; Luthringer, Bérengère; Brandt, David; Klein, Stefanie; Müller, Werner E G

    2007-03-01

    During evolution and with the emergence of multicellular animals, the need arose to ward off foreign organisms that threaten the integrity of the animal body. Among many different receptors that participate in the recognition of microbial invaders, toll-like receptors (TLRs) play an essential role in mediating the innate immune response. After binding distinct microbial components, TLRs activate intracellular signaling cascades that result in an induced expression of diverse antimicrobial molecules. Because sponges (phylum Porifera) are filter feeders, they are abundantly exposed to microorganisms that represent a potential threat. Here, we describe the identification, cloning, and deduced protein sequence from 3 major elements of the poriferan innate response (to bacterial lipopeptides): the TLR, the IL-1 receptor-associated kinase-4-like protein (IRAK-4l), and a novel effector caspase from the demosponge Suberites domuncula. Each molecule shares significant sequence similarity with its homologues in higher Metazoa. Sequence homologies were found in particular within the family-specific domains toll/interleukin-1 receptor/resistance (TLR family), Ser/Thr/Tyr kinase domain (IRAK family), and CASc (caspase family). In addition, in situ hybridization and immunohistological analyses revealed an abundance of SDTLR (TLR) transcripts in epithelial layers of the sponge surface (exopinacoderm and endopinacoderm). Furthermore, it is shown that both SDTLR and SDIRAK-4 like (IRAK) are expressed constitutively, regardless of treatment with synthetic triacyl lipopeptide Pam(3)Cys-Ser-(Lys)(4). In contrast, SDCASL (caspase) expression is highly Pam(3)Cys-Ser-(Lys)(4) inducible. However, blocking of the lipopeptide with recombinant TLR prior to its application completely prevented the induced expression of this poriferan caspase. These results underscore that the phylogenetically oldest extant metazoan phylum is provided already with the signaling pathways of the antimicrobial

  5. Innate immune complexity in the purple sea urchin: diversity of the Sp185/333 system

    Directory of Open Access Journals (Sweden)

    L. Courtney Smith

    2012-04-01

    Full Text Available The California purple sea urchin, Strongylocentrotus purpuratus, is a long-lived echinoderm with a complex and sophisticated innate immune system. Several large gene families that function in immunity in this species includes the Sp185/333 gene family with ~50 (±10 members. The family shows intriguing sequence diversity and encodes a broad array of diverse yet similar proteins. The genes have two exons of which the second encodes the mature protein and has repeats and blocks of sequence called elements. Mosaics of element patterns plus SNPs within the elements result in significant sequence diversity among the genes yet maintains similar structure among the members of the family. An Sp185/333-positive BAC insert has a cluster of six, tightly linked Sp185/333 genes that are flanked by GA microsatellites. The sequences between the GA microsatellites are much more similar to each other than are the sequences outside the microsatellites suggesting processes such as gene conversion, recombination, or duplication. However, close linkage does not correspond with greater sequence similarity compared to randomly cloned and sequenced genes that are unlikely to be linked. There are three segmental duplications that are bounded by GAT microsatellites and include three almost identical genes. RNA editing is detectible throughout the messages and putative post-translational modifications to the proteins result in broad arrays of Sp185/333 proteins that differ among individuals. The mature proteins have an N-terminal glycine-rich region, a central RGD motif, and a C-terminal histidine-rich region. The Sp185/333 proteins are localized to the cell surface and are found within vesicles in subsets of polygonal and small phagocytes. The coelomocyte proteome shows full-length and truncated proteins, including some with missense sequence. Current results suggest that both native and a recombinant Sp185/333 protein bind bacteria and are likely important in sea urchin

  6. Group 2 Innate Lymphoid Cells Promote an Early Antibody Response to a Respiratory Antigen in Mice.

    Science.gov (United States)

    Drake, Li Yin; Iijima, Koji; Bartemes, Kathleen; Kita, Hirohito

    2016-08-15

    Innate lymphoid cells (ILCs) are a new family of immune cells that play important roles in innate immunity in mucosal tissues, and in the maintenance of tissue and metabolic homeostasis. Recently, group 2 ILCs (ILC2s) were found to promote the development and effector functions of Th2-type CD4(+) T cells by interacting directly with T cells or by activating dendritic cells, suggesting a role for ILC2s in regulating adaptive immunity. However, our current knowledge on the role of ILCs in humoral immunity is limited. In this study, we found that ILC2s isolated from the lungs of naive BALB/c mice enhanced the proliferation of B1- as well as B2-type B cells and promoted the production of IgM, IgG1, IgA, and IgE by these cells in vitro. Soluble factors secreted by ILC2s were sufficient to enhance B cell Ig production. By using blocking Abs and ILC2s isolated from IL-5-deficient mice, we found that ILC2-derived IL-5 is critically involved in the enhanced production of IgM. Furthermore, when adoptively transferred to Il7r(-/-) mice, which lack ILC2s and mature T cells, lung ILC2s promoted the production of IgM Abs to a polysaccharide Ag, 4-hydroxy-3-nitrophenylacetyl Ficoll, within 7 d of airway exposure in vivo. These findings add to the growing body of literature regarding the regulatory functions of ILCs in adaptive immunity, and suggest that lung ILC2s promote B cell production of early Abs to a respiratory Ag even in the absence of T cells. Copyright © 2016 by The American Association of Immunologists, Inc.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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.

  9. Effector Mechanisms of Neutrophils within the Innate Immune System in Response to Mycobacterium tuberculosis Infection.

    Science.gov (United States)

    Warren, Eric; Teskey, Garrett; Venketaraman, Vishwanath

    2017-02-07

    Neutrophils have a significant yet controversial role in the innate immune response to Mycobacterium tuberculosis ( M. tb ) infection, which is not yet fully understood. In addition to neutrophils' well-known effector mechanisms, they may also help control infection of M. tb through the formation of neutrophil extracellular traps (NETs), which are thought to further promote the killing of M. tb by resident alveolar macrophages. Cytokines such as IFN-γ have now been shown to serve an immunomodulatory role in neutrophil functioning in conjunction to its pro-inflammatory function. Additionally, the unique transcriptional changes of neutrophils may be used to differentiate between infection with M. tb and other bacterial and chronic rheumatological diseases such as Systemic Lupus Erythematosus. Adversely, during the innate immune response to M. tb , inappropriate phagocytosis of spent neutrophils can result in nonspecific damage to host cells due to necrotic lysis. Furthermore, some individuals have been shown to be more genetically susceptible to tuberculosis (TB) due to a "Trojan Horse" phenomenon whereby neutrophils block the ability of resident macrophages to kill M. tb . Despite these aforementioned negative consequences, through the scope of this review we will provide evidence to support the idea that neutrophils, while sometimes damaging, can also be an important component in warding off M. tb infection. This is exemplified in immunocompromised individuals, such as those with human immunodeficiency virus (HIV) infection or Type 2 diabetes mellitus. These individuals are at an increased risk of developing tuberculosis (TB) due to a diminished innate immune response associated with decreased levels of glutathione. Consequently, there has been a worldwide effort to limit and contain M. tb infection through the use of antibiotics and vaccinations. However, due to several significant limitations, the current bacille Calmette-Guerin vaccine (BCG, vaccine against TB

  10. Effector Mechanisms of Neutrophils within the Innate Immune System in Response to Mycobacterium tuberculosis Infection

    Directory of Open Access Journals (Sweden)

    Eric Warren

    2017-02-01

    Full Text Available Neutrophils have a significant yet controversial role in the innate immune response to Mycobacterium tuberculosis (M. tb infection, which is not yet fully understood. In addition to neutrophils’ well-known effector mechanisms, they may also help control infection of M. tb through the formation of neutrophil extracellular traps (NETs, which are thought to further promote the killing of M. tb by resident alveolar macrophages. Cytokines such as IFN-γ have now been shown to serve an immunomodulatory role in neutrophil functioning in conjunction to its pro-inflammatory function. Additionally, the unique transcriptional changes of neutrophils may be used to differentiate between infection with M. tb and other bacterial and chronic rheumatological diseases such as Systemic Lupus Erythematosus. Adversely, during the innate immune response to M. tb, inappropriate phagocytosis of spent neutrophils can result in nonspecific damage to host cells due to necrotic lysis. Furthermore, some individuals have been shown to be more genetically susceptible to tuberculosis (TB due to a “Trojan Horse” phenomenon whereby neutrophils block the ability of resident macrophages to kill M. tb. Despite these aforementioned negative consequences, through the scope of this review we will provide evidence to support the idea that neutrophils, while sometimes damaging, can also be an important component in warding off M. tb infection. This is exemplified in immunocompromised individuals, such as those with human immunodeficiency virus (HIV infection or Type 2 diabetes mellitus. These individuals are at an increased risk of developing tuberculosis (TB due to a diminished innate immune response associated with decreased levels of glutathione. Consequently, there has been a worldwide effort to limit and contain M. tb infection through the use of antibiotics and vaccinations. However, due to several significant limitations, the current bacille Calmette-Guerin vaccine (BCG

  11. Program structure-based blocking

    Science.gov (United States)

    Bertolli, Carlo; Eichenberger, Alexandre E.; O'Brien, John K.; Sura, Zehra N.

    2017-09-26

    Embodiments relate to program structure-based blocking. An aspect includes receiving source code corresponding to a computer program by a compiler of a computer system. Another aspect includes determining a prefetching section in the source code by a marking module of the compiler. Yet another aspect includes performing, by a blocking module of the compiler, blocking of instructions located in the prefetching section into instruction blocks, such that the instruction blocks of the prefetching section only contain instructions that are located in the prefetching section.

  12. Block copolymer investigations

    Science.gov (United States)

    Yufa, Nataliya A.

    The research presented in this thesis deals with various aspects of block copolymers on the nanoscale: their behavior at a range of temperatures, their use as scaffolds, or for creation of chemically striped surfaces, as well as the behavior of metals on block copolymers under the influence of UV light, and the healing behavior of copolymers. Invented around the time of World War II, copolymers have been used for decades due to their macroscopic properties, such as their ability to be molded without vulcanization, and the fact that, unlike rubber, they can be recycled. In recent years, block copolymers (BCPs) have been used for lithography, as scaffolds for nano-objects, to create a magnetic hard drive, as well as in photonic and other applications. In this work we used primarily atomic force microscopy (AFM) and transmission electron microscopy (TEM), described in Chapter II, to conduct our studies. In Chapter III we demonstrate a new and general method for positioning nanoparticles within nanoscale grooves. This technique is suitable for nanodots, nanocrystals, as well as DNA. We use AFM and TEM to demonstrate selective decoration. In Chapters IV and V we use AFM and TEM to study the structure of polymer surfaces coated with metals and self-assembled monolayers. We describe how the surfaces were created, exhibit their structure on the nanoscale, and prove that their macroscopic wetting properties have been altered compared to the original polymer structures. Finally, Chapters VI and VII report out in-situ AFM studies of BCP at high temperatures, made possible only recently with the invention of air-tight high-temperature AFM imaging cells. We locate the transition between disordered films and cylinders during initial ordering. Fluctuations of existing domains leading to domain coarsening are also described, and are shown to be consistent with reptation and curvature minimization. Chapter VII deals with the healing of PS-b-PMMA following AFM-tip lithography or

  13. Celiac ganglia block

    Energy Technology Data Exchange (ETDEWEB)

    Akinci, Devrim [Department of Radiology, Hacettepe University School of Medicine, Sihhiye, 06100 Ankara (Turkey); Akhan, Okan [Department of Radiology, Hacettepe University School of Medicine, Sihhiye, 06100 Ankara (Turkey)]. E-mail: oakhan@hacettepe.edu.tr

    2005-09-01

    Pain occurs frequently in patients with advanced cancers. Tumors originating from upper abdominal viscera such as pancreas, stomach, duodenum, proximal small bowel, liver and biliary tract and from compressing enlarged lymph nodes can cause severe abdominal pain, which do not respond satisfactorily to medical treatment or radiotherapy. Percutaneous celiac ganglia block (CGB) can be performed with high success and low complication rates under imaging guidance to obtain pain relief in patients with upper abdominal malignancies. A significant relationship between pain relief and degree of tumoral celiac ganglia invasion according to CT features was described in the literature. Performing the procedure in the early grades of celiac ganglia invasion on CT can increase the effectiveness of the CGB, which is contrary to World Health Organization criteria stating that CGB must be performed in patients with advanced stage cancer. CGB may also be effectively performed in patients with chronic pancreatitis for pain palliation.

  14. Photovoltaic building blocks

    DEFF Research Database (Denmark)

    Hanberg, Peter Jesper; Jørgensen, Anders Michael

    2014-01-01

    efficiency of about 15% for commercial Silicon solar cells there is still much to gain. DTU Danchip provides research facilities, equipment and expertise for the building blocks that comprises fabricating the efficient solar cell. In order to get more of the sun light into the device we provide thin film......Photovoltaics (PV), better known as solar cells, are now a common day sight on many rooftops in Denmark.The installed capacity of PV systems worldwide is growing exponentially1 and is the third most importantrenewable energy source today. The cost of PV is decreasing fast with ~10%/year but to make...... it directcompetitive with fossil energy sources a further reduction is needed. By increasing the efficiency of the solar cells one gain an advantage through the whole chain of cost. So that per produced Watt of power less material is spent, installation costs are lower, less area is used etc. With an average...

  15. Atomic Basic Blocks

    Science.gov (United States)

    Scheler, Fabian; Mitzlaff, Martin; Schröder-Preikschat, Wolfgang

    Die Entscheidung, einen zeit- bzw. ereignisgesteuerten Ansatz für ein Echtzeitsystem zu verwenden, ist schwierig und sehr weitreichend. Weitreichend vor allem deshalb, weil diese beiden Ansätze mit äußerst unterschiedlichen Kontrollflussabstraktionen verknüpft sind, die eine spätere Migration zum anderen Paradigma sehr schwer oder gar unmöglich machen. Wir schlagen daher die Verwendung einer Zwischendarstellung vor, die unabhängig von der jeweils verwendeten Kontrollflussabstraktion ist. Für diesen Zweck verwenden wir auf Basisblöcken basierende Atomic Basic Blocks (ABB) und bauen darauf ein Werkzeug, den Real-Time Systems Compiler (RTSC) auf, der die Migration zwischen zeit- und ereignisgesteuerten Systemen unterstützt.

  16. Celiac ganglia block

    International Nuclear Information System (INIS)

    Akinci, Devrim; Akhan, Okan

    2005-01-01

    Pain occurs frequently in patients with advanced cancers. Tumors originating from upper abdominal viscera such as pancreas, stomach, duodenum, proximal small bowel, liver and biliary tract and from compressing enlarged lymph nodes can cause severe abdominal pain, which do not respond satisfactorily to medical treatment or radiotherapy. Percutaneous celiac ganglia block (CGB) can be performed with high success and low complication rates under imaging guidance to obtain pain relief in patients with upper abdominal malignancies. A significant relationship between pain relief and degree of tumoral celiac ganglia invasion according to CT features was described in the literature. Performing the procedure in the early grades of celiac ganglia invasion on CT can increase the effectiveness of the CGB, which is contrary to World Health Organization criteria stating that CGB must be performed in patients with advanced stage cancer. CGB may also be effectively performed in patients with chronic pancreatitis for pain palliation

  17. Osteopontin Bridging Innate and Adaptive Immunity in Autoimmune Diseases

    Science.gov (United States)

    Raineri, Davide; Boggio, Elena; Favero, Francesco; Soluri, Maria Felicia

    2016-01-01

    Osteopontin (OPN) regulates the immune response at multiple levels. Physiologically, it regulates the host response to infections by driving T helper (Th) polarization and acting on both innate and adaptive immunity; pathologically, it contributes to the development of immune-mediated and inflammatory diseases. In some cases, the mechanisms of these effects have been described, but many aspects of the OPN function remain elusive. This is in part ascribable to the fact that OPN is a complex molecule with several posttranslational modifications and it may act as either an immobilized protein of the extracellular matrix or a soluble cytokine or an intracytoplasmic molecule by binding to a wide variety of molecules including crystals of calcium phosphate, several cell surface receptors, and intracytoplasmic molecules. This review describes the OPN structure, isoforms, and functions and its role in regulating the crosstalk between innate and adaptive immunity in autoimmune diseases. PMID:28097158

  18. Cannabinoids and Innate Immunity: Taking a Toll on Neuroinflammation

    Directory of Open Access Journals (Sweden)

    Eric J. Downer

    2011-01-01

    Full Text Available The biologically active components of cannabis have therapeutic potential in neuroinflammatory disorders due to their anti-inflammatory propensity. Cannabinoids influence immune function in both the peripheral and the central nervous system (CNS, and the components of the cannabinoid system, the cannabinoid receptors and their endogenous ligands (endocannabinoids, have been detected on immune cells as well as in brain glia. Neuroinflammation is the complex innate immune response of neural tissue to control infection and eliminate pathogens, and Toll-like receptors (TLRs, a major family of pattern recognition receptors (PRRs that mediate innate immunity, have emerged as players in the neuroinflammatory processes underpinning various CNS diseases. This review will highlight evidence that cannabinoids interact with the immune system by impacting TLR-mediated signaling events, which may provide cues for devising novel therapeutic approaches for cannabinoid ligands.

  19. Crosstalk between microbiota, pathogens and the innate immune responses.

    Science.gov (United States)

    Günther, Claudia; Josenhans, Christine; Wehkamp, Jan

    2016-08-01

    Research in the last decade has convincingly demonstrated that the microbiota is crucial in order to prime and orchestrate innate and adaptive immune responses of their host and influence barrier function as well as multiple developmental and metabolic parameters of the host. Reciprocally, host reactions and immune responses instruct the composition of the microbiota. This review summarizes recent evidence from experimental and human studies which supports these arms of mutual relationship and crosstalk between host and resident microbiota, with a focus on innate immune responses in the gut, the role of cell death pathways and antimicrobial peptides. We also provide some recent examples on how dysbiosis and pathogens can act in concert to promote intestinal infection, inflammatory pathologies and cancer. The future perspectives of these combined research efforts include the discovery of protective species within the microbiota and specific traits and factors of microbes that weaken or enforce host intestinal homeostasis. Copyright © 2016 Elsevier GmbH. All rights reserved.

  20. The multilayered innate immune defense of the gut.

    Science.gov (United States)

    El Chamy, Laure; Matt, Nicolas; Ntwasa, Monde; Reichhart, Jean-Marc

    2015-01-01

    In the wild, the fruit fly Drosophila melanogaster thrives on rotten fruit. The digestive tract maintains a powerful gut immune barrier to regulate the ingested microbiota, including entomopathogenic bacteria. This gut immune barrier includes a chitinous peritrophic matrix that isolates the gut contents from the epithelial cells. In addition, the epithelial cells are tightly sealed by septate junctions and can mount an inducible immune response. This local response can be activated by invasive bacteria, or triggered by commensal bacteria in the gut lumen. As with chronic inflammation in mammals, constitutive activation of the gut innate immune response is detrimental to the health of flies. Accordingly, the Drosophila gut innate immune response is tightly regulated to maintain the endogenous microbiota, while preventing infections by pathogenic microorganisms.

  1. Tissue-Resident Cytolytic Innate Lymphocytes in Cancer.

    Science.gov (United States)

    Nixon, Briana G; Li, Ming O

    2018-01-15

    Innate lymphoid cells (ILCs) are critical components of tissues in the body, providing a first line of defense against challenges to host integrity. In contrast to strictly cytokine-producing helper ILCs, resident innate lymphocyte populations with cytolytic potential have been identified in multiple tissues in both mouse and human. These cells express the transcription factor Tbet, NK cell receptors, granzymes, perforin, and death receptors, and can directly kill tumor cells. Signals in the tumor microenvironment may promote this response, including the cytokine IL-15 and stress-associated ligands for activating NK receptors. Although there is evidence that these cells are tissue and tumor resident, their lineage remains unclear. Whether they are derived from the NK or helper ILC lineages or represent a third differentiation pathway remains to be determined. A better understanding of their lineage will help clarify their regulation and function in the context of antitumor immunity. Copyright © 2018 by The American Association of Immunologists, Inc.

  2. MAMPs/PAMPs - elicitors of innate immunity in plants

    DEFF Research Database (Denmark)

    Erbs, Gitte; Newman, Mari-Anne

    2009-01-01

    Patterns (MAMPs or PAMPs), are recognised by the plant innate immune systems Pattern Recognition Receptors (PRRs). General bacterial elicitors, like lipopolysaccharides (LPS), flagellin (Flg), elongation factor Tu (EF-Tu), cold shock protein (CSP), peptidoglycan (PGN) and the enzyme superoxide dismutase...... elicitors have, in recent years, been identified. Here, the current knowledge regarding bacterial elicitors of innate immunity in plants is presented...... (SodM) are known to act as MAMPs and induce immune responses in plants or plant cells (Gómez-Gómez and Boller, 2000; Erbs and Newman, 2003; Felix and Boller, 2003; Kunze et al., 2004; Watt et al., 2006, Gust et al., 2007; Erbs et al., unpublished). The corresponding PRRs for some of these bacterial...

  3. Autophagy and Retromer Components in Plant Innate Immunity

    DEFF Research Database (Denmark)

    Munch, David

    Innate immunity depends on the recognition of pathogens and subsequent regulation of complex interactions that ultimately leads to production of compounds to deter microbial innovation. This thesis presents different aspects of immunity-associated cell death with focus on autophagy in the plant...... metabolism and its role in plant innate immunity will be presented. A homolog of ACD11 in humans is FOUR-PHOSPHATE ADAPTOR PROTEIN2 (FAPP2) and it has also been shown to be involved in cell death regulation in human Jurkat T cells. The data presented here show that FAPP2 does not appear to be involved......, a component of the retromer complex, was discovered as a relatively weak suppressor. Here I show redundancy between the three VPS35 homologs present in Arabidopsis in regulation of immunity-associated cell death, with a focus on the catabolic pathway autophagy. In addition a role for ACD11 in sphingolipid...

  4. The innate immune response during urinary tract infection and pyelonephritis.

    Science.gov (United States)

    Spencer, John David; Schwaderer, Andrew L; Becknell, Brian; Watson, Joshua; Hains, David S

    2014-07-01

    Despite its proximity to the fecal flora, the urinary tract is considered sterile. The precise mechanisms by which the urinary tract maintains sterility are not well understood. Host immune responses are critically important in the antimicrobial defense of the urinary tract. During recent years, considerable advances have been made in our understanding of the mechanisms underlying immune homeostasis of the kidney and urinary tract. Dysfunctions in these immune mechanisms may result in acute disease, tissue destruction and overwhelming infection. The objective of this review is to provide an overview of the innate immune response in the urinary tract in response to microbial assault. In doing so, we focus on the role of antimicrobial peptides-a ubiquitous component of the innate immune response.

  5. Manipulation of Innate Immunity for Cancer Therapy in Dogs

    Directory of Open Access Journals (Sweden)

    Daniel Regan

    2015-12-01

    Full Text Available Over the last one to two decades, the field of cancer immunotherapy has rapidly progressed from early preclinical studies to a successful clinical reality and fourth major pillar of human cancer therapy. While current excitement in the field of immunotherapy is being driven by several major breakthroughs including immune checkpoint inhibitors and adoptive cell therapies, these advances stem from a foundation of pivotal studies demonstrating the immune systems role in tumor control and eradication. The following will be a succinct review on veterinary cancer immunotherapy as it pertains to manipulation of the innate immune system to control tumor growth and metastasis. In addition, we will provide an update on recent progress in our understanding of the innate immune system in veterinary tumor immunology, and how these gains may lead to novel therapies for the treatment of cancer in companion animals.

  6. Manipulation of Innate Immunity for Cancer Therapy in Dogs.

    Science.gov (United States)

    Regan, Daniel; Dow, Steven

    2015-12-01

    Over the last one to two decades, the field of cancer immunotherapy has rapidly progressed from early preclinical studies to a successful clinical reality and fourth major pillar of human cancer therapy. While current excitement in the field of immunotherapy is being driven by several major breakthroughs including immune checkpoint inhibitors and adoptive cell therapies, these advances stem from a foundation of pivotal studies demonstrating the immune systems role in tumor control and eradication. The following will be a succinct review on veterinary cancer immunotherapy as it pertains to manipulation of the innate immune system to control tumor growth and metastasis. In addition, we will provide an update on recent progress in our understanding of the innate immune system in veterinary tumor immunology, and how these gains may lead to novel therapies for the treatment of cancer in companion animals.

  7. MAP Kinase 4 Substrates and Plant Innate Immunity

    DEFF Research Database (Denmark)

    Rasmussen, Magnus Wohlfahrt

    recognition, which also induce its localization to cytoplasmic processing bodies. All three proteins; PAT1, AOC3 and eIF4E also interacts with MPK4 in vivo although the functional outcome of these interactions are still elusive. The thesis comprise a general introduction to plant innate immunity followed...... by two review articles “MAP kinase cascades in Arabidopsis innate immunity” published in Frontiers in Plant Science and “mRNA decay in plant immunity” under revision for Cellular and Molecular Life Science. Together these sections gives a comprehensive overview of Arabidopsis defense signaling......Multi-layered defense responses are activated in plants upon recognition of invading pathogens. Transmembrane receptors recognize conserved pathogen-associated molecular patterns and activate MAP kinase cascades, which regulate changes in gene expression to produce appropriate immune responses...

  8. Bilingualism changes children's beliefs about what is innate.

    Science.gov (United States)

    Byers-Heinlein, Krista; Garcia, Bianca

    2015-03-01

    Young children engage in essentialist reasoning about natural kinds, believing that many traits are innately determined. This study investigated whether personal experience with second language acquisition could alter children's essentialist biases. In a switched-at-birth paradigm, 5- and 6-year-old monolingual and simultaneous bilingual children expected that a baby's native language, an animal's vocalizations, and an animal's physical traits would match those of a birth rather than of an adoptive parent. We predicted that sequential bilingual children, who had been exposed to a new language after age 3, would show greater understanding that languages are learned. Surprisingly, sequential bilinguals showed reduced essentialist beliefs about all traits: they were significantly more likely than other children to believe that human language, animal vocalizations, and animal physical traits would be learned through experience rather than innately endowed. These findings suggest that bilingualism in the preschool years can profoundly change children's essentialist biases. © 2014 John Wiley & Sons Ltd.

  9. Sublethal Heavy Metal Stress Stimulates Innate Immunity in Tomato

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    Nilanjan Chakraborty

    2015-01-01

    Full Text Available Effect of sublethal heavy metal stress as plant biotic elicitor for triggering innate immunity in tomato plant was investigated. Copper in in vivo condition induced accumulation of defense enzymes like peroxidase (PO, polyphenol oxidase (PPO, phenylalanine ammonia-lyase (PAL, and β-1,3 glucanase along with higher accumulation of total phenol, antioxidative enzymes (catalase and ascorbate peroxidase, and total chlorophyll content. Furthermore, the treatment also induced nitric oxide (NO production which was confirmed by realtime visualization of NO burst using a fluorescent probe 4,5-diaminofluorescein diacetate (DAF-2DA and spectrophotometric analysis. The result suggested that the sublethal dose of heavy metal can induce an array of plant defense responses that lead to the improvement of innate immunity in plants.

  10. The Interface between Fungal Biofilms and Innate Immunity

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    John F. Kernien

    2018-01-01

    Full Text Available Fungal biofilms are communities of adherent cells surrounded by an extracellular matrix. These biofilms are commonly found during infection caused by a variety of fungal pathogens. Clinically, biofilm infections can be extremely difficult to eradicate due to their resistance to antifungals and host defenses. Biofilm formation can protect fungal pathogens from many aspects of the innate immune system, including killing by neutrophils and monocytes. Altered immune recognition during this phase of growth is also evident by changes in the cytokine profiles of monocytes and macrophages exposed to biofilm. In this manuscript, we review the host response to fungal biofilms, focusing on how these structures are recognized by the innate immune system. Biofilms formed by Candida, Aspergillus, and Cryptococcus have received the most attention and are highlighted. We describe common themes involved in the resilience of fungal biofilms to host immunity and give examples of biofilm defenses that are pathogen-specific.

  11. Innate spatial-temporal reasoning and the identification of genius.

    Science.gov (United States)

    Peterson, Matthew R; Balzarini, Doreen; Bodner, Mark; Jones, Edward G; Phillips, Tiffany; Richardson, Debra; Shaw, Gordon L

    2004-01-01

    The teaching of mathematics is invariably language-based, but spatial-temporal (ST) reasoning (making a mental image and thinking ahead in space and time) is crucial to the understanding of math. Here we report that Big Seed, a demanding ST video game, based upon the mathematics of knot theory and previously applied to understanding DNA structure and function, can be used to reveal innate ST reasoning. Big Seed studies with middle and elementary school children provide strong evidence that ST reasoning ability is not only innate but far exceeds optimistic expectations based on age, the percentage of children achieving exceptional ST performance in less than 7 h of training, and retention of ability. A third grader has been identified as a genius (functionally defined) in ST performance. Big Seed may be used for training and assessing 'creativity' (functionally defined) and ST reasoning as well as discovering genius.

  12. Pathogen subversion of cell-intrinsic innate immunity.

    Science.gov (United States)

    Roy, Craig R; Mocarski, Edward S

    2007-11-01

    The mammalian immune system has evolved under continuous selective pressure from a wide range of microorganisms that colonize and replicate in animal hosts. A complex set of signaling networks initiate both innate and adaptive immunity in response to the diverse pathogens that mammalian hosts encounter. In response, viral and microbial pathogens have developed or acquired sophisticated mechanisms to avoid, counteract and subvert sensors, signaling networks and a range of effector functions that constitute the host immune response. This balance of host response and pathogen countermeasures contributes to chronic infection in highly adapted pathogens that have coevolved with their host. In this review we outline some of the themes that are beginning to emerge in the mechanisms by which pathogens subvert the early innate immune response.

  13. Innate Immunity and Immune Evasion by Enterovirus 71.

    Science.gov (United States)

    Pathinayake, Prabuddha S; Hsu, Alan C-Y; Wark, Peter A B

    2015-12-14

    Enterovirus 71 (EV71) is a major infectious disease affecting millions of people worldwide and it is the main etiological agent for outbreaks of hand foot and mouth disease (HFMD). Infection is often associated with severe gastroenterological, pulmonary, and neurological diseases that are most prevalent in children. Currently, no effective vaccine or antiviral drugs exist against EV71 infection. A lack of knowledge on the molecular mechanisms of EV71 infection in the host and the virus-host interactions is a major constraint to developing specific antiviral strategies against this infection. Previous studies have identified and characterized the function of several viral proteins produced by EV71 that interact with the host innate immune proteins, including type I interferon signaling and microRNAs. These interactions eventually promote efficient viral replication and increased susceptibility to the disease. In this review we discuss the functions of EV71 viral proteins in the modulation of host innate immune responses to facilitate viral replication.

  14. Innate immune evasion strategies of DNA and RNA viruses.

    Science.gov (United States)

    Beachboard, Dia C; Horner, Stacy M

    2016-08-01

    Upon infection, both DNA and RNA viruses can be sensed by pattern recognition receptors (PRRs) in the cytoplasm or the nucleus to activate antiviral innate immunity. Sensing of viral products leads to the activation of a signaling cascade that ultimately results in transcriptional activation of type I and III interferons, as well as other antiviral genes that together mediate viral clearance and inhibit viral spread. Therefore, in order for viruses to replicate and spread efficiently, they must inhibit the host signaling pathways that induce the innate antiviral immune response. In this review, we will highlight recent advances in the understanding of the mechanisms by which viruses evade PRR detection, intermediate signaling molecule activation, transcription factor activation, and the actions of antiviral proteins. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Innate Immune Evasion Mediated by Flaviviridae Non-Structural Proteins.

    Science.gov (United States)

    Chen, Shun; Wu, Zhen; Wang, Mingshu; Cheng, Anchun

    2017-10-07

    Flaviviridae-caused diseases are a critical, emerging public health problem worldwide. Flaviviridae infections usually cause severe, acute or chronic diseases, such as liver damage and liver cancer resulting from a hepatitis C virus (HCV) infection and high fever and shock caused by yellow fever. Many researchers worldwide are investigating the mechanisms by which Flaviviridae cause severe diseases. Flaviviridae can interfere with the host's innate immunity to achieve their purpose of proliferation. For instance, dengue virus (DENV) NS2A, NS2B3, NS4A, NS4B and NS5; HCV NS2, NS3, NS3/4A, NS4B and NS5A; and West Nile virus (WNV) NS1 and NS4B proteins are involved in immune evasion. This review discusses the interplay between viral non-structural Flaviviridae proteins and relevant host proteins, which leads to the suppression of the host's innate antiviral immunity.

  16. Trauma: the role of the innate immune system

    Directory of Open Access Journals (Sweden)

    Rijkers GT

    2006-05-01

    Full Text Available Abstract Immune dysfunction can provoke (multiple organ failure in severely injured patients. This dysfunction manifests in two forms, which follow a biphasic pattern. During the first phase, in addition to the injury by trauma, organ damage is caused by the immune system during a systemic inflammatory response. During the second phase the patient is more susceptible for sepsis due to host defence failure (immune paralysis. The pathophysiological model outlined in this review encompasses etiological factors and the contribution of the innate immune system in the end organ damage. The etiological factors can be divided into intrinsic (genetic predisposition and physiological status and extrinsic components (type of injury or "traumaload" and surgery or "intervention load". Of all the factors, the intervention load is the only one which, can be altered by the attending emergency physician. Adjustment of the therapeutic approach and choice of the most appropriate treatment strategy can minimize the damage caused by the immune response and prevent the development of immunological paralysis. This review provides a pathophysiological basis for the damage control concept, in which a staged approach of surgery and post-traumatic immunomonitoring have become important aspects of the treatment protocol. The innate immune system is the main objective of immunomonitoring as it has the most prominent role in organ failure after trauma. Polymorphonuclear phagocytes and monocytes are the main effector-cells of the innate immune system in the processes that lead to organ failure. These cells are controlled by cytokines, chemokines, complement factors and specific tissue signals. The contribution of tissue barrier integrity and its interaction with the innate immune system is further evaluated.

  17. Innate Immunity and the Role of Defensins in Otitis Media

    OpenAIRE

    Underwood, Mark; Bakaletz, Lauren

    2011-01-01

    Otitis media is the most common pediatric disease in developed countries and a significant cause of morbidity and hearing loss in developing countries. The innate immune system is essential to protecting the middle ear from infection. Defensins, broad-spectrum cationic antimicrobial peptides, have been implicated in prevention of and the early response to acute otitis media; however, the mechanisms by which defensins and other antimicrobial molecules mediate this protection have not been comp...

  18. Innate immunity in CKD-associated vascular diseases.

    Science.gov (United States)

    Zewinger, Stephen; Schumann, Timo; Fliser, Danilo; Speer, Thimoteus

    2016-11-01

    Chronic kidney disease (CKD) is associated with an increased risk for cardiovascular events. Therefore, the activation of the innate immune system plays an important role. In contrast to the adaptive immunity, unspecific recognition of conserved endogenous and exogenous structures by pattern recognition receptors (PRRs) represents a key feature of the innate immunity. Of these PRRs, Toll-like receptors (TLRs) as well as the inflammasome complex have been documented to be involved in the pathogenesis of cardiovascular diseases (CVDs). They are not only expressed in leukocytes but also in a variety of cell types such as endothelial cells or fibroblasts. While activation of TLRs on the cell surface leads to nuclear factor κB-dependent expression of pro-inflammatory mediators, the inflammasome is a cytosolic multimeric protein complex, which cleaves cytokines such as interleukin-1β into their biologically active forms. Several endogenous ligands for these PRRs have been identified as contributing to the development of a CKD-specific pro-inflammatory microenvironment. Notably, activation of TLRs as well as the inflammasome is associated with arterial hypertension, formation of atherosclerotic vascular lesions and vascular calcification. However, detailed molecular mechanisms on how the innate immune system contributes to CKD-associated CVDs are as yet poorly understood. Currently, several agents modulating the activation of the innate immune system are the focus of cardiovascular research. Large clinical studies will provide further information on the therapeutic applicability of these substances to reduce cardiovascular morbidity and mortality in the general population. Further trials including patients with CKD will be necessary to assess their effects on CKD-associated CVD. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  19. Dissecting innate immune signaling in viral evasion of cytokine production.

    Science.gov (United States)

    Zhang, Junjie; Zhu, Lining; Feng, Pinghui

    2014-03-02

    In response to a viral infection, the host innate immune response is activated to up-regulate gene expression and production of antiviral cytokines. Conversely, viruses have evolved intricate strategies to evade and exploit host immune signaling for survival and propagation. Viral immune evasion, entailing host defense and viral evasion, provides one of the most fascinating and dynamic interfaces to discern the host-virus interaction. These studies advance our understanding in innate immune regulation and pave our way to develop novel antiviral therapies. Murine γHV68 is a natural pathogen of murine rodents. γHV68 infection of mice provides a tractable small animal model to examine the antiviral response to human KSHV and EBV of which perturbation of in vivo virus-host interactions is not applicable. Here we describe a protocol to determine the antiviral cytokine production. This protocol can be adapted to other viruses and signaling pathways. Recently, we have discovered that γHV68 hijacks MAVS and IKKβ, key innate immune signaling components downstream of the cytosolic RIG-I and MDA5, to abrogate NFΚB activation and antiviral cytokine production. Specifically, γHV68 infection activates IKKβ and that activated IKKβ phosphorylates RelA to accelerate RelA degradation. As such, γHV68 efficiently uncouples NFΚB activation from its upstream activated IKKβ, negating antiviral cytokine gene expression. This study elucidates an intricate strategy whereby the upstream innate immune activation is intercepted by a viral pathogen to nullify the immediate downstream transcriptional activation and evade antiviral cytokine production.

  20. Innate immune recognition and activation during HIV infection

    Directory of Open Access Journals (Sweden)

    Larsen Carsten S

    2010-06-01

    Full Text Available Abstract The pathogenesis of HIV infection, and in particular the development of immunodeficiency, remains incompletely understood. Whichever intricate molecular mechanisms are at play between HIV and the host, it is evident that the organism is incapable of restricting and eradicating the invading pathogen. Both innate and adaptive immune responses are raised, but they appear to be insufficient or too late to eliminate the virus. Moreover, the picture is complicated by the fact that the very same cells and responses aimed at eliminating the virus seem to play deleterious roles by driving ongoing immune activation and progressive immunodeficiency. Whereas much knowledge exists on the role of adaptive immunity during HIV infection, it has only recently been appreciated that the innate immune response also plays an important part in HIV pathogenesis. In this review, we present current knowledge on innate immune recognition and activation during HIV infection based on studies in cell culture, non-human primates, and HIV-infected individuals, and discuss the implications for the understanding of HIV immunopathogenesis.

  1. Antimicrobial Peptides as Mediators of Innate Immunity in Teleosts

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    Barbara A. Katzenback

    2015-09-01

    Full Text Available Antimicrobial peptides (AMPs have been identified throughout the metazoa suggesting their evolutionarily conserved nature and their presence in teleosts is no exception. AMPs are short (18–46 amino acids, usually cationic, amphipathic peptides. While AMPs are diverse in amino acid sequence, with no two AMPs being identical, they collectively appear to have conserved functions in the innate immunity of animals towards the pathogens they encounter in their environment. Fish AMPs are upregulated in response to pathogens and appear to have direct broad-spectrum antimicrobial activity towards both human and fish pathogens. However, an emerging role for AMPs as immunomodulatory molecules has become apparent—the ability of AMPs to activate the innate immune system sheds light onto the multifaceted capacity of these small peptides to combat pathogens through direct and indirect means. Herein, this review focuses on the role of teleost AMPs as modulators of the innate immune system and their regulation in response to pathogens or other exogenous molecules. The capacity to regulate AMP expression by exogenous factors may prove useful in modulating AMP expression in fish to prevent disease, particularly in aquaculture settings where crowded conditions and environmental stress pre-dispose these fish to infection.

  2. Interactions between bile salts, gut microbiota, and hepatic innate immunity.

    Science.gov (United States)

    Schubert, Kristin; Olde Damink, Steven W M; von Bergen, Martin; Schaap, Frank G

    2017-09-01

    Bile salts are the water-soluble end products of hepatic cholesterol catabolism that are released into the duodenum and solubilize lipids due to their amphipathic structure. Bile salts also act as endogenous ligands for dedicated nuclear receptors that exert a plethora of biological processes, mostly related to metabolism. Bile salts are actively reclaimed in the distal part of the small intestine, released into the portal system, and subsequently extracted by the liver. This enterohepatic cycle is critically dependent on dedicated bile salt transporters. In the intestinal lumen, bile salts exert direct antimicrobial activity based on their detergent property and shape the gut microbiota. Bile salt metabolism by gut microbiota serves as a mechanism to counteract this toxicity and generates bile salt species that are distinct from those of the host. Innate immune cells of the liver play an important role in the early recognition and effector response to invading microbes. Bile salts signal primarily via the membrane receptor TGR5 and the intracellular farnesoid-x receptor, both present in innate immune cells. In this review, the interactions between bile salts, gut microbiota, and hepatic innate immunity are discussed. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. The interplay between the innate immune system and the microbiota.

    Science.gov (United States)

    Thaiss, Christoph A; Levy, Maayan; Suez, Jotham; Elinav, Eran

    2014-02-01

    The human gastrointestinal tract harbors one of the highest densities of microorganisms on earth, called the microbiota. In fact, the number of microbial cells in the intestine outnumbers the amount of human cells of the entire organism by a factor of 10. As such, a human being is more and more perceived as a super-organism consisting of a eukaryotic and a prokaryotic part. The compartment mediating the communication between both parts is the innate immune system and its various microbe-sensing pattern-recognition receptors. Co-evolution of the microbiota with the innate immune system has resulted in elaborate interdependency and feedback mechanisms by which both systems control mutual homeostasis. Here, we review the most important innate immune-microbiota interdependencies known to date. While microbial sensing by pattern-recognition receptors is required for stable microbial composition, the presence of the microbiota, in turn, is necessary for proper development and function of the immune system. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. E. fischeriana Root Compound Dpo Activates Antiviral Innate Immunity

    Directory of Open Access Journals (Sweden)

    Jingxuan Chen

    2017-10-01

    Full Text Available E. fischeriana has long been used as a traditional Chinese medicine. Recent studies reported that some compounds of E. fischeriana exhibited antimicrobial and immune enhance activity. Innate immune system is essential for the immune surveillance of inner and outer threats, initial host defense responses and immune modulation. The role of natural drug compounds, including E. fischeriana, in innate immune regulation is largely unknown. Here we demonstrated that E. fischeriana compound Dpo is involved in antiviral signaling. The genome wide RNA-seq analysis revealed that the induction of ISGs by viral infection could be synergized by Dpo. Consistently, Dpo enhanced the antiviral immune responses and protected the mice from death during viral infection. Dpo however was not able to rescue STING deficient mice lethality caused by HSV-1 infection. The enhancement of ISG15 by Dpo was also impaired in STING, IRF3, IRF7, or ELF4 deficient cells, demonstrating that Dpo activates innate immune responses in a STING/IRFs/ELF4 dependent way. The STING/IRFs/ELF4 axis is therefore important for Dpo induced ISGs expression, and can be used by host to counteract infection.

  5. Origin of Toll-like receptor-mediated innate immunity.

    Science.gov (United States)

    Kanzok, Stefan M; Hoa, Ngo T; Bonizzoni, Mariangela; Luna, Coralia; Huang, Yaming; Malacrida, Anna R; Zheng, Liangbiao

    2004-04-01

    Toll-related receptors (TLR) have been found in four animal phyla: Nematoda, Arthropoda, Echinodermata, and Chordata. No TLR has been identified thus far in acoelomates. TLR genes play a pivotal role in the innate immunity in both fruit fly and mammals. The prevailing view is that TLR-mediated immunity is ancient. The two pseudocoelomate TLRs, one each from Caenorhabditis elegans and Strongyloides stercoralis, were distinct from the coelomate ones. Further, the only TLR gene (Tol-1) in Ca. elegans did not appear to play a role in innate immunity. We argue that TLR-mediated innate immunity developed only in the coelomates, after they split from pseudocoelomates and acoelomates. We hypothesize that the function of TLR-mediated immunity is to prevent microbial infection in the body cavity present only in the coelomates. Phylogenetic analysis showed that almost all arthropod TLRs form a separate cluster from the mammalian counterparts. We further hypothesize that TLR-mediated immunity developed independently in the protostomia and deuterostomia coelomates.

  6. Group 2 innate lymphoid cells in the lung.

    Science.gov (United States)

    Drake, Li Yin; Kita, Hirohito

    2014-01-01

    As the first line of defense, innate immunity plays an important role in protecting the host against pathogens. Innate lymphoid cells (ILCs) are emerging as important effector cells in the innate immune system and the cell type that regulate immune and tissue homeostases. Group 2 ILCs (ILC2s) are a subset of ILCs and are characterized by their capacity to produce large quantities of type 2 cytokines and certain tissue growth factors. In animal models, lung ILC2s are involved in allergic airway inflammation induced by exposure to allergens even in the absence of CD4(+) T cells and are likely responsible for tissue repair and recovery after respiratory virus infection. ILC2s are also identified in various organs in humans, and the numbers are increased in mucosal tissues from patients with allergic disorders. Further investigations of this novel cell type will provide major conceptual advances in our understanding of the mechanisms of asthma and allergic diseases. © 2014 Elsevier Inc. All rights reserved.

  7. Wandering pathways in the regulation of innate immunity and inflammation.

    Science.gov (United States)

    Mantovani, Alberto

    2017-12-01

    Tumor-associated macrophages (TAM) have served as a paradigm of cancer-related inflammation. Moreover, investigations on TAM have led to the dissection of macrophage plasticity and polarization and to the discovery and analysis of molecular pathways of innate immunity, in particular cytokines, chemokines and PTX3 as a prototypic fluid phase pattern recognition molecule. Mechanisms of negative regulation are complex and include decoy receptors, receptor antagonists, anti-inflammatory cytokines and the signalling regulator IL-1R8. In this review, topics and open issues in relation to regulation of innate immunity and inflammation are discussed: 1) how macrophage and neutrophil plasticity and polarization underlie diverse pathological conditions ranging from autoimmunity to cancer and may pave the way to innovative diagnostic and therapeutic approaches; 2) the key role of decoy receptors and negative regulators (e.g. IL-1R2, ACKR2, IL-1R8) in striking a balance between amplification of immunity and resolution versus uncontrolled inflammation and tissue damage; 3) role of humoral innate immunity, illustrated by PTX3, in resistance against selected microbes, regulation of inflammation and immunity and tissue repair, with implications for diagnostic and therapeutic translation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Hepatitis C, innate immunity and alcohol: friends or foes?

    Science.gov (United States)

    Osna, Natalia A; Ganesan, Murali; Kharbanda, Kusum K

    2015-02-05

    Hepatitis C and alcohol are the most widespread causes of liver disease worldwide. Approximately 80% of patients with a history of hepatitis C and alcohol abuse develop chronic liver injury. Alcohol consumption in hepatitis C virus (HCV)-infected patients exacerbates liver disease leading to rapid progression of fibrosis, cirrhosis and even hepatocellular carcinoma. Hepatocytes are the main sites of HCV-infection and ethanol metabolism, both of which generate oxidative stress. Oxidative stress levels affect HCV replication and innate immunity, resulting in a greater susceptibility for HCV-infection and virus spread in the alcoholic patients. In this review paper, we analyze the effects of ethanol metabolism and other factors on HCV replication. In addition, we illustrate the mechanisms of how HCV hijacks innate immunity and how ethanol exposure regulates this process. We also clarify the effects of HCV and ethanol metabolism on interferon signaling-a crucial point for activation of anti-viral genes to protect cells from virus-and the role that HCV- and ethanol-induced impairments play in adaptive immunity which is necessary for recognition of virally-infected hepatocytes. In conclusion, ethanol exposure potentiates the suppressive effects of HCV on innate immunity, which activates viral spread in the liver and finally, leads to impairments in adaptive immunity. The dysregulation of immune response results in impaired elimination of HCV-infected cells, viral persistence, progressive liver damage and establishment of chronic infection that worsens the outcomes of chronic hepatitis C in alcoholic patients.

  9. Innate Immunity to Respiratory Infection in Early Life.

    Science.gov (United States)

    Lambert, Laura; Culley, Fiona J

    2017-01-01

    Early life is a period of particular susceptibility to respiratory infections and symptoms are frequently more severe in infants than in adults. The neonatal immune system is generally held to be deficient in most compartments; responses to innate stimuli are weak, antigen-presenting cells have poor immunostimulatory activity and adaptive lymphocyte responses are limited, leading to poor immune memory and ineffective vaccine responses. For mucosal surfaces such as the lung, which is continuously exposed to airborne antigen and to potential pathogenic invasion, the ability to discriminate between harmless and potentially dangerous antigens is essential, to prevent inflammation that could lead to loss of gaseous exchange and damage to the developing lung tissue. We have only recently begun to define the differences in respiratory immunity in early life and its environmental and developmental influences. The innate immune system may be of relatively greater importance than the adaptive immune system in the neonatal and infant period than later in life, as it does not require specific antigenic experience. A better understanding of what constitutes protective innate immunity in the respiratory tract in this age group and the factors that influence its development should allow us to predict why certain infants are vulnerable to severe respiratory infections, design treatments to accelerate the development of protective immunity, and design age specific adjuvants to better boost immunity to infection in the lung.

  10. The Role of Innate Immune System Receptors in Epilepsy Research.

    Science.gov (United States)

    Cordero-Arreola, Jessica; West, Rachel M; Mendoza-Torreblanca, Julieta; Mendez-Hernandez, Edna; Salas-Pacheco, Jose; Menendez-Gonzalez, Manuel; Freire, Rafael C; Machado, Sergio; Murillo-Rodriguez, Eric; Nardi, Antonio E; Arias-Carrion, Oscar

    2017-01-01

    Epilepsy is one of the most complex neurological disorders and its study requires a broad knowledge of neurology and neuroscience. It comprises a diverse group of neurological disorders that share the central feature of spontaneous recurrent seizures, and are often accompanied by cognitive deficits and mood disorder. This condition is one of the most common neurological disorders. Until recently, alterations of neuronal activities had been the focus of epilepsy research. This neurocentric emphasis did not address issues that arise in more complex models of epileptogenesis. An important factor in epilepsy that is not regulated directly by neurons is inflammation and the immune response of the brain. Recent evidence obtained in rodent epilepsy models supports the role of immune responses in the initiation and maintenance of epilepsy. Recognition of exogenous pathogens by the innate immune system is mediated by some pattern recognition receptors such as Toll-like receptors leading to cell activation and cytokine production. Currently, these receptors have been the focus of epilepsy studies looking to determine whether the innate immune activation is neuroprotective or neurotoxic for the brain. Here, we present the evidence in the literature of the involvement of key innate immune receptors in the development of epilepsy. We address some of the contradictory findings in these studies and also mention possible avenues for research into epilepsy treatments that target these receptors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. Optimal Control Strategy for Abnormal Innate Immune Response

    Directory of Open Access Journals (Sweden)

    Jinying Tan

    2015-01-01

    Full Text Available Innate immune response plays an important role in control and clearance of pathogens following viral infection. However, in the majority of virus-infected individuals, the response is insufficient because viruses are known to use different evasion strategies to escape immune response. In this study, we use optimal control theory to investigate how to control the innate immune response. We present an optimal control model based on an ordinary-differential-equation system from a previous study, which investigated the dynamics and regulation of virus-triggered innate immune signaling pathways, and we prove the existence of a solution to the optimal control problem involving antiviral treatment or/and interferon therapy. We conduct numerical experiments to investigate the treatment effects of different control strategies through varying the cost function and control efficiency. The results show that a separate treatment, that is, only inhibiting viral replication (u1(t or enhancing interferon activity (u2(t, has more advantages for controlling viral infection than a mixed treatment, that is, controlling both (u1(t and (u2(t simultaneously, including the smallest cost and operability. These findings would provide new insight for developing effective strategies for treatment of viral infectious diseases.

  12. Dimensional reduction for conformal blocks

    Science.gov (United States)

    Hogervorst, Matthijs

    2016-09-01

    We consider the dimensional reduction of a CFT, breaking multiplets of the d-dimensional conformal group SO( d + 1 , 1) up into multiplets of SO( d, 1). This leads to an expansion of d-dimensional conformal blocks in terms of blocks in d - 1 dimensions. In particular, we obtain a formula for 3 d conformal blocks as an infinite sum over 2 F 1 hypergeometric functions with closed-form coefficients.

  13. Learning Potentials in Number Blocks

    DEFF Research Database (Denmark)

    Majgaard, Gunver; Misfeldt, Morten; Nielsen, Jacob

    2012-01-01

    . The tool is called Number Blocks and it combines physical interaction, learning, and immediate feedback. Number Blocks supports the children's understanding of place value in the sense that it allows them to experiment with creating large numbers. We found the blocks contributed to the learning process...... in several ways. The blocks combined mathematics and play, and they included and supported children at different academic levels. The auditory representation, especially the enhanced rhythmic effects due to using speech synthesis, and the rhythm helped the children to pronounce large numbers. This creates...

  14. Common blocks for ASQS(12

    Directory of Open Access Journals (Sweden)

    Lorenzo Milazzo

    1997-05-01

    Full Text Available An ASQS(v is a particular Steiner system featuring a set of v vertices and two separate families of blocks, B and G, whose elements have a respective cardinality of 4 and 6. It has the property that any three vertices of X belong either to a B-block or to a G-block. The parameter cb is the number of common blocks in two separate ASQSs, both defined on the same set of vertices X . In this paper it is shown that cb ≤ 29 for any pair of ASQSs(12.

  15. 31 CFR 545.301 - Blocked account; blocked property.

    Science.gov (United States)

    2010-07-01

    ... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY TALIBAN (AFGHANISTAN) SANCTIONS... name of the Taliban or persons whose property or interests in property are blocked pursuant to § 545.201, or in which the Taliban or persons whose property or interests in property are blocked pursuant...

  16. Key Role of the Scavenger Receptor MARCO in Mediating Adenovirus Infection and Subsequent Innate Responses of Macrophages

    Directory of Open Access Journals (Sweden)

    Mareike D. Maler

    2017-08-01

    Full Text Available The scavenger receptor MARCO is expressed in several subsets of naive tissue-resident macrophages and has been shown to participate in the recognition of various bacterial pathogens. However, the role of MARCO in antiviral defense is largely unexplored. Here, we investigated whether MARCO might be involved in the innate sensing of infection with adenovirus and recombinant adenoviral vectors by macrophages, which elicit vigorous immune responses in vivo. Using cells derived from mice, we show that adenovirus infection is significantly more efficient in MARCO-positive alveolar macrophages (AMs and in AM-like primary macrophage lines (Max Planck Institute cells than in MARCO-negative bone marrow-derived macrophages. Using antibodies blocking ligand binding to MARCO, as well as gene-deficient and MARCO-transfected cells, we show that MARCO mediates the rapid adenovirus transduction of macrophages. By enhancing adenovirus infection, MARCO contributes to efficient innate virus recognition through the cytoplasmic DNA sensor cGAS. This leads to strong proinflammatory responses, including the production of interleukin-6 (IL-6, alpha/beta interferon, and mature IL-1α. These findings contribute to the understanding of viral pathogenesis in macrophages and may open new possibilities for the development of tools to influence the outcome of infection with adenovirus or adenovirus vectors.

  17. Classical Virasoro irregular conformal block

    Science.gov (United States)

    Rim, Chaiho; Zhang, Hong

    2015-07-01

    Virasoro irregular conformal block with arbitrary rank is obtained for the classical limit or equivalently Nekrasov-Shatashvili limit using the beta-deformed irregular matrix model (Penner-type matrix model for the irregular conformal block). The same result is derived using the generalized Mathieu equation which is equivalent to the loop equation of the irregular matrix model.

  18. Classical Virasoro irregular conformal block

    Energy Technology Data Exchange (ETDEWEB)

    Rim, Chaiho; Zhang, Hong [Department of Physics and Center for Quantum Spacetime (CQUeST), Sogang University,Seoul 121-742 (Korea, Republic of)

    2015-07-30

    Virasoro irregular conformal block with arbitrary rank is obtained for the classical limit or equivalently Nekrasov-Shatashvili limit using the beta-deformed irregular matrix model (Penner-type matrix model for the irregular conformal block). The same result is derived using the generalized Mathieu equation which is equivalent to the loop equation of the irregular matrix model.

  19. Four-block beam collimator

    CERN Document Server

    CERN PhotoLab

    1977-01-01

    The photo shows a four-block collimator installed on a control table for positioning the alignment reference marks. Designed for use with the secondary beams, the collimators operated in vacuum conditions. The blocks were made of steel and had a standard length of 1 m. The maximum aperture had a square coss-section of 144 cm2. (See Annual Report 1976.)

  20. OPAL Various Lead Glass Blocks

    CERN Document Server

    These lead glass blocks were part of a CERN detector called OPAL (one of the four experiments at the LEP particle detector). OPAL uses some 12 000 blocks of glass like this to measure particle energies in the electromagnetic calorimeter. This detector measured the energy deposited when electrons and photons were slowed down and stopped.

  1. Writing Blocks and Tacit Knowledge.

    Science.gov (United States)

    Boice, Robert

    1993-01-01

    A review of the literature on writing block looks at two kinds: inability to write in a timely, fluent fashion, and reluctance by academicians to assist others in writing. Obstacles to fluent writing are outlined, four historical trends in treating blocks are discussed, and implications are examined. (MSE)

  2. Block storage subsystem performance analysis

    CERN Multimedia

    CERN. Geneva

    2016-01-01

    You feel that your service is slow because of the storage subsystem? But there are too many abstraction layers between your software and the raw block device for you to debug all this pile... Let's dive on the platters and check out how the block storage sees your I/Os! We can even figure out what those patterns are meaning.

  3. Registered report: Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion.

    Science.gov (United States)

    Blum, David; LaBarge, Samuel

    2014-12-10

    The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of 50 papers in the field of cancer biology published between 2010 and 2012. This Registered Report describes the proposed replication plan of key experiments from "Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion" by Straussman and colleagues, published in Nature in 2012 (Straussman et al., 2012). The key experiments being replicated in this study are from Figure 2A, C, and D (and Supplemental Figure 11) and Figure 4C (and Supplemental Figure 19) (Straussman et al., 2012). Figure 2 demonstrates resistance to drug sensitivity conferred by co-culture with some stromal cell lines and identifies the secreted factor responsible as HGF. In Figure 4, Straussman and colleagues show that blocking the HGF receptor MET abrogates HGF’s rescue of drug sensitivity. The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published by eLife.

  4. Fundamental roles of the innate-like repertoire of natural antibodies in immune homeostasis

    Directory of Open Access Journals (Sweden)

    Jaya eVas

    2013-02-01

    Full Text Available The composition of the early immune repertoire is biased with prominent expression of spontaneously arising B-cell clones that produce IgM with recurrent and often autoreactive binding specificities. Amongst these naturally-arising antibodies (NAbs are IgM antibodies that specifically recognize damaged and senescent cells, often via oxidation-associated neo-determinants. These NAbs are present from birth and can be further boosted by apoptotic cell challenge. Recent studies have shown that IgM NAb to apoptotic cells can enhance phagocytic clearance, as well as suppress pro-inflammatory responses induced via Toll-like receptors, and block pathogenic IgG-immune complex (IC-mediated inflammatory responses. Specific antibody effector functions appear to be involved, as these anti-inflammatory properties are dependent on IgM-mediated recruitment of the early recognition factors of complement. Clinical surveys have suggested that anti-AC IgM NAbs may modulate disease activity in some patients with autoimmune disease. In mechanistic studies, anti-AC NAbs were shown to act in dendritic cells by inhibition of the Mitogen Activated Protein Kinase (MAPK pathway, a primary signal transduction pathway that controls inflammatory responses. This immunomodulatory pathway has an absolute requirement for the induction of MAPK Phosphatase-1. Taken together, recent studies have elucidated the novel properties of a class of protective NAbs, which may directly blunt inflammatory responses through a primitive pathway for regulation of the innate immune system.

  5. Evasion of antiviral innate immunity by Theiler's virus L* protein through direct inhibition of RNase L.

    Directory of Open Access Journals (Sweden)

    Frédéric Sorgeloos

    Full Text Available Theiler's virus is a neurotropic picornavirus responsible for chronic infections of the central nervous system. The establishment of a persistent infection and the subsequent demyelinating disease triggered by the virus depend on the expression of L*, a viral accessory protein encoded by an alternative open reading frame of the virus. We discovered that L* potently inhibits the interferon-inducible OAS/RNase L pathway. The antagonism of RNase L by L* was particularly prominent in macrophages where baseline oligoadenylate synthetase (OAS and RNase L expression levels are elevated, but was detectable in fibroblasts after IFN pretreatment. L* mutations significantly affected Theiler's virus replication in primary macrophages derived from wild-type but not from RNase L-deficient mice. L* counteracted the OAS/RNase L pathway through direct interaction with the ankyrin domain of RNase L, resulting in the inhibition of this enzyme. Interestingly, RNase L inhibition was species-specific as Theiler's virus L* protein blocked murine RNase L but not human RNase L or RNase L of other mammals or birds. Direct RNase L inhibition by L* and species specificity were confirmed in an in vitro assay performed with purified proteins. These results demonstrate a novel viral mechanism to elude the antiviral OAS/RNase L pathway. By targeting the effector enzyme of this antiviral pathway, L* potently inhibits RNase L, underscoring the importance of this enzyme in innate immunity against Theiler's virus.

  6. Key Role of the Scavenger Receptor MARCO in Mediating Adenovirus Infection and Subsequent Innate Responses of Macrophages.

    Science.gov (United States)

    Maler, Mareike D; Nielsen, Peter J; Stichling, Nicole; Cohen, Idan; Ruzsics, Zsolt; Wood, Connor; Engelhard, Peggy; Suomalainen, Maarit; Gyory, Ildiko; Huber, Michael; Müller-Quernheim, Joachim; Schamel, Wolfgang W A; Gordon, Siamon; Jakob, Thilo; Martin, Stefan F; Jahnen-Dechent, Willi; Greber, Urs F; Freudenberg, Marina A; Fejer, György

    2017-08-01

    The scavenger receptor MARCO is expressed in several subsets of naive tissue-resident macrophages and has been shown to participate in the recognition of various bacterial pathogens. However, the role of MARCO in antiviral defense is largely unexplored. Here, we investigated whether MARCO might be involved in the innate sensing of infection with adenovirus and recombinant adenoviral vectors by macrophages, which elicit vigorous immune responses in vivo Using cells derived from mice, we show that adenovirus infection is significantly more efficient in MARCO-positive alveolar macrophages (AMs) and in AM-like primary macrophage lines (Max Planck Institute cells) than in MARCO-negative bone marrow-derived macrophages. Using antibodies blocking ligand binding to MARCO, as well as gene-deficient and MARCO-transfected cells, we show that MARCO mediates the rapid adenovirus transduction of macrophages. By enhancing adenovirus infection, MARCO contributes to efficient innate virus recognition through the cytoplasmic DNA sensor cGAS. This leads to strong proinflammatory responses, including the production of interleukin-6 (IL-6), alpha/beta interferon, and mature IL-1α. These findings contribute to the understanding of viral pathogenesis in macrophages and may open new possibilities for the development of tools to influence the outcome of infection with adenovirus or adenovirus vectors. IMPORTANCE Macrophages play crucial roles in inflammation and defense against infection. Several macrophage subtypes have been identified with differing abilities to respond to infection with both natural adenoviruses and recombinant adenoviral vectors. Adenoviruses are important respiratory pathogens that elicit vigorous innate responses in vitro and in vivo The cell surface receptors mediating macrophage type-specific adenovirus sensing are largely unknown. The scavenger receptor MARCO is expressed on some subsets of naive tissue-resident macrophages, including lung alveolar macrophages

  7. Structural analysis of an innate immunostimulant from broccoli, Brassica oleracea var. italica.

    Science.gov (United States)

    Urai, Makoto; Kataoka, Keiko; Nishida, Satoshi; Sekimizu, Kazuhisa

    2017-11-22

    Vegetables are eaten as part of a healthy diet throughout the world, and some are also applied topically as a traditional medicine. We evaluated the innate immunostimulating activities of hot water extracts of various vegetables using the silkworm muscle contraction assay system, and found that broccoli, Brassica oleracea var. italica, contains a strong innate immunostimulant. We purified the innate immunostimulant from broccoli, and characterized the chemical structure by chemical analyses and NMR spectroscopy. The innate immunostimulant comprised galacturonic acid, galactose, glucose, arabinose, and rhamnose, and had a pectic-like polysaccharide structure. To determine the structural motif involved in the innate immunostimulating activity, we modified the structure by chemical and enzymatic treatment, and found that the activity was attenuated by pectinase digestion. These findings suggest that a pectic-like polysaccharide purified from broccoli has innate immune-stimulating activity, for which the polygalacturonic acid structure is necessary.

  8. Role of innate immunity in the pathogenesis of type 1 and type 2 diabetes.

    Science.gov (United States)

    Lee, Myung-Shik

    2014-08-01

    The importance of innate immunity in host defense is becoming clear after discovery of innate immune receptors such as Toll-like receptor or Nod-like receptor. Innate immune system plays an important role in diverse pathological situations such as autoimmune diseases. Role of innate immunity in the pathogenesis of metabolic disorders such as type 2 diabetes, metabolic syndrome or atherosclerosis that has not been previously considered as inflammatory disorders, is also being appreciated. Here, the role of innate immunity in the development of type 1 diabetes, a classical organ-specific autoimmune disease, and type 2 diabetes will be discussed, focusing on the role of specific innate immune receptors involved in these disease processes.

  9. Innate immunity, hemostasis and matrix remodeling: PTX3 as a link.

    Science.gov (United States)

    Doni, Andrea; Garlanda, Cecilia; Mantovani, Alberto

    2016-12-01

    Innate immunity is evolutionarily connected with hemostasis. PTX3 is an essential fluid-phase pattern recognition molecule of the innate immune system that acts as a functional ancestor of antibodies. PTX3 by interacting with defense collagens and fibrinogens amplifies effector functions of the innate immune system. At wound sites, PTX3 regulates the injury-induced thrombotic response and promotes wound healing by favoring timely fibrinolysis. Therefore, PTX3 interacts with ancestral domains conserved in innate immunity, hemostasis and extracellular matrix and exerts functions related to both antimicrobial resistance and tissue repair. These findings strengthen the connection between innate immune system and hemostasis, and suggest that recognition of microbes and extracellular matrix are evolutionarily conserved and integrated functions of the innate immune system. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Criminal Justice Systems. Block I: Law Enforcement. Block II: The Courts. Block III: Corrections. Block IV: Community Relations. Block V: Proficiency Skills. Block VI: Criminalistics. Student Guide.

    Science.gov (United States)

    Florida State Dept. of Education, Tallahassee. Div. of Vocational, Adult, and Community Education.

    This student guide together with an instructor guide comprise a set of curriculum materials on the criminal justice system. The student guide contains self-contained instructional material that students can study at their own pace most of the time. Six major subject areas or blocks, which are further broken down into several units, with some units…

  11. Criminal Justice Systems. Block I: Law Enforcement. Block II: The Courts. Block III: Corrections. Block IV: Community Relations. Block V: Proficiency Skills. Block VI: Criminalistics. Instructor Guide.

    Science.gov (United States)

    Florida State Dept. of Education, Tallahassee. Div. of Vocational, Adult, and Community Education.

    This instructor guide together with a student guide comprise a set of curriculum materials on the criminal justice system. The instructor guide is a resource for planning and managing individualized, competency-based instruction in six major subject areas or blocks, which are further broken down into several units with some units having several…

  12. Mitochondria-Endoplasmic Reticulum Contact Sites Mediate Innate Immune Responses.

    Science.gov (United States)

    Misawa, Takuma; Takahama, Michihiro; Saitoh, Tatsuya

    2017-01-01

    Mitochondria and the endoplasmic reticulum (ER) are fundamental organelles that coordinate high-order cell functions. Mitochondria are centers of energy production, whereas the ER is responsible for folding, transport, and degradation of proteins. In addition to their specific functions, mitochondria and ER actively communicate with each other to promote a variety of cellular events, such as material transfer and signal transduction. Recent studies have shown the critical involvement of these organelles in regulation of the innate immune system, which functions in host defense. The innate immune system utilizes a wide range of germ-line-encoded pattern recognition receptors (PRRs) to recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and induces inflammatory and antiviral responses. Contact sites between mitochondria and the ER function in assembly of the NLR family pyrin domain containing 3 (NLRP3)-inflammasome to promote the inflammatory response. The NLRP3-inflammasome is a protein complex composed of the receptor NLRP3 on the ER side and the adaptor apoptosis-associated speck-like protein containing a CARD on the mitochondrial side; it induces caspase-1-dependent maturation of proinflammatory cytokines such as interleukin (IL)-1β and IL-18. Furthermore, ER-mitochondria contact sites function in initiation and mediation of signal transduction pathways downstream of intracellular PRRs, such as retinoic acid-inducible gene I-like receptor and cyclic GMP-AMP synthase, to promote the antiviral response. Therefore, ER-mitochondria contact sites, also known as mitochondria-associated membranes, play key roles in regulation of innate immune responses.

  13. Candesartan ameliorates impaired fear extinction induced by innate immune activation.

    Science.gov (United States)

    Quiñones, María M; Maldonado, Lizette; Velazquez, Bethzaly; Porter, James T

    2016-02-01

    Patients with post-traumatic stress disorder (PTSD) tend to show signs of a relatively increased inflammatory state suggesting that activation of the immune system may contribute to the development of PTSD. In the present study, we tested whether activation of the innate immune system can disrupt acquisition or recall of auditory fear extinction using an animal model of PTSD. Male adolescent rats received auditory fear conditioning in context A. The next day, an intraperitoneal injection of lipopolysaccharide (LPS; 100 μg/kg) prior to auditory fear extinction in context B impaired acquisition and recall of extinction. LPS (100 μg/kg) given after extinction training did not impair extinction recall suggesting that LPS did not affect consolidation of extinction. In contrast to cued fear extinction, contextual fear extinction was not affected by prior injection of LPS (100 μg/kg). Although LPS also reduced locomotion, we could dissociate the effects of LPS on extinction and locomotion by using a lower dose of LPS (50 μg/kg) which impaired locomotion without affecting extinction. In addition, 15 h after an injection of 250 μg/kg LPS in adult rats, extinction learning and recall were impaired without affecting locomotion. A sub-chronic treatment with candesartan, an angiotensin II type 1 receptor blocker, prevented the LPS-induced impairment of extinction in adult rats. Our results demonstrate that activation of the innate immune system can disrupt auditory fear extinction in adolescent and adult animals. These findings also provide direction for clinical studies of novel treatments that modulate the innate immune system for stress-related disorders like PTSD. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Innate Immune Responses of Drosophila melanogaster Are Altered by Spaceflight

    Science.gov (United States)

    Marcu, Oana; Lera, Matthew P.; Sanchez, Max E.; Levic, Edina; Higgins, Laura A.; Shmygelska, Alena; Fahlen, Thomas F.; Nichol, Helen; Bhattacharya, Sharmila

    2011-01-01

    Alterations and impairment of immune responses in humans present a health risk for space exploration missions. The molecular mechanisms underpinning innate immune defense can be confounded by the complexity of the acquired immune system of humans. Drosophila (fruit fly) innate immunity is simpler, and shares many similarities with human innate immunity at the level of molecular and genetic pathways. The goals of this study were to elucidate fundamental immune processes in Drosophila affected by spaceflight and to measure host-pathogen responses post-flight. Five containers, each containing ten female and five male fruit flies, were housed and bred on the space shuttle (average orbit altitude of 330.35 km) for 12 days and 18.5 hours. A new generation of flies was reared in microgravity. In larvae, the immune system was examined by analyzing plasmatocyte number and activity in culture. In adults, the induced immune responses were analyzed by bacterial clearance and quantitative real-time polymerase chain reaction (qPCR) of selected genes following infection with E. coli. The RNA levels of relevant immune pathway genes were determined in both larvae and adults by microarray analysis. The ability of larval plasmatocytes to phagocytose E. coli in culture was attenuated following spaceflight, and in parallel, the expression of genes involved in cell maturation was downregulated. In addition, the level of constitutive expression of pattern recognition receptors and opsonins that specifically recognize bacteria, and of lysozymes, antimicrobial peptide (AMP) pathway and immune stress genes, hallmarks of humoral immunity, were also reduced in larvae. In adults, the efficiency of bacterial clearance measured in vivo following a systemic infection with E. coli post-flight, remained robust. We show that spaceflight altered both cellular and humoral immune responses in Drosophila and that the disruption occurs at multiple interacting pathways. PMID:21264297

  15. FOXO-dependent regulation of innate immune homeostasis.

    Science.gov (United States)

    Becker, Thomas; Loch, Gerrit; Beyer, Marc; Zinke, Ingo; Aschenbrenner, Anna C; Carrera, Pilar; Inhester, Therese; Schultze, Joachim L; Hoch, Michael

    2010-01-21

    The innate immune system represents an ancient host defence mechanism that protects against invading microorganisms. An important class of immune effector molecules to fight pathogen infections are antimicrobial peptides (AMPs) that are produced in plants and animals. In Drosophila, the induction of AMPs in response to infection is regulated through the activation of the evolutionarily conserved Toll and immune deficiency (IMD) pathways. Here we show that AMP activation can be achieved independently of these immunoregulatory pathways by the transcription factor FOXO, a key regulator of stress resistance, metabolism and ageing. In non-infected animals, AMP genes are activated in response to nuclear FOXO activity when induced by starvation, using insulin signalling mutants, or by applying small molecule inhibitors. AMP induction is lost in foxo null mutants but enhanced when FOXO is overexpressed. Expression of AMP genes in response to FOXO activity can also be triggered in animals unable to respond to immune challenges due to defects in both the Toll and IMD pathways. Molecular experiments at the Drosomycin promoter indicate that FOXO directly binds to its regulatory region, thereby inducing its transcription. In vivo studies in Drosophila, but also studies in human lung, gut, kidney and skin cells indicate that a FOXO-dependent regulation of AMPs is evolutionarily conserved. Our results indicate a new mechanism of cross-regulation of metabolism and innate immunity by which AMP genes can be activated under normal physiological conditions in response to the oscillating energy status of cells and tissues. This regulation seems to be independent of the pathogen-responsive innate immunity pathways whose activation is often associated with tissue damage and repair. The sparse production of AMPs in epithelial tissues in response to FOXO may help modulating the defence reaction without harming the host tissues, in particular when animals are suffering from energy shortage

  16. Subversion and utilization of host innate defense by Leishmania amazonensis

    Directory of Open Access Journals (Sweden)

    Lynn eSoong

    2012-03-01

    Full Text Available Infection with Leishmania amazonensis and other members of the L. mexicana complex can lead to diverse clinical manifestations, some of which are relatively difficult to control, even with standard chemotherapy. Diffuse cutaneous leishmaniasis is a rare but severe form, and its clinical hallmark is excessive parasitic growth in infected cells accompanied by profound impairments in host immune responses to the parasites. Since these parasites also cause non-healing cutaneous leishmaniasis in most inbred strains of mice, these animals are valuable models for dissecting the mechanisms of persistent infection and disease pathogenesis. In comparison to other Leishmania species, L. amazonensis infections are most remarkable for their ability to repress the activation and effector functions of macrophages, dendritic cells and CD4+ T cells, implying discrete mechanisms at work. In addition to this multilateral suppression of host innate and adaptive immunity, the activation of types I and II interferon-mediated responses and autophagic/lipid metabolic pathways actually promotes rather than restrains L. amazonensis infection. These seemingly contradictory findings reflect the remarkable adaptation of the parasites to the ancient defense machinery of the host, as well as the complex parasite-host interactions at different stages of infection, which collectively contribute to non-healing leishmaniasis in the New World. This review article highlights new evidence that reveals the strategies utilized by L. amazonensis parasites to subvert or modulate host innate defense machinery in neutrophils and macrophages, as well as the regulatory roles of host innate responses in promoting parasite survival and replication within the huge parasitophorous vacuoles. A better understanding of unique features in host responses to these parasites at early and late stages of infection is important for the rational design of control strategies for non-healing leishmaniasis.

  17. Subversion and Utilization of Host Innate Defense by Leishmania amazonensis.

    Science.gov (United States)

    Soong, Lynn

    2012-01-01

    Infection with Leishmania amazonensis and other members of the Leishmania mexicana complex can lead to diverse clinical manifestations, some of which are relatively difficult to control, even with standard chemotherapy. Diffuse cutaneous leishmaniasis (CL) is a rare but severe form, and its clinical hallmark is excessive parasitic growth in infected cells accompanied by profound impairments in host immune responses to the parasites. Since these parasites also cause non-healing CL in most inbred strains of mice, these animals are valuable models for dissecting the mechanisms of persistent infection and disease pathogenesis. In comparison to other Leishmania species, L. amazonensis infections are most remarkable for their ability to repress the activation and effector functions of macrophages, dendritic cells, and CD4(+) T cells, implying discrete mechanisms at work. In addition to this multilateral suppression of host innate and adaptive immunity, the activation of types I and II interferon-mediated responses and autophagic/lipid metabolic pathways actually promotes rather than restrains L. amazonensis infection. These seemingly contradictory findings reflect the remarkable adaptation of the parasites to the ancient defense machinery of the host, as well as the complex parasite-host interactions at different stages of infection, which collectively contribute to non-healing leishmaniasis in the New World. This review article highlights new evidence that reveals the strategies utilized by L. amazonensis parasites to subvert or modulate host innate defense machinery in neutrophils and macrophages, as well as the regulatory roles of host innate responses in promoting parasite survival and replication within the huge parasitophorous vacuoles. A better understanding of unique features in host responses to these parasites at early and late stages of infection is important for the rational design of control strategies for non-healing leishmaniasis.

  18. Marginal zone B-cells, a gatekeeper of innate immunity

    Directory of Open Access Journals (Sweden)

    Moncef eZOUALI

    2011-12-01

    Full Text Available To maintain the integrity of an organism constantly challenged by pathogens, the immune system is endowed with a variety of cell types. B-lymphocytes were initially thought to only play a role in the adaptative branch of immunity. However, a number of converging observations revealed that two B-cell subsets, marginal zone (MZ and B1 cells, exhibit unique developmental and functional characteristics, and can contribute to innate immune responses. In addition to their capacity to mount local antibody response against type 2 T-independent (TI-2 antigens, MZ B-cells can participate to T-dependent (TD immune response through the capture and import of blood-borne antigens to follicular areas of the spleen. Here, we discuss the multiple roles of MZ B-cells in rodents and primates. We also summarize studies —performed in transgenic mice expressing fully human antibodies on their B-cells and macaques whose infection with Simian Immunodeficiency Virus (SIV represents a suitable model for HIV-1 infection in humans— showing that infectious agents have developed strategies to subvert MZ B-cell functions. In these two experimental models, we observed that two microbial superantigens for B-cells (protein A from Staphylococcus aureus and protein L from Peptostreptococcus magnus as well as inactivated AT-2 virions of HIV-1 and infectious SIV preferentially deplete innate-like B-cells —MZ B-cells and/or B1 B-cells— with different consequences on TI and TD antibody responses. These data revealed that viruses and bacteria have developed strategies to deplete innate-like B-cells during the acute phase of infection and to impair the antibody response. Unraveling the intimate mechanisms responsible for targeting MZ B-cells in humans will be important for understanding disease pathogenesis and for designing novel vaccine strategies.

  19. Yersinia type III effectors perturb host innate immune responses

    Science.gov (United States)

    Pha, Khavong; Navarro, Lorena

    2016-01-01

    The innate immune system is the first line of defense against invading pathogens. Innate immune cells recognize molecular patterns from the pathogen and mount a response to resolve the infection. The production of proinflammatory cytokines and reactive oxygen species, phagocytosis, and induced programmed cell death are processes initiated by innate immune cells in order to combat invading pathogens. However, pathogens have evolved various virulence mechanisms to subvert these responses. One strategy utilized by Gram-negative bacterial pathogens is the deployment of a complex machine termed the type III secretion system (T3SS). The T3SS is composed of a syringe-like needle structure and the effector proteins that are injected directly into a target host cell to disrupt a cellular response. The three human pathogenic Yersinia spp. (Y. pestis, Y. enterocolitica, and Y. pseudotuberculosis) are Gram-negative bacteria that share in common a 70 kb virulence plasmid which encodes the T3SS. Translocation of the Yersinia effector proteins (YopE, YopH, YopT, YopM, YpkA/YopO, and YopP/J) into the target host cell results in disruption of the actin cytoskeleton to inhibit phagocytosis, downregulation of proinflammatory cytokine/chemokine production, and induction of cellular apoptosis of the target cell. Over the past 25 years, studies on the Yersinia effector proteins have unveiled tremendous knowledge of how the effectors enhance Yersinia virulence. Recently, the long awaited crystal structure of YpkA has been solved providing further insights into the activation of the YpkA kinase domain. Multisite autophosphorylation by YpkA to activate its kinase domain was also shown and postulated to serve as a mechanism to bypass regulation by host phosphatases. In addition, novel Yersinia effector protein targets, such as caspase-1, and signaling pathways including activation of the inflammasome were identified. In this review, we summarize the recent discoveries made on Yersinia

  20. Review: Gp-340/DMBT1 in mucosal innate immunity

    DEFF Research Database (Denmark)

    Madsen, Jens; Mollenhauer, Jan; Holmskov, Uffe

    2010-01-01

    ) is secreted into broncho-alveolar surface lining fluid whereas DMBT(SAG) is present in the saliva. The two molecules were shown to be identical and both interact with and agglutinate several Gram-negative and Gram-positive bacteria including Streptococcus mutans, a bacterium responsible for caries in the oral...... proteins, including serum and secretory IgA, C1q, lactoferrin, MUC5B and trefoil factor 2 (TFF2), all molecules with involvement in innate immunity and/or wound-healing processes. Recent generation of Dmbt1-deficient mice has provided the research field of DMBT1 with a model that allows research...

  1. Role of heat shock protein 70 in innate alloimmunity

    Directory of Open Access Journals (Sweden)

    Walter G. eLand

    2012-01-01

    Full Text Available This article briefly describes our own experience with the proven demonstration of heat shock protein 70 in reperfused renal allografts from brain-deaddonors and reflects about its potential role as a typical damage-associated molecular pattern (DAMP in the setting of innate alloimmunity. In fact, our group was able to demonstrate a dramatic up-regulation of heat shock protein 70 expression after postischemic reperfusion of renal allografts. Of note, up-regulation of this stress protein expression, although to a lesser extent, was already observed after cold storage of the organ indicating that this molecule is already induced in the stressed organism of a brain-dead donor. However, whether or not the dramatic up-regulation of heat shock protein 70 expression contributes to mounting an innate alloimmune response cannot be judged in view of these clinical findings.Nevertheless, heat shock protein 70, since generated in association with postischemic reperfusion-induced allograft injury, can be called a typical DAMP - as can everymolecule be termed a DAMP that is generated in associationwith any stressful tissue injury regardless of its final positive or negative regulatory function within the innate immune response elicited by it.In fact, as we discuss in this article, the context-dependent, even contradistinctive activities of heat shock protein 70 reflect the biological phenomenon that, throughout evolution, mammals have developed an elaborate network of positive and negative regulatory mechanisms, which provide balance between defensive and protective measures against unwarranted destruction of the host. In this sense, up-regulated expression of heat shock protein 70 in an injured allograft might reflect a pure protective response against the severe oxidative injury of a reperfused donor organ. On the other hand, up-regulated expression of this stress protein in an injured allograft might reflect a(futile attempt of the innate immune system to

  2. Native and aspirin-triggered lipoxins control innate immunity by inducing proteasomal degradation of TRAF6

    OpenAIRE

    Machado, Fabiana S.; Esper, L?sia; Dias, Alexandra; Madan, Rajat; Gu, YuanYuan; Hildeman, David; Serhan, Charles N.; Karp, Christopher L.; Aliberti, J?lio

    2008-01-01

    Innate immune signaling is critical for the development of protective immunity. Such signaling is, perforce, tightly controlled. Lipoxins (LXs) are eicosanoid mediators that play key counterregulatory roles during infection. The molecular mechanisms underlying LX-mediated control of innate immune signaling are of interest. In this study, we show that LX and aspirin (ASA)-triggered LX (ATL) inhibit innate immune signaling by inducing suppressor of cytokine signaling (SOCS) 2–dependent ubiquiti...

  3. Block by Block: Civic Action in the Battle of Baghdad

    Science.gov (United States)

    2007-11-01

    bedding, and latrine facilities. Additionally, provide milk , baby formula, diapers, 7 Bogart: Block by Block and infant/family care items such as...viable agricultural businesses. The cattle are a cross breed of a “regular” Iraqi cow and a water buffalo. Chicken farms are mostly egg farms, and...a problem. Contractors did not want to work for fear of being shot or kid - napped. For example, four contractors were shot over the duration of

  4. Harmony of spinning conformal blocks

    Energy Technology Data Exchange (ETDEWEB)

    Schomerus, Volker [DESY Hamburg, Theory Group,Notkestraße 85, 22607 Hamburg (Germany); Sobko, Evgeny [Nordita and Stockholm University,Roslagstullsbacken 23, SE-106 91 Stockholm (Sweden); Isachenkov, Mikhail [Department of Particle Physics and Astrophysics, Weizmann Institute of Science,Rehovot 7610001 (Israel)

    2017-03-15

    Conformal blocks for correlation functions of tensor operators play an increasingly important role for the conformal bootstrap programme. We develop a universal approach to such spinning blocks through the harmonic analysis of certain bundles over a coset of the conformal group. The resulting Casimir equations are given by a matrix version of the Calogero-Sutherland Hamiltonian that describes the scattering of interacting spinning particles in a 1-dimensional external potential. The approach is illustrated in several examples including fermionic seed blocks in 3D CFT where they take a very simple form.

  5. Harmony of spinning conformal blocks

    Energy Technology Data Exchange (ETDEWEB)

    Schomerus, Volker [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany). Theory Group; Sobko, Evgeny [Stockholm Univ. (Sweden); Nordita, Stockholm (Sweden); Isachenkov, Mikhail [Weizmann Institute of Science, Rehovoth (Israel). Dept. of Particle Physics and Astrophysics

    2016-12-07

    Conformal blocks for correlation functions of tensor operators play an increasingly important role for the conformal bootstrap programme. We develop a universal approach to such spinning blocks through the harmonic analysis of certain bundles over a coset of the conformal group. The resulting Casimir equations are given by a matrix version of the Calogero-Sutherland Hamiltonian that describes the scattering of interacting spinning particles in a 1-dimensional external potential. The approach is illustrated in several examples including fermionic seed blocks in 3D CFT where they take a very simple form.

  6. Anthrax Lethal Toxin Impairs Innate Immune Functions of Alveolar Macrophages and Facilitates Bacillus anthracis Survival

    National Research Council Canada - National Science Library

    Ribot, Wilson J; Panchal, Rekha G; Brittingham, Katherine C; Ruthel, Gordon; Kenny, Tara A; Lane, Douglas; Curry, Bob; Hoover, Timothy A; Friedlander, Arthur M; Bavari, Sina

    2006-01-01

    .... Although several factors contribute to inhalational anthrax, we hypothesized that unimpeded infection of Bacillus anthracis is directly linked to disabling the innate immune functions contributed by AM...

  7. Innate Control of Adaptive Immunity: Beyond the Three-Signal Paradigm.

    Science.gov (United States)

    Jain, Aakanksha; Pasare, Chandrashekhar

    2017-05-15

    Activation of cells in the adaptive immune system is a highly orchestrated process dictated by multiples cues from the innate immune system. Although the fundamental principles of innate control of adaptive immunity are well established, it is not fully understood how innate cells integrate qualitative pathogenic information to generate tailored protective adaptive immune responses. In this review, we discuss complexities involved in the innate control of adaptive immunity that extend beyond TCR engagement, costimulation, and priming cytokine production but are critical for the generation of protective T cell immunity. Copyright © 2017 by The American Association of Immunologists, Inc.

  8. Generalized selection to overcome innate immunity selects for host breadth in an RNA virus.

    Science.gov (United States)

    Wasik, Brian R; Muñoz-Rojas, Andrés R; Okamoto, Kenichi W; Miller-Jensen, Kathryn; Turner, Paul E

    2016-02-01

    Virus-host coevolution has selected for generalized host defense against viruses, exemplified by interferon production/signaling and other innate immune function in eukaryotes such as humans. Although cell-surface binding primarily limits virus infection success, generalized adaptation to counteract innate immunity across disparate hosts may contribute to RNA virus emergence potential. We examined this idea using vesicular stomatitis virus (VSV) populations previously evolved on strictly immune-deficient (HeLa) cells, strictly immune competent (MDCK) cells, or on alternating deficient/competent cells. By measuring viral fitness in unselected human cancer cells of differing innate immunity, we confirmed that HeLa-adapted populations were specialized for innate immune-deficient hosts, whereas MDCK-adapted populations were relatively more generalized for fitness on hosts of differing innate immune capacity and of different species origin. We also confirmed that HeLa-evolved populations maintained fitness in immune-deficient nonhuman primate cells. These results suggest that innate immunity is more prominent than host species in determining viral fitness at the host-cell level. Finally, our prediction was inexact that selection on alternating deficient/competent hosts should produce innate viral generalists. Rather, fitness differences among alternating host-evolved VSV populations indicated variable capacities to evade innate immunity. Our results suggest that the evolutionary history of innate immune selection can affect whether RNA viruses evolve greater host-breadth. © 2016 The Author(s). Evolution © 2016 The Society for the Study of Evolution.

  9. Comparative genomics RNAi screen identifies Eftud2 as a novel regulator of innate immunity.

    Science.gov (United States)

    De Arras, Lesly; Laws, Rebecca; Leach, Sonia M; Pontis, Kyle; Freedman, Jonathan H; Schwartz, David A; Alper, Scott

    2014-06-01

    The extent of the innate immune response is regulated by many positively and negatively acting signaling proteins. This allows for proper activation of innate immunity to fight infection while ensuring that the response is limited to prevent unwanted complications. Thus mutations in innate immune regulators can lead to immune dysfunction or to inflammatory diseases such as arthritis or atherosclerosis. To identify novel innate immune regulators that could affect infectious or inflammatory disease, we have taken a comparative genomics RNAi screening approach in which we inhibit orthologous genes in the nematode Caenorhabditis elegans and murine macrophages, expecting that genes with evolutionarily conserved function also will regulate innate immunity in humans. Here we report the results of an RNAi screen of approximately half of the C. elegans genome, which led to the identification of many candidate genes that regulate innate immunity in C. elegans and mouse macrophages. One of these novel conserved regulators of innate immunity is the mRNA splicing regulator Eftud2, which we show controls the alternate splicing of the MyD88 innate immunity signaling adaptor to modulate the extent of the innate immune response. Copyright © 2014 by the Genetics Society of America.

  10. Viral Infection: An Evolving Insight into the Signal Transduction Pathways Responsible for the Innate Immune Response

    Directory of Open Access Journals (Sweden)

    Girish J. Kotwal

    2012-01-01

    Full Text Available The innate immune response is initiated by the interaction of stereotypical pathogen components with genetically conserved receptors for extracytosolic pathogen-associated molecular patterns (PAMPs or intracytosolic nucleic acids. In multicellular organisms, this interaction typically clusters signal transduction molecules and leads to their activations, thereby initiating signals that activate innate immune effector mechanisms to protect the host. In some cases programmed cell death—a fundamental form of innate immunity—is initiated in response to genotoxic or biochemical stress that is associated with viral infection. In this paper we will summarize innate immune mechanisms that are relevant to viral pathogenesis and outline the continuing evolution of viral mechanisms that suppress the innate immunity in mammalian hosts. These mechanisms of viral innate immune evasion provide significant insight into the pathways of the antiviral innate immune response of many organisms. Examples of relevant mammalian innate immune defenses host defenses include signaling to interferon and cytokine response pathways as well as signaling to the inflammasome. Understanding which viral innate immune evasion mechanisms are linked to pathogenesis may translate into therapies and vaccines that are truly effective in eliminating the morbidity and mortality associated with viral infections in individuals.

  11. Viral Infection: An Evolving Insight into the Signal Transduction Pathways Responsible for the Innate Immune Response

    Science.gov (United States)

    Kotwal, Girish J.; Hatch, Steven; Marshall, William L.

    2012-01-01

    The innate immune response is initiated by the interaction of stereotypical pathogen components with genetically conserved receptors for extracytosolic pathogen-associated molecular patterns (PAMPs) or intracytosolic nucleic acids. In multicellular organisms, this interaction typically clusters signal transduction molecules and leads to their activations, thereby initiating signals that activate innate immune effector mechanisms to protect the host. In some cases programmed cell death—a fundamental form of innate immunity—is initiated in response to genotoxic or biochemical stress that is associated with viral infection. In this paper we will summarize innate immune mechanisms that are relevant to viral pathogenesis and outline the continuing evolution of viral mechanisms that suppress the innate immunity in mammalian hosts. These mechanisms of viral innate immune evasion provide significant insight into the pathways of the antiviral innate immune response of many organisms. Examples of relevant mammalian innate immune defenses host defenses include signaling to interferon and cytokine response pathways as well as signaling to the inflammasome. Understanding which viral innate immune evasion mechanisms are linked to pathogenesis may translate into therapies and vaccines that are truly effective in eliminating the morbidity and mortality associated with viral infections in individuals. PMID:22997518

  12. Innate immune complexity in the purple sea urchin: diversity of the sp185/333 system.

    Science.gov (United States)

    Smith, L Courtney

    2012-01-01

    The California purple sea urchin, Strongylocentrotus purpuratus, is a long-lived echinoderm with a complex and sophisticated innate immune system. There are several large gene families that function in immunity in this species including the Sp185/333 gene family that has ∼50 (±10) members. The family shows intriguing sequence diversity and encodes a broad array of diverse yet similar proteins. The genes have two exons of which the second encodes the mature protein and has repeats and blocks of sequence called elements. Mosaics of element patterns plus single nucleotide polymorphisms-based variants of the elements result in significant sequence diversity among the genes yet maintains similar structure among the members of the family. Sequence of a bacterial artificial chromosome insert shows a cluster of six, tightly linked Sp185/333 genes that are flanked by GA microsatellites. The sequences between the GA microsatellites in which the Sp185/333 genes and flanking regions are located, are much more similar to each other than are the sequences outside the microsatellites suggesting processes such as gene conversion, recombination, or duplication. However, close linkage does not correspond with greater sequence similarity compared to randomly cloned and sequenced genes that are unlikely to be linked. There are three segmental duplications that are bounded by GAT microsatellites and include three almost identical genes plus flanking regions. RNA editing is detectible throughout the mRNAs based on comparisons to the genes, which, in combination with putative post-translational modifications to the proteins, results in broad arrays of Sp185/333 proteins that differ among individuals. The mature proteins have an N-terminal glycine-rich region, a central RGD motif, and a C-terminal histidine-rich region. The Sp185/333 proteins are localized to the cell surface and are found within vesicles in subsets of polygonal and small phagocytes. The coelomocyte proteome shows full

  13. Innate Immune Complexity in the Purple Sea Urchin: Diversity of the Sp185/333 System

    Science.gov (United States)

    Smith, L. Courtney

    2012-01-01

    The California purple sea urchin, Strongylocentrotus purpuratus, is a long-lived echinoderm with a complex and sophisticated innate immune system. There are several large gene families that function in immunity in this species including the Sp185/333 gene family that has ∼50 (±10) members. The family shows intriguing sequence diversity and encodes a broad array of diverse yet similar proteins. The genes have two exons of which the second encodes the mature protein and has repeats and blocks of sequence called elements. Mosaics of element patterns plus single nucleotide polymorphisms-based variants of the elements result in significant sequence diversity among the genes yet maintains similar structure among the members of the family. Sequence of a bacterial artificial chromosome insert shows a cluster of six, tightly linked Sp185/333 genes that are flanked by GA microsatellites. The sequences between the GA microsatellites in which the Sp185/333 genes and flanking regions are located, are much more similar to each other than are the sequences outside the microsatellites suggesting processes such as gene conversion, recombination, or duplication. However, close linkage does not correspond with greater sequence similarity compared to randomly cloned and sequenced genes that are unlikely to be linked. There are three segmental duplications that are bounded by GAT microsatellites and include three almost identical genes plus flanking regions. RNA editing is detectible throughout the mRNAs based on comparisons to the genes, which, in combination with putative post-translational modifications to the proteins, results in broad arrays of Sp185/333 proteins that differ among individuals. The mature proteins have an N-terminal glycine-rich region, a central RGD motif, and a C-terminal histidine-rich region. The Sp185/333 proteins are localized to the cell surface and are found within vesicles in subsets of polygonal and small phagocytes. The coelomocyte proteome shows full

  14. John Stuart Mill, innate differences, and the regulation of reproduction.

    Science.gov (United States)

    Paul, Diane B; Day, Benjamin

    2008-06-01

    In this paper, we show that the question of the relative importance of innate characteristics and institutional arrangements in explaining human difference was vehemently contested in Britain during the first half of the nineteenth century. Thus Sir Francis Galton's work of the 1860s should be seen as an intervention in a pre-existing controversy. The central figure in these earlier debates-as well as many later ones-was the philosopher and economist John Stuart Mill. In Mill's view, human nature was fundamentally shaped by history and culture, factors that accounted for most mental and behavioral differences between men and women and among people of different classes, nationalities, and races. Indeed, Mill's whole program of social reform depended on the assumption that human differences were not fixed by nature. To identify the leading figures in these disputes about difference and the concrete context in which they occurred, we explore three debates in which Mill played a key role: over the capacities and rights of women, the viability of peasant proprietorship in India and Ireland, and the status of black labor in Jamaica. The last two draw our attention to the important colonial context of the nature-nurture debate. We also show that ideas that for us seem of a piece were not always linked for these earlier thinkers, nor did views on innateness necessarily have the political correlates that we now take for granted.

  15. Differential activity of innate defense antimicrobial peptides against Nocardia species.

    Science.gov (United States)

    Rieg, Siegbert; Meier, Benjamin; Fähnrich, Eva; Huth, Anja; Wagner, Dirk; Kern, Winfried V; Kalbacher, Hubert

    2010-02-23

    Members of the genus Nocardia are ubiquitous environmental saprophytes capable to cause human pulmonary, disseminated and cutaneous nocardiosis or bovine mastitis. Innate immunity appears to play an important role in early defense against Nocardia species. To elucidate the contribution of antimicrobial peptides (AMPs) in innate defense against Nocardia, the activity of human alpha-defensins human neutrophil peptides (HNPs) 1-3, human beta-defensin (hBD)-3 and cathelicidin LL-37 as well as bovine beta-defensins lingual and tracheal antimicrobial peptides (LAP, TAP) and bovine neutrophil-derived indolicidin against four important Nocardia species was investigated. Whereas N. farcinica ATCC 3318 and N. nova ATCC 33726 were found to be susceptible to all investigated human and bovine AMPs, N. asteroides ATCC 19247 was killed exclusively by neutrophil-derived human alpha-defensins HNP 1-3 and bovine indolicidin. N. brasiliensis ATCC 19296 was found to exhibit complete resistance to investigated human AMPs and to be susceptible only to bovine indolicidin. Selected AMPs are capable to contribute to the first line of defense against Nocardia, yet, susceptibility appears to vary across different Nocardia species. Obtained results of neutrophil-derived AMPs to possess the broadest antinocardial spectrum are remarkable, since nocardiosis is characterized by a neutrophil-rich infiltrate in vivo.

  16. Antimicrobial proteins and polypeptides in pulmonary innate defence

    Directory of Open Access Journals (Sweden)

    Taggart Clifford C

    2006-02-01

    Full Text Available Abstract Inspired air contains a myriad of potential pathogens, pollutants and inflammatory stimuli. In the normal lung, these pathogens are rarely problematic. This is because the epithelial lining fluid in the lung is rich in many innate immunity proteins and peptides that provide a powerful anti-microbial screen. These defensive proteins have anti-bacterial, anti- viral and in some cases, even anti-fungal properties. Their antimicrobial effects are as diverse as inhibition of biofilm formation and prevention of viral replication. The innate immunity proteins and peptides also play key immunomodulatory roles. They are involved in many key processes such as opsonisation facilitating phagocytosis of bacteria and viruses by macrophages and monocytes. They act as important mediators in inflammatory pathways and are capable of binding bacterial endotoxins and CPG motifs. They can also influence expression of adhesion molecules as well as acting as powerful anti-oxidants and anti-proteases. Exciting new antimicrobial and immunomodulatory functions are being elucidated for existing proteins that were previously thought to be of lesser importance. The potential therapeutic applications of these proteins and peptides in combating infection and preventing inflammation are the subject of ongoing research that holds much promise for the future.

  17. Interplay Between Innate Immunity and the Plant Microbiota.

    Science.gov (United States)

    Hacquard, Stéphane; Spaepen, Stijn; Garrido-Oter, Ruben; Schulze-Lefert, Paul

    2017-08-04

    The innate immune system of plants recognizes microbial pathogens and terminates their growth. However, recent findings suggest that at least one layer of this system is also engaged in cooperative plant-microbe interactions and influences host colonization by beneficial microbial communities. This immune layer involves sensing of microbe-associated molecular patterns (MAMPs) by pattern recognition receptors (PRRs) that initiate quantitative immune responses to control host-microbial load, whereas diversification of MAMPs and PRRs emerges as a mechanism that locally sculpts microbial assemblages in plant populations. This suggests a more complex microbial management role of the innate immune system for controlled accommodation of beneficial microbes and in pathogen elimination. The finding that similar molecular strategies are deployed by symbionts and pathogens to dampen immune responses is consistent with this hypothesis but implies different selective pressures on the immune system due to contrasting outcomes on plant fitness. The reciprocal interplay between microbiota and the immune system likely plays a critical role in shaping beneficial plant-microbiota combinations and maintaining microbial homeostasis.

  18. Microbiota activation and regulation of innate and adaptive immunity.

    Science.gov (United States)

    Alexander, Katie L; Targan, Stephan R; Elson, Charles O

    2014-07-01

    The human host has coevolved with the collective of bacteria species, termed microbiota, in a complex fashion that affects both innate and adaptive immunity. Differential regulation of regulatory T-cell and effector T-cell responses are a direct result of specific microbial species present within the gut, and this relationship is subject to dysregulation during inflammation and disease. The microbiota varies widely between individuals and has a profound effect on how one reacts to various environmental stimuli, particularly if a person is genetically predisposed to an immune-mediated inflammatory disorder such as inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Approximately, half of all CD patients have elevated antibodies to CBir1, a microbiota flagellin common to mice and humans, demonstrating flagellins as immunodominant antigens in the intestines. This review focuses on the use of flagellins as probes to study microbiota-specific responses in the context of health and disease as well as probes of innate and adaptive responses employed by the host to deal with the overwhelming bacterial presence of the microbiota. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Initiation of innate immune responses by surveillance of homeostasis perturbations.

    Science.gov (United States)

    Colaço, Henrique G; Moita, Luis F

    2016-07-01

    Pathogen recognition, signaling transduction pathways, and effector mechanisms are necessary steps of innate immune responses that play key roles in the early phase of defense and in the stimulation of the later specific response of adaptive immunity. Here, we argue that in addition to the direct recognition of conserved common structural and functional molecular signatures of microorganisms using pattern recognition receptors, hosts can mount an immune response following the sensing of disruption in homeostasis as proximal reporters for infections. Surveillance of disruption of core cellular activities leading to defense responses is a flexible strategy that requires few additional components and that can effectively detect relevant threats. It is likely to be evolutionarily very conserved and ancient because it is operational in organisms that lack pattern recognition triggered immunity. A homeostasis disruption model of immune response initiation and modulation has broad implications for pathophysiology and treatment of disease and might constitute an often overlooked but central component of a comprehensive conceptual framework for innate immunity. © 2016 Federation of European Biochemical Societies.

  20. Regulation of intestinal homeostasis by innate and adaptive immunity.

    Science.gov (United States)

    Kayama, Hisako; Takeda, Kiyoshi

    2012-11-01

    The intestine is a unique tissue where an elaborate balance is maintained between tolerance and immune responses against a variety of environmental factors such as food and the microflora. In a healthy individual, the microflora stimulates innate and adaptive immune systems to maintain gut homeostasis. However, the interaction of environmental factors with particular genetic backgrounds can lead to dramatic changes in the composition of the microflora (i.e. dysbiosis). Many of the specific commensal-bacterial products and the signaling pathways they trigger have been characterized. The role of T(h)1, T(h)2 and T(h)17 cells in inflammatory bowel disease has been widely investigated, as has the contribution of epithelial cells and subsets of dendritic cells and macrophages. To date, multiple regulatory cells in adaptive immunity, such as regulatory T cells and regulatory B cells, have been shown to maintain gut homeostasis by preventing inappropriate innate and adaptive immune responses to commensal bacteria. Additionally, regulatory myeloid cells have recently been identified that prevent intestinal inflammation by inhibiting T-cell proliferation. An increasing body of evidence has shown that multiple regulatory mechanisms contribute to the maintenance of gut homeostasis.

  1. Autophagy, Innate Immunity and Tissue Repair in Acute Kidney Injury

    Directory of Open Access Journals (Sweden)

    Pu Duann

    2016-05-01

    Full Text Available Kidney is a vital organ with high energy demands to actively maintain plasma hemodynamics, electrolytes and water homeostasis. Among the nephron segments, the renal tubular epithelium is endowed with high mitochondria density for their function in active transport. Acute kidney injury (AKI is an important clinical syndrome and a global public health issue with high mortality rate and socioeconomic burden due to lack of effective therapy. AKI results in acute cell death and necrosis of renal tubule epithelial cells accompanied with leakage of tubular fluid and inflammation. The inflammatory immune response triggered by the tubular cell death, mitochondrial damage, associative oxidative stress, and the release of many tissue damage factors have been identified as key elements driving the pathophysiology of AKI. Autophagy, the cellular mechanism that removes damaged organelles via lysosome-mediated degradation, had been proposed to be renoprotective. An in-depth understanding of the intricate interplay between autophagy and innate immune response, and their roles in AKI pathology could lead to novel therapies in AKI. This review addresses the current pathophysiology of AKI in aspects of mitochondrial dysfunction, innate immunity, and molecular mechanisms of autophagy. Recent advances in renal tissue regeneration and potential therapeutic interventions are also discussed.

  2. Innate Lymphoid Cells in HIV/SIV Infections

    Directory of Open Access Journals (Sweden)

    Spandan V. Shah

    2017-12-01

    Full Text Available Over the past several years, new populations of innate lymphocytes have been described in mice and primates that are critical for mucosal homeostasis, microbial regulation, and immune defense. Generally conserved from mice to humans, innate lymphoid cells (ILC have been divided primarily into three subpopulations based on phenotypic and functional repertoires: ILC1 bear similarities to natural killer cells; ILC2 have overlapping functions with TH2 cells; and ILC3 that share many functions with TH17/TH22 cells. ILC are specifically enriched at mucosal surfaces and are possibly one of the earliest responders during viral infections besides being involved in the homeostasis of gut-associated lymphoid tissue and maintenance of gut epithelial barrier integrity. Burgeoning evidence also suggests that there is an early and sustained abrogation of ILC function and numbers during HIV and pathogenic SIV infections, most notably ILC3 in the gastrointestinal tract, which leads to disruption of the mucosal barrier and dysregulation of the local immune system. A better understanding of the direct or indirect mechanisms of loss and dysfunction will be critical to immunotherapeutics aimed at restoring these cells. Herein, we review the current literature on ILC with a particular emphasis on ILC3 and their role(s in mucosal immunology and the significance of disrupting the ILC niche during HIV and SIV infections.

  3. Joint replacement surgery and the innate immune system.

    Science.gov (United States)

    Goodman, Stuart B; Konttinen, Yrjo T; Takagi, Michiaki

    2014-01-01

    Total joint replacement is a highly successful, cost-effective surgical procedure that relieves pain and improves function for patients with end-stage arthritis. The most commonly used materials for modern joint replacements include metal alloys such as cobalt chrome and titanium alloys, polymers including polymethylmethacrylate and polyethylene, and ceramics. Implantation of a joint prosthesis incites an acute inflammatory reaction that is regulated by the innate immune system, a preprogrammed non-antigen specific biological response composed of cells, proteins, and other factors. This "frontline" immune mechanism was originally designed to combat invading microorganisms, but now responds to both pathogen-associated molecular patterns or PAMPS (by-products from microorganisms), and damage associated molecular patterns or DAMPS (molecular by-products from cells), via pattern recognition receptors (PRRs). In this way, potentially injurious stimuli that might disrupt the normal homeostatic regulatory mechanisms of the organism are efficiently dealt with, ensuring the survival of the host. Initial surgical implantation of the joint replacement, as well as ongoing generation of wear debris and byproducts during usage of the joint, activates the innate immune system. Understanding and potentially modulating these events may lead to improved function and increased longevity of joint replacements in the future.

  4. Hematopoietic Stem and Progenitor Cells as Effectors in Innate Immunity

    Directory of Open Access Journals (Sweden)

    Jennifer L. Granick

    2012-01-01

    Full Text Available Recent research has shed light on novel functions of hematopoietic stem and progenitor cells (HSPC. While they are critical for maintenance and replenishment of blood cells in the bone marrow, these cells are not limited to the bone marrow compartment and function beyond their role in hematopoiesis. HSPC can leave bone marrow and circulate in peripheral blood and lymph, a process often manipulated therapeutically for the purpose of transplantation. Additionally, these cells preferentially home to extramedullary sites of inflammation where they can differentiate to more mature effector cells. HSPC are susceptible to various pathogens, though they may participate in the innate immune response without being directly infected. They express pattern recognition receptors for detection of endogenous and exogenous danger-associated molecular patterns and respond not only by the formation of daughter cells but can themselves secrete powerful cytokines. This paper summarizes the functional and phenotypic characterization of HSPC, their niche within and outside of the bone marrow, and what is known regarding their role in the innate immune response.

  5. Feliform carnivores have a distinguished constitutive innate immune response

    Directory of Open Access Journals (Sweden)

    Sonja K. Heinrich

    2016-05-01

    Full Text Available Determining the immunological phenotype of endangered and threatened populations is important to identify those vulnerable to novel pathogens. Among mammals, members of the order Carnivora are particularly threatened by diseases. We therefore examined the constitutive innate immune system, the first line of protection against invading microbes, of six free-ranging carnivore species; the black-backed jackal (Canis mesomelas, the brown hyena (Hyena brunnea, the caracal (Caracal caracal, the cheetah (Acinonyx jubatus, the leopard (Panthera pardus and the lion (Panthera leo using a bacterial killing assay. The differences in immune responses amongst the six species were independent of their foraging behaviour, body mass or social organisation but reflected their phylogenetic relatedness. The bacterial killing capacity of black-backed jackals, a member of the suborder Caniformia, followed the pattern established for a wide variety of vertebrates. In contrast, the five representatives of the suborder Feliformia demonstrated a killing capacity at least an order of magnitude higher than any species reported previously, with a particularly high capacity in caracals and cheetahs. Our results suggest that the immunocompetence of threatened felids such as the cheetah has been underestimated and its assessment ought to consider both innate and adaptive components of the immune system.

  6. Hantaan virus triggers TLR4-dependent innate immune responses.

    Science.gov (United States)

    Yu, Hai-Tao; Jiang, Hong; Zhang, Ye; Nan, Xue-Ping; Li, Yu; Wang, Wei; Jiang, Wei; Yang, Dong-Qiang; Su, Wen-Jing; Wang, Jiu-Ping; Wang, Ping-Zhong; Bai, Xue-Fan

    2012-10-01

    The innate immune response induced by Hantavirus is responsible for endothelial cell dysfunction and viral pathogenicity. Recent studies demonstrate that TLR4 expression is upregulated and mediates the secretion of several cytokines in Hantaan virus (HTNV)-infected endothelial cells. To examine viral interactions with host endothelial cells and characterize the innate antiviral responses associated with Toll-like receptors, we selected TLR4 as the target molecule to investigate anti-hantavirus immunity. TLR4 mRNA-silenced EVC-304 (EVC-304 TLR4-) cells and EVC-304 cells were used to investigate signaling molecules downstream of TLR4. The expression of the adaptor protein TRIF was higher in HTNV-infected EVC-304 cells than in EVC-304 TLR4- cells. However, there was no apparent difference in the expression of MyD88 in either cell line. The transcription factors for NF-κB and IRF-3 were translocated from the cytoplasm into the nucleus in HTNV-infected EVC-304 cells, but not in HTNV-infected EVC-304 TLR4- cells. Our results demonstrate that TLR4 may play an important role in the antiviral immunity of the host against HTNV infection through an MyD88-independent signaling pathway.

  7. Cytokine Networks between Innate Lymphoid Cells and Myeloid Cells

    Directory of Open Access Journals (Sweden)

    Arthur Mortha

    2018-02-01

    Full Text Available Innate lymphoid cells (ILCs are an essential component of the innate immune system in vertebrates. They are developmentally rooted in the lymphoid lineage and can diverge into at least three transcriptionally distinct lineages. ILCs seed both lymphoid and non-lymphoid tissues and are locally self-maintained in tissue-resident pools. Tissue-resident ILCs execute important effector functions making them key regulator in tissue homeostasis, repair, remodeling, microbial defense, and anti-tumor immunity. Similar to T lymphocytes, ILCs possess only few sensory elements for the recognition of non-self and thus depend on extrinsic cellular sensory elements residing within the tissue. Myeloid cells, including mononuclear phagocytes (MNPs, are key sentinels of the tissue and are able to translate environmental cues into an effector profile that instructs lymphocyte responses. The adaptation of myeloid cells to the tissue state thus influences the effector program of ILCs and serves as an example of how environmental signals are integrated into the function of ILCs via a tissue-resident immune cell cross talks. This review summarizes our current knowledge on the role of myeloid cells in regulating ILC functions and discusses how feedback communication between ILCs and myeloid cells contribute to stabilize immune homeostasis in order to maintain the healthy state of an organ.

  8. Mechanisms of Borrelia burgdorferi internalization and intracellular innate immune signaling

    Directory of Open Access Journals (Sweden)

    Tanja ePetnicki-Ocwieja

    2014-12-01

    Full Text Available Lyme disease is a long-term infection whose most severe pathology is characterized by inflammatory arthritis of the lower bearing joints, carditis and neuropathy. The inflammatory cascades are initiated through the early recognition of invading Borrelia burgdorferi spirochetes by cells of the innate immune response, such as neutrophils and macrophage. B. burgdorferi does not have an intracellular niche and thus much research has focused on immune pathways activated by pathogen recognition molecules at the cell surface, such as the Toll-like receptors (TLRs. However, in recent years, studies have shown that internalization of the bacterium by host cells is an important component of the defense machinery in response to B. burgdorferi. Upon internalization, B. burgdorferi is trafficked through an endo/lysosomal pathway resulting in the activation of a number of intracellular pathogen recognition receptors including TLRs and Nod-like receptors (NLRs. Here we will review the innate immune molecules that participate in both cell surface and intracellular immune activation by B. burgdorferi.

  9. Differential activity of innate defense antimicrobial peptides against Nocardia species

    Directory of Open Access Journals (Sweden)

    Wagner Dirk

    2010-02-01

    Full Text Available Abstract Background Members of the genus Nocardia are ubiquitous environmental saprophytes capable to cause human pulmonary, disseminated and cutaneous nocardiosis or bovine mastitis. Innate immunity appears to play an important role in early defense against Nocardia species. To elucidate the contribution of antimicrobial peptides (AMPs in innate defense against Nocardia, the activity of human α-defensins human neutrophil peptides (HNPs 1-3, human β-defensin (hBD-3 and cathelicidin LL-37 as well as bovine β-defensins lingual and tracheal antimicrobial peptides (LAP, TAP and bovine neutrophil-derived indolicidin against four important Nocardia species was investigated. Results Whereas N. farcinica ATCC 3318 and N. nova ATCC 33726 were found to be susceptible to all investigated human and bovine AMPs, N. asteroides ATCC 19247 was killed exclusively by neutrophil-derived human α-defensins HNP 1-3 and bovine indolicidin. N. brasiliensis ATCC 19296 was found to exhibit complete resistance to investigated human AMPs and to be susceptible only to bovine indolicidin. Conclusion Selected AMPs are capable to contribute to the first line of defense against Nocardia, yet, susceptibility appears to vary across different Nocardia species. Obtained results of neutrophil-derived AMPs to possess the broadest antinocardial spectrum are remarkable, since nocardiosis is characterized by a neutrophil-rich infiltrate in vivo.

  10. Innate lymphoid cells at the interface between obesity and asthma.

    Science.gov (United States)

    Everaere, Laetitia; Ait Yahia, Saliha; Bouté, Mélodie; Audousset, Camille; Chenivesse, Cécile; Tsicopoulos, Anne

    2018-01-01

    Obesity and asthma prevalence has dramatically and concomitantly increased over the last 25 years, and many epidemiological studies have highlighted obesity as an important risk factor for asthma. Although many studies have been performed, the underlying mechanisms remain poorly understood. Innate mechanisms have been involved in both diseases, in particular through the recently described innate lymphoid cells (ILCs). ILCs are subdivided into three groups that are defined by their cytokine production and by their master transcription factor expression, in sharp correlation with their T helper counterparts. However, unlike T helper cells, ILCs do not express antigen-specific receptors, but respond to damage-induced signals. ILCs have been found in target tissues of both diseases, and data have implicated these cells in the pathogenesis of both diseases. In particular group 2 ILCs (ILC2) are activated in both the adipose and lung tissues under the effect of interleukin-33 and interleukin-25 expression. However, counter-intuitively to the well-known association between obesity and asthma, ILC2 are beneficial for obesity but deleterious for asthma. This review will examine the roles of ILCs in each disease and recent data highlighting ILCs as a putative link between obesity and asthma. © 2017 John Wiley & Sons Ltd.

  11. Antiviral Defense and Innate Immune Memory in the Oyster

    Science.gov (United States)

    Speck, Peter

    2018-01-01

    The Pacific oyster, Crassostrea gigas, is becoming a valuable model for investigating antiviral defense in the Lophotrochozoa superphylum. In the past five years, improvements to laboratory-based experimental infection protocols using Ostreid herpesvirus I (OsHV-1) from naturally infected C. gigas combined with next-generation sequencing techniques has revealed that oysters have a complex antiviral response involving the activation of all major innate immune pathways. Experimental evidence indicates C. gigas utilizes an interferon-like response to limit OsHV-1 replication and spread. Oysters injected with a viral mimic (polyI:C) develop resistance to OsHV-1. Improved survival following polyI:C injection was found later in life (within-generational immune priming) and in the next generation (multi-generational immune priming). These studies indicate that the oyster’s antiviral defense system exhibits a form of innate immune-memory. An important priority is to identify the molecular mechanisms responsible for this phenomenon. This knowledge will motivate the development of practical and cost-effective treatments for improving oyster health in aquaculture. PMID:29547519

  12. Innate Immunity and Immune Evasion by Enterovirus 71

    Directory of Open Access Journals (Sweden)

    Prabuddha S. Pathinayake

    2015-12-01

    Full Text Available Enterovirus 71 (EV71 is a major infectious disease affecting millions of people worldwide and it is the main etiological agent for outbreaks of hand foot and mouth disease (HFMD. Infection is often associated with severe gastroenterological, pulmonary, and neurological diseases that are most prevalent in children. Currently, no effective vaccine or antiviral drugs exist against EV71 infection. A lack of knowledge on the molecular mechanisms of EV71 infection in the host and the virus-host interactions is a major constraint to developing specific antiviral strategies against this infection. Previous studies have identified and characterized the function of several viral proteins produced by EV71 that interact with the host innate immune proteins, including type I interferon signaling and microRNAs. These interactions eventually promote efficient viral replication and increased susceptibility to the disease. In this review we discuss the functions of EV71 viral proteins in the modulation of host innate immune responses to facilitate viral replication.

  13. Left bundle-branch block

    DEFF Research Database (Denmark)

    Risum, Niels; Strauss, David; Sogaard, Peter

    2013-01-01

    The relationship between myocardial electrical activation by electrocardiogram (ECG) and mechanical contraction by echocardiography in left bundle-branch block (LBBB) has never been clearly demonstrated. New strict criteria for LBBB based on a fundamental understanding of physiology have recently...

  14. The wild tapered block bootstrap

    DEFF Research Database (Denmark)

    Hounyo, Ulrich

    -based method in terms of asymptotic accuracy of variance estimation and distribution approximation. For stationary time series, the asymptotic validity, and the favorable bias properties of the new bootstrap method are shown in two important cases: smooth functions of means, and M-estimators. The first......-order asymptotic validity of the tapered block bootstrap as well as the wild tapered block bootstrap approximation to the actual distribution of the sample mean is also established when data are assumed to satisfy a near epoch dependent condition. The consistency of the bootstrap variance estimator for the sample......In this paper, a new resampling procedure, called the wild tapered block bootstrap, is introduced as a means of calculating standard errors of estimators and constructing confidence regions for parameters based on dependent heterogeneous data. The method consists in tapering each overlapping block...

  15. Recursion Relations for Conformal Blocks

    CERN Document Server

    Penedones, João; Yamazaki, Masahito

    2016-09-12

    In the context of conformal field theories in general space-time dimension, we find all the possible singularities of the conformal blocks as functions of the scaling dimension $\\Delta$ of the exchanged operator. In particular, we argue, using representation theory of parabolic Verma modules, that in odd spacetime dimension the singularities are only simple poles. We discuss how to use this information to write recursion relations that determine the conformal blocks. We first recover the recursion relation introduced in 1307.6856 for conformal blocks of external scalar operators. We then generalize this recursion relation for the conformal blocks associated to the four point function of three scalar and one vector operator. Finally we specialize to the case in which the vector operator is a conserved current.

  16. Defying gravity using Jenga™ blocks

    Science.gov (United States)

    Tan, Yin-Soo; Yap, Kueh-Chin

    2007-11-01

    This paper describes how Jenga™ blocks can be used to demonstrate the physics of an overhanging tower that appears to defy gravity. We also propose ideas for how this demonstration can be adapted for the A-level physics curriculum.

  17. Divergent Roles of Interferon-γ and Innate Lymphoid Cells in Innate and Adaptive Immune Cell-Mediated Intestinal Inflammation

    Science.gov (United States)

    Brasseit, Jennifer; Kwong Chung, Cheong K. C.; Noti, Mario; Zysset, Daniel; Hoheisel-Dickgreber, Nina; Genitsch, Vera; Corazza, Nadia; Mueller, Christoph

    2018-01-01

    Aberrant interferon gamma (IFNγ) expression is associated with the pathogenesis of numerous autoimmune- and inflammatory disorders, including inflammatory bowel diseases (IBD). However, the requirement of IFNγ for the pathogenesis of chronic intestinal inflammation remains controversial. The aim of this study was thus to investigate the role of IFNγ in experimental mouse models of innate and adaptive immune cell-mediated intestinal inflammation using genetically and microbiota-stabilized hosts. While we find that IFNγ drives acute intestinal inflammation in the anti-CD40 colitis model in an innate lymphoid cell (ILC)-dependent manner, IFNγ secreted by both transferred CD4 T cells and/or cells of the lymphopenic Rag1−/− recipient mice was dispensable for CD4 T cell-mediated colitis. In the absence of IFNγ, intestinal inflammation in CD4 T cell recipient mice was associated with enhanced IL17 responses; consequently, targeting IL17 signaling in IFNγ-deficient mice reduced T cell-mediated colitis. Intriguingly, in contrast to the anti-CD40 model of colitis, depletion of ILC in the Rag1−/− recipients of colitogenic CD4 T cells did not prevent induction of colonic inflammation. Together, our findings demonstrate that IFNγ represents an essential, or a redundant, pro-inflammatory cytokine for the induction of intestinal inflammation, depending on the experimental mouse model used and on the nature of the critical disease inducing immune cell populations involved. PMID:29416538

  18. Characteristic and functional analysis of toll-like receptors (TLRs in the lophotrocozoan, Crassostrea gigas, reveals ancient origin of TLR-mediated innate immunity.

    Directory of Open Access Journals (Sweden)

    Yang Zhang

    Full Text Available The evolution of TLR-mediated innate immunity is a fundamental question in immunology. Here, we report the characterization and functional analysis of four TLR members in the lophotrochozoans Crassostreagigas (CgTLRs. All CgTLRs bear a conserved domain organization and have a close relationship with TLRs in ancient non-vertebrate chordates. In HEK293 cells, every CgTLR could constitutively activate NF-κB responsive reporter, but none of the PAMPs tested could stimulate CgTLR-activated NF-κB induction. Subcellular localization showed that CgTLR members have similar and dual distribution on late endosomes and plasma membranes. Moreover, CgTLRs and CgMyD88 mRNA show a consistent response to multiple PAMP challenges in oyster hemocytes. As CgTLR-mediated NF-κB activation is dependent on CgMyD88, we designed a blocking peptide for CgTLR signaling that would inhibit CgTLR-CgMyD88 dependent NF-κB activation. This was used to demonstrate that a Vibrio parahaemolyticus infection-induced enhancement of degranulation and increase of cytokines TNF mRNA in hemocytes, could be inhibited by blocking CgTLR signaling. In summary, our study characterized the primitive TLRs in the lophotrocozoan C. gigas and demonstrated a fundamental role of TLR signaling in infection-induced hemocyte activation. This provides further evidence for an ancient origin of TLR-mediated innate immunity.

  19. Analysis of Separated Flow over Blocked Surface

    Directory of Open Access Journals (Sweden)

    Onur YEMENİCİ

    2013-04-01

    Full Text Available In this study, the separated flow over flat and blocked surfaces was investigated experimentally. Velocity and turbulence intensity measurements were carried out by a constanttemperature hot wire anemometer and static pressure measurements by a micro-manometer. The flow separations and reattachments were occurred before the first block, on the first block, between blocks and after the last block, and the presence of the blocks significantly increased the turbulent intensity

  20. Aberrant innate immune activation following tissue injury impairs pancreatic regeneration.

    Directory of Open Access Journals (Sweden)

    Alexandra E Folias

    Full Text Available Normal tissue architecture is disrupted following injury, as resident tissue cells become damaged and immune cells are recruited to the site of injury. While injury and inflammation are critical to tissue remodeling, the inability to resolve this response can lead to the destructive complications of chronic inflammation. In the pancreas, acinar cells of the exocrine compartment respond to injury by transiently adopting characteristics of progenitor cells present during embryonic development. This process of de-differentiation creates a window where a mature and stable cell gains flexibility and is potentially permissive to changes in cellular fate. How de-differentiation can turn an acinar cell into another cell type (such as a pancreatic β-cell, or a cell with cancerous potential (as in cases of deregulated Kras activity is of interest to both the regenerative medicine and cancer communities. While it is known that inflammation and acinar de-differentiation increase following pancreatic injury, it remains unclear which immune cells are involved in this process. We used a combination of genetically modified mice, immunological blockade and cellular characterization to identify the immune cells that impact pancreatic regeneration in an in vivo model of pancreatitis. We identified the innate inflammatory response of macrophages and neutrophils as regulators of pancreatic regeneration. Under normal conditions, mild innate inflammation prompts a transient de-differentiation of acinar cells that readily dissipates to allow normal regeneration. However, non-resolving inflammation developed when elevated pancreatic levels of neutrophils producing interferon-γ increased iNOS levels and the pro-inflammatory response of macrophages. Pancreatic injury improved following in vivo macrophage depletion, iNOS inhibition as well as suppression of iNOS levels in macrophages via interferon-γ blockade, supporting the impairment in regeneration and the

  1. Oxidative stress, innate immunity, and age-related macular degeneration

    Science.gov (United States)

    Shaw, Peter X.; Stiles, Travis; Douglas, Christopher; Ho, Daisy; Fan, Wei; Du, Hongjun; Xiao, Xu

    2016-01-01

    Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD is characterized by the appearance of soft drusen, as well as pigmentary changes in the retinal pigment epithelium (RPE). These soft, confluent drusen can progress into two forms of advanced AMD: geographic atrophy (GA, or dry AMD) or choroidal neovascularization (CNV, or wet AMD). Both forms of AMD result in a similar clinical progression in terms of loss of central vision. The exact mechanism for developing early AMD, as well as triggers responsible for progressing to advanced stage of disease, is still largely unknown. However, significant evidence exists demonstrating a complex interplay of genetic and environmental factors as causes of AMD progression. Multiple genes and/or single nucleotide polymorphisms (SNPs) have been found associated with AMD, including various genes involved in the complement pathway, lipid metabolism and extracellular matrix (ECM) remodeling. Of the known genetic contributors to disease risk, the CFH Y402H and HTRA1/ARMS polymorphisms contribute to more than 50% of the genetic risk for AMD. Environmentally, oxidative stress plays a critical role in many aging diseases including cardiovascular disease, cancer, Alzheimer’s disease and AMD. Due to the exposure to sunlight and high oxygen concentration, the oxidative stress burden is higher in the eye than other tissues, which can be further complicated by additional oxidative stressors such as smoking. Increasingly, evidence is accumulating suggesting that functional abnormalities of the innate immune system incurred via high risk genotypes may be contributing to the pathogenesis of AMD by altering the inflammatory homeostasis in the eye, specifically in the handling of oxidation products. As the eye in non-pathological instances maintains a low level of inflammation despite the presence of a relative abundance of potentially inflammatory molecules, we have

  2. Various semiclassical limits of torus conformal blocks

    Energy Technology Data Exchange (ETDEWEB)

    Alkalaev, Konstantin [I.E. Tamm Department of Theoretical Physics, P.N. Lebedev Physical Institute,Leninsky ave. 53, Moscow, 119991 (Russian Federation); Department of General and Applied Physics, Moscow Institute of Physics and Technology,Institutskiy per. 7, Dolgoprudnyi, Moscow region, 141700 (Russian Federation); Geiko, Roman [Mathematics Department, National Research University Higher School of Economics,Usacheva str. 6, Moscow, 119048 (Russian Federation); Rappoport, Vladimir [I.E. Tamm Department of Theoretical Physics, P.N. Lebedev Physical Institute,Leninsky ave. 53, Moscow, 119991 (Russian Federation); Department of Quantum Physics, Institute for Information Transmission Problems,Bolshoy Karetny per. 19, Moscow, 127994 (Russian Federation)

    2017-04-12

    We study four types of one-point torus blocks arising in the large central charge regime. There are the global block, the light block, the heavy-light block, and the linearized classical block, according to different regimes of conformal dimensions. It is shown that the blocks are not independent being connected to each other by various links. We find that the global, light, and heavy-light blocks correspond to three different contractions of the Virasoro algebra. Also, we formulate the c-recursive representation of the one-point torus blocks which is relevant in the semiclassical approximation.

  3. 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

  4. Innate immune response of channel catfish (Ictalurus punctatus) mannose-binding lectin to channel catfish virus

    Science.gov (United States)

    The channel catfish virus (CCV) is a pathogenic herpesvirus that infects channel catfish (Ictalurus punctatus) in pond aquaculture in the Southeast USA. The innate immune protein mannose-binding lectin (MBL) could play an important role in the innate response of channel catfish by binding to the CC...

  5. Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines

    NARCIS (Netherlands)

    Blok, B.A.; Arts, R.J.W.; Crevel, R. van; Benn, C.S.; Netea, M.G.

    2015-01-01

    An increasing body of evidence shows that the innate immune system has adaptive characteristics that involve a heterologous memory of past insults. Both experimental models and proof-of-principle clinical trials show that innate immune cells, such as monocytes, macrophages, and NK cells, can provide

  6. Manipulation of innate immunity by a bacterial secreted peptide: Lantibiotic nisin Z is selectively immunomodulatory

    NARCIS (Netherlands)

    Kindrachuk, J.; Jenssen, H.; Elliott, M.; Breukink, E.J.; Hancock, R.E.W.; et al., [No Value

    2013-01-01

    Innate immunity is triggered by a variety of bacterial molecules, resulting in both protective and potentially harmful proinflammatory responses. Further, innate immunity also provides a mechanism for the maintenance of homeostasis between the host immune system and symbiotic or non-pathogenic

  7. Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines

    DEFF Research Database (Denmark)

    Blok, Bastiaan A; Arts, Rob J W; van Crevel, Reinout

    2015-01-01

    An increasing body of evidence shows that the innate immune system has adaptive characteristics that involve a heterologous memory of past insults. Both experimental models and proof-of-principle clinical trials show that innate immune cells, such as monocytes, macrophages, and NK cells, can...

  8. DMPD: Cytosolic DNA recognition for triggering innate immune responses. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18280611 Cytosolic DNA recognition for triggering innate immune responses. Takaoka ...A, Taniguchi T. Adv Drug Deliv Rev. 2008 Apr 29;60(7):847-57. Epub 2007 Dec 31. (.png) (.svg) (.html) (.csml) Show Cytosolic DNA reco...gnition for triggering innate immune responses. PubmedID 18280611 Title Cytosolic DNA reco

  9. DMPD: Peptidoglycan signaling in innate immunity and inflammatory disease. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15802263 Peptidoglycan signaling in innate immunity and inflammatory disease. McDon...ald C, Inohara N, Nunez G. J Biol Chem. 2005 May 27;280(21):20177-80. Epub 2005 Mar 31. (.png) (.svg) (.html) (.csml) Show Peptidog...lycan signaling in innate immunity and inflammatory disease. PubmedID 15802263 Title Peptidog

  10. DMPD: IRAK1: a critical signaling mediator of innate immunity. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17890055 IRAK1: a critical signaling mediator of innate immunity. Gottipati S, Rao ...NL, Fung-Leung WP. Cell Signal. 2008 Feb;20(2):269-76. Epub 2007 Aug 23. (.png) (.svg) (.html) (.csml) Show IRAK1: a critical sign...aling mediator of innate immunity. PubmedID 17890055 Title IRAK1: a critical signaling

  11. Another Armament in Gut Immunity: Lymphotoxin-Mediated Crosstalk between Innate Lymphoid and Dendritic Cells

    NARCIS (Netherlands)

    Spits, H.

    2011-01-01

    Innate lymphoid cells (ILCs) are novel players in innate immunity. Tumanov et al. (Tumanov et al., 2011) demonstrate that crosstalk between ILCs and dendritic cells involving membrane-bound lymphotoxin in ILCs and its receptor is critical for protection against colitogenic bacteria

  12. Innate Immunity and the Etiology of Late-Onset Alzheimer's Disease

    NARCIS (Netherlands)

    Eikelenboom, Piet; van Exel, Erik; Veerhuis, Rob; Rozemuller, Annemieke J. M.; van Gool, Willem A.; Hoozemans, Jeroen J. M.

    2012-01-01

    Background: Neuropathological studies supported by experimental animal studies show that the constituents of the innate immunity are intimately involved in the early steps of the pathological cascade of Alzheimer's disease (AD). Objectives: To show the evidence that constituents of the innate

  13. Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans

    NARCIS (Netherlands)

    Kox, M.; Eijk, L.T.G.J. van; Zwaag, J.; Wildenberg, J. van den; Sweep, F.C.; Hoeven, J.G. van der; Pickkers, P.

    2014-01-01

    Excessive or persistent proinflammatory cytokine production plays a central role in autoimmune diseases. Acute activation of the sympathetic nervous system attenuates the innate immune response. However, both the autonomic nervous system and innate immune system are regarded as systems that cannot

  14. DMPD: Macrophage migration inhibitory factor and host innate immune responses tomicrobes. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 14620137 Macrophage migration inhibitory factor and host innate immune responses to...microbes. Calandra T. Scand J Infect Dis. 2003;35(9):573-6. (.png) (.svg) (.html) (.csml) Show Macrophage migration... inhibitory factor and host innate immune responses tomicrobes. PubmedID 14620137 Title Macrophage migration

  15. Evasion of influenza A viruses from innate and adaptive immune responses

    NARCIS (Netherlands)

    C.E. van de Sandt (Carolien); J.H.C.M. Kreijtz (Joost); G.F. Rimmelzwaan (Guus)

    2012-01-01

    textabstractThe influenza A virus is one of the leading causes of respiratory tract infections in humans. Upon infection with an influenza A virus, both innate and adaptive immune responses are induced. Here we discuss various strategies used by influenza A viruses to evade innate immune responses

  16. Innate antiviral immune signaling, viral evasion and modulation by HIV-1.

    Science.gov (United States)

    Rustagi, Arjun; Gale, Michael

    2014-03-20

    The intracellular innate antiviral response in human cells is an essential component of immunity against virus infection. As obligate intracellular parasites, all viruses must evade the actions of the host cell's innate immune response in order to replicate and persist. Innate immunity is induced when pathogen recognition receptors of the host cell sense viral products including nucleic acid as "non-self". This process induces downstream signaling through adaptor proteins to activate latent transcription factors that drive the expression of genes encoding antiviral and immune modulatory effector proteins that restrict virus replication and regulate adaptive immunity. The interferon regulatory factors (IRFs) are transcription factors that play major roles in innate immunity. In particular, IRF3 is activated in response to infection by a range of viruses including RNA viruses, DNA viruses and retroviruses. Among these viruses, human immunodeficiency virus type 1 (HIV-1) remains a major global health problem mediating chronic infection in millions of people wherein recent studies show that viral persistence is linked with the ability of the virus to dysregulate and evade the innate immune response. In this review, we discuss viral pathogen sensing, innate immune signaling pathways and effectors that respond to viral infection, the role of IRF3 in these processes and how it is regulated by pathogenic viruses. We present a contemporary overview of the interplay between HIV-1 and innate immunity, with a focus on understanding how innate immune control impacts infection outcome and disease. Copyright © 2013. Published by Elsevier Ltd.

  17. A novel GH secretagogue, A233, exhibits enhanced growth activity and innate immune system stimulation in teleosts fish.

    Science.gov (United States)

    Martinez, Rebeca; Ubieta, Kenia; Herrera, Fidel; Forellat, Alina; Morales, Reynold; de la Nuez, Ania; Rodriguez, Rolando; Reyes, Osvaldo; Oliva, Ayme; Estrada, Mario P

    2012-09-01

    In teleosts fish, secretion of GH is regulated by several hypothalamic factors that are influenced by the physiological state of the animal. There is an interaction between immune and endocrine systems through hormones and cytokines. GH in fish is involved in many physiological processes that are not overtly growth related, such as saltwater osmoregulation, antifreeze synthesis, and the regulation of sexual maturation and immune functions. This study was conducted to characterize a decapeptide compound A233 (GKFDLSPEHQ) designed by molecular modeling to evaluate its function as a GH secretagogue (GHS). In pituitary cell culture, the peptide A233 induces GH secretion and it is also able to increase superoxide production in tilapia head-kidney leukocyte cultures. This effect is blocked by preincubation with the GHS receptor antagonist [d-Lys(3)]-GHRP6. Immunoneutralization of GH by addition of anti-tilapia GH monoclonal antibody blocked the stimulatory effect of A233 on superoxide production. These experiments propose a GH-mediated mechanism for the action of A233. The in vivo biological action of the decapeptide was also demonstrated for growth stimulation in goldfish and tilapia larvae (P<0.001). Superoxide dismutase levels, antiprotease activity, and lectin titer were enhanced in tilapia larvae treated with this novel molecule. The decapeptide A233 designed by molecular modeling is able to function as a GHS in teleosts and enhance parameters of the innate immune system in the fish larvae.

  18. Functions of innate immune cells and commensal bacteria in gut homeostasis.

    Science.gov (United States)

    Kayama, Hisako; Takeda, Kiyoshi

    2016-02-01

    The intestinal immune system remains unresponsive to beneficial microbes and dietary antigens while activating pro-inflammatory responses against pathogens for host defence. In intestinal mucosa, abnormal activation of innate immunity, which directs adaptive immune responses, causes the onset and/or progression of inflammatory bowel diseases. Thus, innate immunity is finely regulated in the gut. Multiple innate immune cell subsets have been identified in both murine and human intestinal lamina propria. Some innate immune cells play a key role in the maintenance of gut homeostasis by preventing inappropriate adaptive immune responses while others are associated with the pathogenesis of intestinal inflammation through development of Th1 and Th17 cells. In addition, intestinal microbiota and their metabolites contribute to the regulation of innate/adaptive immune responses. Accordingly, perturbation of microbiota composition can trigger intestinal inflammation by driving inappropriate immune responses. © The Authors 2015. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

  19. The innate immune signaling in cancer and cardiometabolic diseases: Friends or foes?

    Science.gov (United States)

    Wang, Weijun; Zhang, Yaxing; Yang, Ling; Li, Hongliang

    2017-02-28

    The innate immune system is responsible for sensing pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) by several types of germline-encoded pattern-recognition receptors (PRRs). It has the capacity to help the human body maintain homeostasis under normal conditions. However, in pathological conditions, PAMPs or DAMPs trigger aberrant innate immune and inflammatory responses and thus negatively or positively influence the progression of cancer and cardiometabolic diseases. Interestingly, we found that some elements of innate immune signaling are involved in these diseases partially via immune-independent manners, indicating a deeper understanding of the function of innate immune signaling in these diseases is urgent. In this review, we summarize the primary innate immune signaling pathways and their association with cancer and cardiometabolic diseases, with the aim of providing effective therapies for these diseases. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. New insights into innate immune control of systemic candidiasis

    Science.gov (United States)

    Lionakis, Michail S.

    2014-01-01

    Systemic infection caused by Candida species is the fourth leading cause of nosocomial bloodstream infection in modern hospitals and carries high morbidity and mortality despite antifungal therapy. A recent surge of immunological studies in the mouse models of systemic candidiasis and the parallel discovery and phenotypic characterization of inherited genetic disorders in antifungal immune factors that are associated with enhanced susceptibility or resistance to the infection have provided new insights into the cellular and molecular basis of protective innate immune responses against Candida. In this review, the new developments in our understanding of how the mammalian immune system responds to systemic Candida challenge are synthesized and important future research directions are highlighted. PMID:25023483

  1. BACH transcription factors in innate and adaptive immunity.

    Science.gov (United States)

    Igarashi, Kazuhiko; Kurosaki, Tomohiro; Roychoudhuri, Rahul

    2017-07-01

    BTB and CNC homology (BACH) proteins are transcriptional repressors of the basic region leucine zipper (bZIP) transcription factor family. Recent studies indicate widespread roles of BACH proteins in controlling the development and function of the innate and adaptive immune systems, including the differentiation of effector and memory cells of the B and T cell lineages, CD4 + regulatory T cells and macrophages. Here, we emphasize similarities at a molecular level in the cell-type-specific activities of BACH factors, proposing that competitive interactions of BACH proteins with transcriptional activators of the bZIP family form a common mechanistic theme underlying their diverse actions. The findings contribute to a general understanding of how transcriptional repressors shape lineage commitment and cell-type-specific functions through repression of alternative lineage programmes.

  2. Innate and adaptive immune responses in neurodegeneration and repair

    Science.gov (United States)

    Amor, Sandra; Woodroofe, M Nicola

    2014-01-01

    Emerging evidence suggests important roles of the innate and adaptive immune responses in the central nervous system (CNS) in neurodegenerative diseases. In this special review issue, five leading researchers discuss the evidence for the beneficial as well as the detrimental impact of the immune system in the CNS in disorders including Alzheimer's disease, multiple sclerosis and CNS injury. Several common pathological mechanisms emerge indicating that these pathways could provide important targets for manipulating the immune reposes in neurodegenerative disorders. The articles highlight the role of the traditional resident immune cell of the CNS - the microglia - as well as the role of other glia astrocytes and oligodendrocytes in immune responses and their interplay with other immune cells including, mast cells, T cells and B cells. Future research should lead to new discoveries which highlight targets for therapeutic interventions which may be applicable to a range of neurodegenerative diseases. PMID:23758741

  3. The maternal microbiota drives early postnatal innate immune development.

    Science.gov (United States)

    Gomez de Agüero, Mercedes; Ganal-Vonarburg, Stephanie C; Fuhrer, Tobias; Rupp, Sandra; Uchimura, Yasuhiro; Li, Hai; Steinert, Anna; Heikenwalder, Mathias; Hapfelmeier, Siegfried; Sauer, Uwe; McCoy, Kathy D; Macpherson, Andrew J

    2016-03-18

    Postnatal colonization of the body with microbes is assumed to be the main stimulus to postnatal immune development. By transiently colonizing pregnant female mice, we show that the maternal microbiota shapes the immune system of the offspring. Gestational colonization increases intestinal group 3 innate lymphoid cells and F4/80(+)CD11c(+) mononuclear cells in the pups. Maternal colonization reprograms intestinal transcriptional profiles of the offspring, including increased expression of genes encoding epithelial antibacterial peptides and metabolism of microbial molecules. Some of these effects are dependent on maternal antibodies that potentially retain microbial molecules and transmit them to the offspring during pregnancy and in milk. Pups born to mothers transiently colonized in pregnancy are better able to avoid inflammatory responses to microbial molecules and penetration of intestinal microbes. Copyright © 2016, American Association for the Advancement of Science.

  4. Innate immune cell response upon Candida albicans infection

    Science.gov (United States)

    Qin, Yulin; Zhang, Lulu; Xu, Zheng; Zhang, Jinyu; Jiang, Yuan-ying; Cao, Yongbing; Yan, Tianhua

    2016-01-01

    abstract Candida albicans is a polymorphic fungus which is the predominant cause of superficial and deep tissue fungal infections. This microorganism has developed efficient strategies to invade the host and evade host defense systems. However, the host immune system will be prepared for defense against the microbe by recognition of receptors, activation of signal transduction pathways and cooperation of immune cells. As a consequence, C. albicans could either be eliminated by immune cells rapidly or disseminate hematogenously, leading to life-threatening systemic infections. The interplay between Candida albicans and the host is complex, requiring recognition of the invaded pathogens, activation of intricate pathways and collaboration of various immune cells. In this review, we will focus on the effects of innate immunity that emphasize the first line protection of host defense against invaded C. albicans including the basis of receptor-mediated recognition and the mechanisms of cell-mediated immunity. PMID:27078171

  5. Innate immune response in the sea urchin Echinometra lucunter (Echinodermata).

    Science.gov (United States)

    de Faria, Marcos Tucunduva; da Silva, José Roberto Machado Cunha

    2008-05-01

    Echinometra lucunter, (Pindá) is a sea urchin encountered in the Brazilian coast and exposed to high and low temperatures related to low and high tides. Despite their great distribution and importance, few studies have been done on the biological function of their coelomocytes. Thus, Echinometra lucunter perivisceral coelomocytes were characterized under optical and transmission electron microscopy. Phagocytic amoebocytes in the perivisceral coelom were labelled by injecting ferritin, and ferritin labelled phagocytic amoebocytes were found in the peristomial connective tissue after injecting India ink into the tissue, indicating the amoebocytes ability to respond to an inflammatory stimulus. Results showed that the phagocytic amoebocytes were the main inflammatory cells found in the innate immune response of E. lucunter. While other works have recorded these phenomena in sea urchins found in moderate and constant temperature, this study reports on these same phenomena in a tropical sea urchin under great variation of temperature, thus providing new data to inflammatory studies in invertebrate pathology.

  6. Cytosolic nucleic acid sensors and innate immune regulation.

    Science.gov (United States)

    Ori, Daisuke; Murase, Motoya; Kawai, Taro

    2017-03-04

    During viral and bacterial infections, pathogen-derived cytosolic nucleic acids are recognized by the intracellular RNA sensors retinoic acid-inducible gene I and melanoma-differentiated gene 5 and intracellular DNA sensors, including cyclic-di-GMP-AMP synthase, absent in melanoma 2, interferon (IFN)-gamma inducible protein 16, polymerase III, and so on. Binding of intracellular nucleic acids to these sensors activates downstream signaling cascades, resulting in the production of type I IFNs and pro-inflammatory cytokines to induce appropriate systematic immune responses. While these sensors also recognize endogenous nucleic acids and activate immune responses, they can discriminate between self- and non-self-nucleic acids. However, dysfunction of these sensors or failure of regulatory mechanisms causes aberrant activation of immune response and autoimmune disorders. In this review, we focus on how intracellular immune sensors recognize exogenous nucleic acids and activate the innate immune system, and furthermore, how autoimmune diseases result from dysfunction of these sensors.

  7. Viral evasion of DNA-stimulated innate immune responses.

    Science.gov (United States)

    Christensen, Maria H; Paludan, Søren R

    2017-01-01

    Cellular sensing of virus-derived nucleic acids is essential for early defenses against virus infections. In recent years, the discovery of DNA sensing proteins, including cyclic GMP-AMP synthase (cGAS) and gamma-interferon-inducible protein (IFI16), has led to understanding of how cells evoke strong innate immune responses against incoming pathogens carrying DNA genomes. The signaling stimulated by DNA sensors depends on the adaptor protein STING (stimulator of interferon genes), to enable expression of antiviral proteins, including type I interferon. To facilitate efficient infections, viruses have evolved a wide range of evasion strategies, targeting host DNA sensors, adaptor proteins and transcription factors. In this review, the current literature on virus-induced activation of the STING pathway is presented and we discuss recently identified viral evasion mechanisms targeting different steps in this antiviral pathway.

  8. Therapeutic targeting of the innate immune system in domestic animals.

    Science.gov (United States)

    Coffey, Tracey J; Werling, Dirk

    2011-01-01

    Since first being described in the fruit fly Drosophila melanogaster, the knowledge regarding Toll-like receptors (TLRs) has transformed our understanding of immunology. TLRs are a family of conserved pattern recognition receptors (PRR) that recognise specific microbial-associated molecular patterns and allow the cell to distinguish between self and non-self materials. The very property of the TLRs, to link innate and adaptive immunity, offers a novel opportunity to develop vaccines that engage TLR signalling. The presence of TLR ligands as adjuvants in conjunction with a vaccine is shown to increase the efficacy and response to the immunisation with a particular antigen. Here, we focus on the findings pertaining to TLR ligands as adjuvants and discuss the importance of these studies in the development of an optimal vaccine in farm and companion animals.

  9. Functional and phenotypic profiling of innate immunity during Salmonella infection

    DEFF Research Database (Denmark)

    Sørensen, Rikke Brandt; Pedersen, Susanne Brix

    . The results presented in this thesis add to the current knowledge about innate immunity to Salmonella, suggest new host immune cell subsets important for bacterial containment and provide a basic understanding of bacteria-induced DC inflammatory programs. The two latter could prove important in regard......Salmonellae are food borne pathogens, typically acquired by the oral ingestion of contaminated food or water, causing disease in both healthy and immunocompromised individuals. To gain insight into early immune regulation events caused by Salmonella as well as inflammatory signatures induced......DC) in bacterial infections, whereas the other major dendritic cell subset, plasmacytoid DC (pDC), plays an important part in antiviral responses, and is less well characterised in regard to antibacterial immunity. Using multi-parametric flow cytometry, we were able to show for the first time that pDC accumulated...

  10. Glucosinolate metabolites required for an Arabidopsis innate immune response.

    Science.gov (United States)

    Clay, Nicole K; Adio, Adewale M; Denoux, Carine; Jander, Georg; Ausubel, Frederick M

    2009-01-02

    The perception of pathogen or microbe-associated molecular pattern molecules by plants triggers a basal defense response analogous to animal innate immunity and is defined partly by the deposition of the glucan polymer callose at the cell wall at the site of pathogen contact. Transcriptional and metabolic profiling in Arabidopsis mutants, coupled with the monitoring of pathogen-triggered callose deposition, have identified major roles in pathogen response for the plant hormone ethylene and the secondary metabolite 4-methoxy-indol-3-ylmethylglucosinolate. Two genes, PEN2 and PEN3, are also necessary for resistance to pathogens and are required for both callose deposition and glucosinolate activation, suggesting that the pathogen-triggered callose response is required for resistance to microbial pathogens. Our study shows that well-studied plant metabolites, previously identified as important in avoiding damage by herbivores, are also required as a component of the plant defense response against microbial pathogens.

  11. Glucosinolate Metabolites Required for an Arabidopsis Innate Immune Response*

    Science.gov (United States)

    Clay, Nicole K.; Adio, Adewale M.; Denoux, Carine; Jander, Georg; Ausubel, Frederick M.

    2008-01-01

    Summary The perception of pathogen or microbe-associated molecular pattern molecules by plants triggers a basal defense response analogous to animal innate immunity, and is defined in part by the deposition of the glucan polymer callose at the cell wall at the site of pathogen contact. Transcriptional and metabolic profiling in Arabidopsis mutants, coupled with the monitoring of pathogen triggered callose deposition, have identified major roles in pathogen response for the plant hormone ethylene and the secondary metabolite 4-methoxy-indol-3-ylmethylglucosinolate. Two genes, PEN2 and PEN3, are also necessary for resistance to pathogens and are required for both callose deposition and glucosinolate activation, suggesting that the pathogen triggered callose response is required for resistance to microbial pathogens. Our study shows that well-studied plant metabolites, previously identified as important in avoiding damage by herbivores, are also required as a component of the plant defense response against microbial pathogens. PMID:19095898

  12. Lipoprotein Lipase Maintains Microglial Innate Immunity in Obesity

    Directory of Open Access Journals (Sweden)

    Yuanqing Gao

    2017-09-01

    Full Text Available Consumption of a hypercaloric diet upregulates microglial innate immune reactivity along with a higher expression of lipoprotein lipase (Lpl within the reactive microglia in the mouse brain. Here, we show that knockdown of the Lpl gene specifically in microglia resulted in deficient microglial uptake of lipid, mitochondrial fuel utilization shifting to glutamine, and significantly decreased immune reactivity. Mice with knockdown of the Lpl gene in microglia gained more body weight than control mice on a high-carbohydrate high-fat (HCHF diet. In these mice, microglial reactivity was significantly decreased in the mediobasal hypothalamus, accompanied by downregulation of phagocytic capacity and increased mitochondrial dysmorphologies. Furthermore, HCHF-diet-induced POMC neuronal loss was accelerated. These results show that LPL-governed microglial immunometabolism is essential to maintain microglial function upon exposure to an HCHF diet. In a hypercaloric environment, lack of such an adaptive immunometabolic response has detrimental effects on CNS regulation of energy metabolism.

  13. Long noncoding RNAs in Innate and Adaptive Immunity

    Science.gov (United States)

    Fitzgerald, Katherine A.; Caffrey, Daniel R.

    2014-01-01

    The differentiation and activation of both innate and adaptive immune cells is highly dependent on a coordinated set of transcriptional and post-transcriptional events. Chromatin-modifiers and transcription factors regulate the accessibility and transcription of immune genes, respectively. Immune cells also express miRNA and RNA-binding proteins that provide an additional layer of regulation at the mRNA level. However, long noncoding RNA (lncRNA), which have been primarily studied in the context of genomic imprinting, cancer, and cell differentiation, are now emerging as important regulators of immune cell differentiation and activation. In this review, we provide a brief overview of lncRNA, their known functions in immunity, and discuss their potential to be more broadly involved in other aspects of the immune response. PMID:24556411

  14. Regulators of innate immunity as novel targets for panviral therapeutics.

    Science.gov (United States)

    Es-Saad, Salwa; Tremblay, Nicolas; Baril, Martin; Lamarre, Daniel

    2012-10-01

    Interferons (IFNs) have long been used as an immunomodulatory therapy for a large array of acute and chronic viral infections. However, IFN therapies have been plagued by severe side effects. The discovery of pathogen recognition receptors (PRR) rejuvenated the interest for immunomodulatory therapies. The successes obtained with Toll-like receptor (TLR) agonists in activating immune cells and as adjuvant for prophylactic vaccines against different viruses paved the way to targeted immunomodulatory therapy. Better characterization of pathogen-induced immune disorders and newly discovered regulators of innate immunity have now the potential to specifically withdraw prevailing subversion mechanisms and to transform antiviral treatments by introducing panviral therapeutics with less adverse effects than IFN therapies. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. Subversion of innate immune signaling through molecular mimicry.

    Science.gov (United States)

    Xiao, Tsan Sam

    2010-09-01

    Innate immune signaling is mediated by a number of membrane-anchored or cytosolic receptor or sensor molecules. Several receptor families utilize conserved signaling domains such as the Toll/interleukin-1 receptor (TIR) domain and Pyrin domain (PYD) to link microbe recognition to induction of proinflammatory cytokines and interferons. Recent studies have identified a number of bacterial and viral TIR domains and PYD domains that directly target the signaling function of their host homologues. Emerging biochemical and structural studies of these microbial TIR and PYD domains suggest that they are mimics of their host counterparts at the sequence and structure levels. Unraveling the mechanisms of such molecular mimicry is crucial to our understanding and clinical intervention of infectious diseases and inflammatory disorders.

  16. MAMPs/PAMPs - elicitors of innate immunity in plants

    DEFF Research Database (Denmark)

    Erbs, Gitte; Newman, Mari-Anne

    2009-01-01

    Plants perceive several general elicitors from both host and non-host pathogens. These elicitors are essential structures for pathogen survival and are for that reason conserved among pathogens. These conserved microbe-specific molecules, also referred to as Microbe or Pathogen Associated Molecular...... Patterns (MAMPs or PAMPs), are recognised by the plant innate immune systems Pattern Recognition Receptors (PRRs). General bacterial elicitors, like lipopolysaccharides (LPS), flagellin (Flg), elongation factor Tu (EF-Tu), cold shock protein (CSP), peptidoglycan (PGN) and the enzyme superoxide dismutase...... (SodM) are known to act as MAMPs and induce immune responses in plants or plant cells (Gómez-Gómez and Boller, 2000; Erbs and Newman, 2003; Felix and Boller, 2003; Kunze et al., 2004; Watt et al., 2006, Gust et al., 2007; Erbs et al., unpublished). The corresponding PRRs for some of these bacterial...

  17. Evasion of the human innate immune system by dengue virus.

    Science.gov (United States)

    Pagni, Sarah; Fernandez-Sesma, Ana

    2012-12-01

    Dengue virus is a worldwide health problem, with billions of people at risk annually. Dengue virus causes a spectrum of diseases, namely dengue fever, dengue hemorrhagic fever and dengue shock syndrome with the latter two being linked to death. Understanding how dengue is able to evade the immune system and cause enhanced severity of disease is the main topics of interest in the Fernandez-Sesma laboratory at Mount Sinai School of Medicine. Using primary human immune cells, our group investigates the contribution of dengue virus-specific proteins to the evasion of innate immunity by this virus and the host factors that the virus interacts with in order to evade immune recognition and to establish infection in humans. Here, we review recent findings from our group as well as published data from other groups regarding immune modulation by dengue virus.

  18. Innate immune response to Mycobacterium tuberculosis Beijing and other genotypes.

    Directory of Open Access Journals (Sweden)

    Chongzhen Wang

    Full Text Available BACKGROUND: As a species, Mycobacterium tuberculosis is more diverse than previously thought. In particular, the Beijing family of M. tuberculosis strains is spreading and evaluating throughout the world and this is giving rise to public health concerns. Genetic diversity within this family has recently been delineated further and a specific genotype, called Bmyc10, has been shown to represent over 60% of all Beijing clinical isolates in several parts of the world. How the host immune system senses and responds to various M. tuberculosis strains may profoundly influence clinical outcome and the relative epidemiological success of the different mycobacterial lineages. We hypothesised that the success of the Bmyc10 group may, at least in part, rely upon its ability to alter innate immune responses and the secretion of cytokines and chemokines by host phagocytes. METHODOLOGY/PRINCIPAL FINDINGS: We infected human macrophages and dendritic cells with a collection of genetically well-defined M. tuberculosis clinical isolates belonging to various mycobacterial families, including Beijing. We analyzed cytokine and chemokine secretion on a semi-global level using antibody arrays allowing the detection of sixty-five immunity-related soluble molecules. Our data indicate that Beijing strains induce significantly less interleukin (IL-6, tumor necrosis factor (TNF, IL-10 and GRO-α than the H37Rv reference strain, a feature that is variously shared by other modern and ancient M. tuberculosis families and which constitutes a signature of the Beijing family as a whole. However, Beijing strains did not differ relative to each other in their ability to modulate cytokine secretion. CONCLUSIONS/SIGNIFICANCE: Our results confirm and expand upon previous reports showing that M. tuberculosis Beijing strains in general are poor in vitro cytokine inducers in human phagocytes. The results suggest that the epidemiological success of the Beijing Bmyc10 is unlikely to rely

  19. Alphacoronavirus Protein 7 Modulates Host Innate Immune Response

    Science.gov (United States)

    Cruz, Jazmina L. G.; Becares, Martina; Sola, Isabel; Oliveros, Juan Carlos; Zúñiga, Sonia

    2013-01-01

    Innate immune response is the first line of antiviral defense resulting, in most cases, in pathogen clearance with minimal clinical consequences. Viruses have developed diverse strategies to subvert host defense mechanisms and increase their survival. In the transmissible gastroenteritis virus (TGEV) as a model, we previously reported that accessory gene 7 counteracts the host antiviral response by associating with the catalytic subunit of protein phosphatase 1 (PP1c). In the present work, the effect of the absence of gene 7 on the host cell, during infection, was further analyzed by transcriptomic analysis. The pattern of gene expression of cells infected with a recombinant mutant TGEV, lacking gene 7 expression (rTGEV-Δ7), was compared to that of cells infected with the parental virus (rTGEV-wt). Genes involved in the immune response, the interferon response, and inflammation were upregulated during TGEV infection in the absence of gene 7. An exacerbated innate immune response during infection with rTGEV-Δ7 virus was observed both in vitro and in vivo. An increase in macrophage recruitment and activation in lung tissues infected with rTGEV-Δ7 virus was observed compared to cells infected with the parental virus. In summary, the absence of protein 7 both in vitro and in vivo led to increased proinflammatory responses and acute tissue damage after infection. In a porcine animal model, which is immunologically similar to humans, we present a novel example of how viral proteins counteract host antiviral pathways to determine the infection outcome and pathogenesis. PMID:23824792

  20. Autophagy, inflammation and innate immunity in inflammatory myopathies.

    Directory of Open Access Journals (Sweden)

    Cristina Cappelletti

    Full Text Available Autophagy has a large range of physiological functions and its dysregulation contributes to several human disorders, including autoinflammatory/autoimmune diseases such as inflammatory myopathies (IIMs. In order to better understand the pathogenetic mechanisms of these muscular disorders, we sought to define the role of autophagic processes and their relation with the innate immune system in the three main subtypes of IIM, specifically sporadic inclusion body myositis (sIBM, polymyositis (PM, dermatomyositis (DM and juvenile dermatomyositis (JDM. We found that although the mRNA transcript levels of the autophagy-related genes BECN1, ATG5 and FBXO32 were similar in IIM and controls, autophagy activation in all IIM subgroups was suggested by immunoblotting results and confirmed by immunofluorescence. TLR4 and TLR3, two potent inducers of autophagy, were highly increased in IIM, with TLR4 transcripts significantly more expressed in PM and DM than in JDM, sIBM and controls, and TLR3 transcripts highly up-regulated in all IIM subgroups compared to controls. Co-localization between autophagic marker, LC3, and TLR4 and TLR3 was observed not only in sIBM but also in PM, DM and JDM muscle tissues. Furthermore, a highly association with the autophagic processes was observed in all IIM subgroups also for some TLR4 ligands, endogenous and bacterial HSP60, other than the high-mobility group box 1 (HMGB1. These findings indicate that autophagic processes are active not only in sIBM but also in PM, DM and JDM, probably in response to an exogenous or endogenous 'danger signal'. However, autophagic activation and regulation, and also interaction with the innate immune system, differ in each type of IIM. Better understanding of these differences may lead to new therapies for the different IIM types.

  1. Radial Coordinates for Conformal Blocks

    CERN Document Server

    Hogervorst, Matthijs

    2013-01-01

    We develop the theory of conformal blocks in CFT_d expressing them as power series with Gegenbauer polynomial coefficients. Such series have a clear physical meaning when the conformal block is analyzed in radial quantization: individual terms describe contributions of descendants of a given spin. Convergence of these series can be optimized by a judicious choice of the radial quantization origin. We argue that the best choice is to insert the operators symmetrically. We analyze in detail the resulting "rho-series" and show that it converges much more rapidly than for the commonly used variable z. We discuss how these conformal block representations can be used in the conformal bootstrap. In particular, we use them to derive analytically some bootstrap bounds whose existence was previously found numerically.

  2. Diversity Gain through Antenna Blocking

    Directory of Open Access Journals (Sweden)

    V. Dehghanian

    2012-01-01

    Full Text Available As part of the typical usage mode, interaction between a handheld receiver antenna and the operator's RF absorbing body and nearby objects is known to generate variability in antenna radiation characteristics through blocking and pattern changes. It is counterintuitive that random variations in blocking can result in diversity gain of practical applicability. This diversity gain is quantified from a theoretical and experimental perspective. Measurements carried out at 1947.5 MHz verify the theoretical predictions, and a diversity gain of 3.1 dB was measured through antenna blocking and based on the utilized measurement setup. The diversity gain can be exploited to enhance signal detectability of handheld receivers based on a single antenna in indoor multipath environments.

  3. Cryptanalysis of Selected Block Ciphers

    DEFF Research Database (Denmark)

    Alkhzaimi, Hoda A.

    , pseudorandom number generators, and authenticated encryption designs. For this reason a multitude of initiatives over the years has been established to provide a secure and sound designs for block ciphers as in the calls for Data Encryption Standard (DES) and Advanced Encryption Standard (AES), lightweight...... ciphers initiatives, and the Competition for Authenticated Encryption: Security, Applicability, and Robustness (CAESAR). In this thesis, we first present cryptanalytic results on different ciphers. We propose attack named the Invariant Subspace Attack. It is utilized to break the full block cipher...... on the family of lightweight block cipher SIMON that was published by the U.S National Security Agency (NSA). The ciphers are developed with optimization towards both hardware and software in mind. While the specification paper discusses design requirements and performance of the presented lightweight ciphers...

  4. Climatological features of blocking anticyclones

    International Nuclear Information System (INIS)

    Lupo, A.R.; Smith, P.J.; Oglesby, R.J.

    1994-01-01

    Several climatological studies have been previously performed using large observational data sets (i.e., 10 years or longer) in order to determine the predominant characteristics of blocking anticyclones, including favored development regions, duration, preferred seasonal occurrence, and frequency of occurrence. These studies have shown that blocking anticyclones occur most frequently from October to April over the eastern Atlantic and Pacific oceans downstream from both the North American and Asian continental regions and the storm track regions to the east of these continents. Some studies have also revealed the presence of a third region block formation in western Russia near 40 degrees E which is associated with another storm track region over the Mediterranean and western Asia

  5. Projectors, shadows, and conformal blocks

    Energy Technology Data Exchange (ETDEWEB)

    Simmons-Duffin, David [Jefferson Physical Laboratory, Harvard University,Cambridge, MA 02138 (United States)

    2014-04-24

    We introduce a method for computing conformal blocks of operators in arbitrary Lorentz representations in any spacetime dimension, making it possible to apply bootstrap techniques to operators with spin. The key idea is to implement the “shadow formalism' of Ferrara, Gatto, Grillo, and Parisi in a setting where conformal invariance is manifest. Conformal blocks in d-dimensions can be expressed as integrals over the projective null-cone in the “embedding space' ℝ{sup d+1,1}. Taking care with their analytic structure, these integrals can be evaluated in great generality, reducing the computation of conformal blocks to a bookkeeping exercise. To facilitate calculations in four-dimensional CFTs, we introduce techniques for writing down conformally-invariant correlators using auxiliary twistor variables, and demonstrate their use in some simple examples.

  6. Projectors, Shadows, and Conformal Blocks

    OpenAIRE

    Simmons-Duffin, David

    2012-01-01

    We introduce a method for computing conformal blocks of operators in arbitrary Lorentz representations in any spacetime dimension, making it possible to apply bootstrap techniques to operators with spin. The key idea is to implement the “shadow formalism” of Ferrara, Gatto, Grillo, and Parisi in a setting where conformal invariance is manifest. Conformal blocks in d -dimensions can be expressed as integrals over the projective null-cone in the “embedding space” $ \\mathbb{R} $ d +1,1 . Taking ...

  7. Sex and death: the effects of innate immune factors on the sexual reproduction of malaria parasites.

    Directory of Open Access Journals (Sweden)

    Ricardo S Ramiro

    2011-03-01

    Full Text Available Malaria parasites must undergo a round of sexual reproduction in the blood meal of a mosquito vector to be transmitted between hosts. Developing a transmission-blocking intervention to prevent parasites from mating is a major goal of biomedicine, but its effectiveness could be compromised if parasites can compensate by simply adjusting their sex allocation strategies. Recently, the application of evolutionary theory for sex allocation has been supported by experiments demonstrating that malaria parasites adjust their sex ratios in response to infection genetic diversity, precisely as predicted. Theory also predicts that parasites should adjust sex allocation in response to host immunity. Whilst data are supportive, the assumptions underlying this prediction - that host immune responses have differential effects on the mating ability of males and females - have not yet been tested. Here, we combine experimental work with theoretical models in order to investigate whether the development and fertility of male and female parasites is affected by innate immune factors and develop new theory to predict how parasites' sex allocation strategies should evolve in response to the observed effects. Specifically, we demonstrate that reactive nitrogen species impair gametogenesis of males only, but reduce the fertility of both male and female gametes. In contrast, tumour necrosis factor-α does not influence gametogenesis in either sex but impairs zygote development. Therefore, our experiments demonstrate that immune factors have complex effects on each sex, ranging from reducing the ability of gametocytes to develop into gametes, to affecting the viability of offspring. We incorporate these results into theory to predict how the evolutionary trajectories of parasite sex ratio strategies are shaped by sex differences in gamete production, fertility and offspring development. We show that medical interventions targeting offspring development are more likely

  8. Sex and death: the effects of innate immune factors on the sexual reproduction of malaria parasites.

    Science.gov (United States)

    Ramiro, Ricardo S; Alpedrinha, João; Carter, Lucy; Gardner, Andy; Reece, Sarah E

    2011-03-01

    Malaria parasites must undergo a round of sexual reproduction in the blood meal of a mosquito vector to be transmitted between hosts. Developing a transmission-blocking intervention to prevent parasites from mating is a major goal of biomedicine, but its effectiveness could be compromised if parasites can compensate by simply adjusting their sex allocation strategies. Recently, the application of evolutionary theory for sex allocation has been supported by experiments demonstrating that malaria parasites adjust their sex ratios in response to infection genetic diversity, precisely as predicted. Theory also predicts that parasites should adjust sex allocation in response to host immunity. Whilst data are supportive, the assumptions underlying this prediction - that host immune responses have differential effects on the mating ability of males and females - have not yet been tested. Here, we combine experimental work with theoretical models in order to investigate whether the development and fertility of male and female parasites is affected by innate immune factors and develop new theory to predict how parasites' sex allocation strategies should evolve in response to the observed effects. Specifically, we demonstrate that reactive nitrogen species impair gametogenesis of males only, but reduce the fertility of both male and female gametes. In contrast, tumour necrosis factor-α does not influence gametogenesis in either sex but impairs zygote development. Therefore, our experiments demonstrate that immune factors have complex effects on each sex, ranging from reducing the ability of gametocytes to develop into gametes, to affecting the viability of offspring. We incorporate these results into theory to predict how the evolutionary trajectories of parasite sex ratio strategies are shaped by sex differences in gamete production, fertility and offspring development. We show that medical interventions targeting offspring development are more likely to be 'evolution

  9. Rational modulation of the innate immune system for neuroprotection in ischemic stroke

    Directory of Open Access Journals (Sweden)

    Diana eAmantea

    2015-04-01

    Full Text Available The innate immune system plays a dualistic role in the evolution of ischemic brain damage and has also been implicated in ischemic tolerance produced by different conditioning stimuli. Early after ischemia, perivascular astrocytes release cytokines and activate metalloproteases (MMPs that contribute to blood–brain barrier (BBB disruption and vasogenic oedema; whereas at later stages, they provide extracellular glutamate uptake, BBB regeneration and neurotrophic factors release. Similarly, early activation of microglia contributes to ischemic brain injury via the production of inflammatory cytokines, including tumor necrosis factor (TNF and interleukin (IL-1, reactive oxygen and nitrogen species and proteases. Nevertheless, microglia also contributes to the resolution of inflammation, by releasing IL-10 and tumor growth factor (TGF-beta, and to the late reparative processes by phagocytic activity and growth factors production. Indeed, after ischemia, microglia/macrophages differentiate towards several phenotypes: the M1 pro-inflammatory phenotype is classically activated via toll-like receptors or interferon-γ, whereas M2 phenotypes are alternatively activated by regulatory mediators, such as ILs 4, 10, 13 or TGF-beta. Thus, immune cells exert a dualistic role on the evolution of ischemic brain damage, since the classic phenotypes promote injury, whereas alternatively activated M2 macrophages or N2 neutrophils prompt tissue remodeling and repair.Moreover, a subdued activation of the immune system has been involved in ischemic tolerance, since different preconditioning stimuli act via modulation of inflammatory mediators, including toll-like receptors and cytokine signaling pathways. This further underscores that the immuno-modulatory approach for the treatment of ischemic stroke should be aimed at blocking the detrimental effects, while promoting the beneficial responses of the immune reaction.

  10. DMPD: Innate immune sensing of pathogens and danger signals by cell surface Toll-likereceptors. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17275324 Innate immune sensing of pathogens and danger signals by cell surface Toll... Show Innate immune sensing of pathogens and danger signals by cell surface Toll-likereceptors. PubmedID 172...75324 Title Innate immune sensing of pathogens and danger signals by cell surface

  11. DMPD: Nod1 and Nod2 in innate immunity and human inflammatory disorders. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18031249 Nod1 and Nod2 in innate immunity and human inflammatory disorders. Le Bour...w Nod1 and Nod2 in innate immunity and human inflammatory disorders. PubmedID 18031249 Title Nod1 and Nod2 in innate immunity and hum...an inflammatory disorders. Authors Le Bourhis L, Benko S

  12. DMPD: Glucocorticoids and the innate immune system: crosstalk with the toll-likereceptor signaling network. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17576036 Glucocorticoids and the innate immune system: crosstalk with the toll-like...07 May 13. (.png) (.svg) (.html) (.csml) Show Glucocorticoids and the innate immune system: crosstalk with t...nd the innate immune system: crosstalk with the toll-likereceptor signaling network. Authors Chinenov Y, Rog

  13. Human metapneumovirus M2-2 protein inhibits innate immune response in monocyte-derived dendritic cells.

    Directory of Open Access Journals (Sweden)

    Junping Ren

    Full Text Available Human metapneumovirus (hMPV is a leading cause of lower respiratory infection in young children, the elderly and immunocompromised patients. Repeated hMPV infections occur throughout life. However, immune evasion mechanisms of hMPV infection are largely unknown. Recently, our group has demonstrated that hMPV M2-2 protein, an important virulence factor, contributes to immune evasion in airway epithelial cells by targeting the mitochondrial antiviral-signaling protein (MAVS. Whether M2-2 regulates the innate immunity in human dendritic cells (DC, an important family of immune cells controlling antigen presenting, is currently unknown. We found that human DC infected with a virus lacking M2-2 protein expression (rhMPV-ΔM2-2 produced higher levels of cytokines, chemokines and IFNs, compared to cells infected with wild-type virus (rhMPV-WT, suggesting that M2-2 protein inhibits innate immunity in human DC. In parallel, we found that myeloid differentiation primary response gene 88 (MyD88, an essential adaptor for Toll-like receptors (TLRs, plays a critical role in inducing immune response of human DC, as downregulation of MyD88 by siRNA blocked the induction of immune regulatory molecules by hMPV. Since M2-2 is a cytoplasmic protein, we investigated whether M2-2 interferes with MyD88-mediated antiviral signaling. We found that indeed M2-2 protein associated with MyD88 and inhibited MyD88-dependent gene transcription. In this study, we also identified the domains of M2-2 responsible for its immune inhibitory function in human DC. In summary, our results demonstrate that M2-2 contributes to hMPV immune evasion by inhibiting MyD88-dependent cellular responses in human DC.

  14. Inhibition of host cell translation elongation by Legionella pneumophila blocks the host cell unfolded protein response.

    Science.gov (United States)

    Hempstead, Andrew D; Isberg, Ralph R

    2015-12-08

    Cells of the innate immune system recognize bacterial pathogens by detecting common microbial patterns as well as pathogen-specific activities. One system that responds to these stimuli is the IRE1 branch of the unfolded protein response (UPR), a sensor of endoplasmic reticulum (ER) stress. Activation of IRE1, in the context of Toll-like receptor (TLR) signaling, induces strong proinflammatory cytokine induction. We show here that Legionella pneumophila, an intravacuolar pathogen that replicates in an ER-associated compartment, blocks activation of the IRE1 pathway despite presenting pathogen products that stimulate this response. L. pneumophila TLR ligands induced the splicing of mRNA encoding XBP1s, the main target of IRE1 activity. L. pneumophila was able to inhibit both chemical and bacterial induction of XBP1 splicing via bacterial translocated proteins that interfere with host protein translation. A strain lacking five translocated translation elongation inhibitors was unable to block XBP1 splicing, but this could be rescued by expression of a single such inhibitor, consistent with limitation of the response by translation elongation inhibitors. Chemical inhibition of translation elongation blocked pattern recognition receptor-mediated XBP1 splicing, mimicking the effects of the bacterial translation inhibitors. In contrast, host cell-promoted inhibition of translation initiation in response to the pathogen was ineffective in blocking XBP1 splicing, demonstrating the need for the elongation inhibitors for protection from the UPR. The inhibition of host translation elongation may be a common strategy used by pathogens to limit the innate immune response by interfering with signaling via the UPR.

  15. Main-chain supramolecular block copolymers.

    Science.gov (United States)

    Yang, Si Kyung; Ambade, Ashootosh V; Weck, Marcus

    2011-01-01

    Block copolymers are key building blocks for a variety of applications ranging from electronic devices to drug delivery. The material properties of block copolymers can be tuned and potentially improved by introducing noncovalent interactions in place of covalent linkages between polymeric blocks resulting in the formation of supramolecular block copolymers. Such materials combine the microphase separation behavior inherent to block copolymers with the responsiveness of supramolecular materials thereby affording dynamic and reversible materials. This tutorial review covers recent advances in main-chain supramolecular block copolymers and describes the design principles, synthetic approaches, advantages, and potential applications.

  16. Building Blocks for Personal Brands

    Science.gov (United States)

    Thomas, Lisa Carlucci

    2011-01-01

    In this article, the author discusses the four essential building blocks for personal brands: (1) name; (2) message; (3) channels; and (4) bridges. However, outstanding building materials can only take a person so far. The author emphasizes that vision, determination, faith, a sense of humor, and humility are also required.

  17. Control rod removal blocking device

    International Nuclear Information System (INIS)

    Yoshioka, Ritsuo.

    1981-01-01

    Purpose: To prevent excess power increase resulted from erroneous control rod removal during high power operation in BWR type reactor by decreasing the continuous removal enabling distance for the control rods along with increase in the reactor power where the reactor power is greater than a predetermined level. Constitution: When control rod selection signals are supplied from a control unit to a control rod removal blocking device, the blocking device judges whether the reactor core power is greater than a predetermined value A or not, using reactor core power signals outputted from an average power monitor. Where the reactor core power exceeds the predetermined value A and if the reactor core power is relatively low, a large continuous removal enabling distance N 1 is calculated in the blocking device to allow the continuous removal as far as the notch N 1 . The continuous removal enabling distance is shortened as the reactor core power increases and the removal is blocked, for example, at notch N 2 . While on the other hand, if the reactor core power is below the predetermined value A, both of the notchwise removal and the continuous removal are enabled. (Seki, T.)

  18. First Degree Pacemaker Exit Block

    Directory of Open Access Journals (Sweden)

    Johnson Francis

    2016-10-01

    Full Text Available Usually atrial and ventricular depolarizations follow soon after the pacemaker stimulus (spike on the ECG. But there can be an exit block due to fibrosis at the electrode - tissue interface at the lead tip. This can increase the delay between the spike and atrial or ventricular depolarization.

  19. Vagal Blocking for Obesity Control

    DEFF Research Database (Denmark)

    Johannessen, Helene; Revesz, David; Kodama, Yosuke

    2017-01-01

    BACKGROUND: Recently, the US FDA has approved "vagal blocking therapy or vBLoc® therapy" as a new treatment for obesity. The aim of the present study was to study the mechanism-of-action of "VBLOC" in rat models. METHODS: Rats were implanted with VBLOC, an intra-abdominal electrical device...

  20. Thermo-responsive block copolymers

    NARCIS (Netherlands)

    Mocan Cetintas, Merve

    2017-01-01

    Block copolymers (BCPs) are remarkable materials because of their self-assembly behavior into nano-sized regular structures and high tunable properties. BCPs are in used various applications such as surfactants, nanolithography, biomedicine and nanoporous membranes. In these thesis, we aimed to

  1. Scintigraphic visualization of 'Blocking' thyroid

    International Nuclear Information System (INIS)

    Simeonova, A.; Kostadinova, I.

    2006-01-01

    Full text: An important problem in nuclear endocrinology is 'blocking' of thyroid gland, which necessitates postpone of the investigation, adverse clinical effect of stopping medications and a delay of making diagnosis. The aim of the study was to introduce and to determine the clinical value of the scintigraphy with 99mTc-MIBI in patients (Pts) with 'blocked thyroid'. In 365 Pts (aged 38-75 years), indicated for a thyroid scintigraphy after proper preparation, an investigation was performed with 74 MBq 99mTc-pertechnetate, 20 min. p.i. In 14 of them (3.8%), the thyroid was 'blocked' and additional scintigraphy was done with 370-555 MBq 99mTc-MIBI, 15 and 120 min.p.i. It was estimated that in all Pts there was a visualization of thyroid. In 1 of them, a large 'hot' nodule was visualized in the early and late image. Later on a differentiated thyroid carcinoma was proved histologically. In the rest of the patients 'cold' nodules with different size were visualized, eventually as a result of cysts. As a conclusion we consider, that a scintigraphy with 99mTc-MIBI is a useful tool in Pts with 'blocked' thyroid. In addition an evaluation of the thyroid nodule could be done and therefore- a recommendation for therapy

  2. Subversion of innate defenses by the interplay between DENV and pre-existing enhancing antibodies: TLRs signaling collapse.

    Science.gov (United States)

    Modhiran, Naphak; Kalayanarooj, Siripen; Ubol, Sukathida

    2010-12-21

    The phenomenon of antibody dependent enhancement as a major determinant that exacerbates disease severity in DENV infections is well accepted. While the detailed mechanism of antibody enhanced disease severity is unclear, evidence suggests that it is associated with both increased DENV infectivity and suppression of the type I IFN and pro-inflammatory cytokine responses. Therefore, it is imperative for us to understand the intracellular mechanisms altered during ADE infection to decipher the mechanism of severe pathogenesis. In this present work, qRT-PCR, immunoblotting and gene array analysis were conducted to determine whether DENV-antibody complex infection exerts a suppressive effect on the expression and/or function of the pathogen recognition patterns, focusing on the TLR-signaling pathway. We show here that FcγRI and FcγRIIa synergistically facilitated entry of DENV-antibody complexes into monocytic THP-1 cells. Ligation between DENV-antibody complexes and FcR not only down regulated TLRs gene expression but also up regulated SARM, TANK, and negative regulators of the NF-κB pathway, resulting in suppression of innate responses but increased viral production. These results were confirmed by blocking with anti-FcγRI or anti-FcγRIIa antibodies which reduced viral production, up-regulated IFN-β synthesis, and increased gene expression in the TLR-dependent signaling pathway. The negative impact of DENV-ADE infection on the TLR-dependent pathway was strongly supported by gene array screening which revealed that both MyD88-dependent and -independent signaling molecules were down regulated during DENV-ADE infection. Importantly, the same phenomenon was seen in PBMC of secondary DHF/DSS patients but not in PBMC of DF patients. Our present work demonstrates the mechanism by which DENV uses pre-existing immune mediators to defeat the principal activating pathway of innate defense resulting in suppression of an array of innate immune responses. Interestingly, this

  3. Identification and Validation of Ifit1 as an Important Innate Immune Bottleneck

    Energy Technology Data Exchange (ETDEWEB)

    McDermott, Jason E.; Vartanian, Keri B.; Mitchell, Hugh D.; Stevens, S.L.; Sanfilippo, Antonio P.; Stenzel-Poore, Mary

    2012-06-20

    The innate immune system plays important roles in a number of disparate processes. Foremost, innate immunity is a first responder to invasion by pathogens and triggers early defensive responses and recruits the adaptive immune system. The innate immune system also responds to endogenous damage signals that arise from tissue injury. Recently it has been found that innate immunity plays an important role in neuroprotection against ischemic stroke through the activation of the primary innate immune receptors, Toll-like receptors (TLRs). Using several large-scale transcriptomic data sets from mouse and mouse macrophage studies we identified targets predicted to be important in controlling innate immune processes initiated by TLR activation. Targets were identified as genes with high betweenness centrality, so-called bottlenecks, in networks inferred from statistical associations between gene expression patterns. A small set of putative bottlenecks were identified in each of the data sets investigated including interferon-stimulated genes (Ifit1, Ifi47, Tgtp and Oasl2) as well as genes uncharacterized in immune responses (Axud1 and Ppp1r15a). We further validated one of these targets, Ifit1, in mouse macrophages by showing that silencing it suppresses induction of predicted downstream genes by lipopolysaccharide (LPS)-mediated TLR4 activation through an unknown direct or indirect mechanism. Our study demonstrates the utility of network analysis for identification of interesting targets related to innate immune function, and highlights that Ifit1 can exert a positive regulatory effect on downstream genes.

  4. Innate immunity and the sensing of infection, damage and danger in the female genital tract.

    Science.gov (United States)

    Sheldon, Iain Martin; Owens, Siân-Eleri; Turner, Matthew Lloyd

    2017-02-01

    Tissue homeostasis in the female genital tract is challenged by infection, damage, and even physiological events during reproductive cycles. We propose that the evolutionarily ancient system of innate immunity is sufficient to sense and respond to danger in the non-pregnant female genital tract. Innate immunity produces a rapidly inducible, non-specific response when cells sense danger. Here we provide a primer on innate immunity and discuss what is known about how danger signals are sensed in the endometrium and ovary, the impact of inflammatory responses on reproduction, and how endocrinology and innate immunity are integrated. Endometrial epithelial and stromal cells, and ovarian granulosa cells express pattern recognition receptors, similar to cells of the innate immune system. These pattern recognition receptors, such as the Toll-like receptors, bind pathogen-associated or damage-associated molecular patterns. Activation of pattern recognition receptors leads to inflammation, recruitment of immune cells from the peripheral circulation, and phagocytosis. Although the inflammatory response helps maintain or restore endometrial health, there may also be negative consequences for fertility, including perturbation of oocyte competence. The intensity of the inflammatory response reflects the balance between the level of danger and the systems that regulate innate immunity, including the endocrine environment. Understanding innate immunity is important because disease and inappropriate inflammatory responses in the endometrium or ovary cause infertility. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  5. Tim-3: An activation marker and activation limiter of innate immune cells

    Directory of Open Access Journals (Sweden)

    Gencheng eHan

    2013-12-01

    Full Text Available Tim-3 was initially identified on activated Th1, Th17, and Tc1 cells and induces T cell death or exhaustion after binding to its ligand, Gal-9. The observed relationship between dysregulated Tim-3 expression on T cells and the progression of many clinical diseases has identified this molecule as an important target for intervention in adaptive immunity. Recent data have shown that it also plays critical roles in regulating the activities of macrophages, monocytes, dendritic cells, mast cells, natural killer cells, and endothelial cells. Although the underlying mechanisms remain unclear, dysregulation of Tim-3 expression on these innate immune cells leads to an excessive or inhibited inflammatory response and subsequent autoimmune damage or viral or tumor evasion. In this review, we focus on the expression and function of Tim-3 on innate immune cells and discuss 1 how Tim-3 is expressed and regulated on different innate immune cells; 2 how it affects the activity of different innate immune cells; and 3 how dysregulated Tim-3 expression on innate immune cells affects adaptive immunity and disease progression. Tim-3 is involved in the optimal activation of innate immune cells through its varied expression. A better understanding of the physiopathological role of the Tim-3 pathway in innate immunity will shed new light on the pathogenesis of clinical diseases, such as autoimmune diseases, chronic viral infections, and cancer, and suggest new approaches to intervention.

  6. Innate immunity as the orchestrator of allergic airway inflammation and resolution in asthma.

    Science.gov (United States)

    Thiriou, Despoina; Morianos, Ioannis; Xanthou, Georgina; Samitas, Konstantinos

    2017-07-01

    The respiratory system is constantly in direct contact with the environment and, has therefore, developed strong innate and adaptive immune responses to combat pathogens. Unlike adaptive immunity which is mounted later in the course of the immune response and is naive at the outset, innate immunity provides the first line of defense against microbial agents, while also promoting resolution of inflammation. In the airways, innate immune effector cells mainly consist of eosinophils, neutrophils, mast cells, basophils, macrophages/monocytes, dendritic cells and innate lymphoid cells, which attack pathogens directly or indirectly through the release of inflammatory cytokines and antimicrobial peptides, and coordinate T and B cell-mediated adaptive immunity. Airway epithelial cells are also critically involved in shaping both the innate and adaptive arms of the immune response. Chronic allergic airway inflammation and linked asthmatic disease is often considered a result of aberrant activation of type 2 T helper cells (Th2) towards innocuous environmental allergens; however, innate immune cells are increasingly recognized as key players responsible for the initiation and the perpetuation of allergic responses. Moreover, innate cells participate in immune response regulation through the release of anti-inflammatory mediators, and guide tissue repair and the maintenance of airway homeostasis. The scope of this review is to outline existing knowledge on innate immune responses involved in allergic airway inflammation, highlight current gaps in our understanding of the underlying molecular and cellular mechanisms and discuss the potential use of innate effector cells in new therapeutic avenues. Copyright © 2017. Published by Elsevier B.V.

  7. The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation

    DEFF Research Database (Denmark)

    Klose, Christoph S N; Mahlakõiv, Tanel; Moeller, Jesper B

    2017-01-01

    The type 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13 have important roles in stimulating innate and adaptive immune responses that are required for resistance to helminth infection, promotion of allergic inflammation, metabolic homeostasis and tissue repair. Group 2 innate lymphoid cells......, these data indicate that the NMU-NMUR1 neuronal signalling circuit provides a selective mechanism through which the enteric nervous system and innate immune system integrate to promote rapid type 2 cytokine responses that can induce anti-microbial, inflammatory and tissue-protective type 2 responses...

  8. Global immune disregulation in multiple sclerosis: from the adaptive response to the innate immunity.

    Science.gov (United States)

    Ristori, G; Montesperelli, C; Perna, A; Cannoni, S; Battistini, L; Borsellino, G; Riccio, P; Pesole, G; Chersi, A; Pozzilli, C; Buttinelli, C; Salvetti, M

    2000-07-24

    Increasing evidences show a global immune disregulation in multiple sclerosis (MS). The possible involvement of myelin and non-myelin (auto-)antigens in the autoaggressive process as well as the disregulation of both adaptive and innate immunity challenge the concept of specific immunotherapy. T cells at the boundary between innate and adaptive immunity, whose immunoregulatory role is becoming increasingly clear, have recently been shown to bear relevance for MS pathogenesis. Global immune interventions (and type I interferons may be considered as such) aimed at interfering with both innate and acquired immune responses seem to be a most promising therapeutic option in MS.

  9. The role of innate lymphoid cells in healthy and inflamed skin

    DEFF Research Database (Denmark)

    Bonefeld, Charlotte M.; Geisler, Carsten

    2016-01-01

    The skin constitutes the interface between the organism and the environment, and it protects the body from harmful substances in the environment via physical, chemical and immunological barriers. The immunological barrier of the skin comprises both cells from the innate and the adaptive immune...... system. During the last years, it has become clear that innate lymphoid cells play a role in homeostasis and inflammation of the skin in humans and mice. In this review, we will discuss the role of innate lymphoid cells in healthy and inflamed skin with special focus on their role in atopic dermatitis....

  10. Evolutionary perspectives on innate immunity from the study of Caenorhabditis elegans.

    Science.gov (United States)

    Kim, Dennis H; Ausubel, Frederick M

    2005-02-01

    Genetic and functional genomic approaches have begun to define the molecular determinants of pathogen resistance in Caenorhabditis elegans. Conserved signal transduction components are required for pathogen resistance, including a Toll/IL-1 receptor domain adaptor protein that functions upstream of a conserved p38 MAP kinase pathway. We suggest that this pathway is an ancestral innate immune signaling pathway present in the common ancestor of nematodes, arthropods and vertebrates, which is likely to predate the involvement of canonical Toll signaling pathways in innate immunity. We anticipate that the study of pathogen resistance in C. elegans will continue to provide evolutionary and mechanistic insights into the signal transduction and physiology of innate immunity.

  11. The quantitative basis of the Arabidopsis innate immune system to endemic pathogens depends on pathogen genetics

    DEFF Research Database (Denmark)

    Corwin, Jason A; Copeland, Daniel; Feusier, Julie

    2016-01-01

    The most established model of the eukaryotic innate immune system is derived from examples of large effect monogenic quantitative resistance to pathogens. However, many host-pathogen interactions involve many genes of small to medium effect and exhibit quantitative resistance. We used...... the Arabidopsis-Botrytis pathosystem to explore the quantitative genetic architecture underlying host innate immune system in a population of Arabidopsis thaliana. By infecting a diverse panel of Arabidopsis accessions with four phenotypically and genotypically distinct isolates of the fungal necrotroph B...... shows that the genetic architecture underlying host innate immune system is extremely complex and is likely able to sense and respond to differential virulence among pathogen genotypes....

  12. Humoral innate immunity at the crossroad between microbe and matrix recognition: The role of PTX3 in tissue damage.

    Science.gov (United States)

    Doni, Andrea; D'Amico, Giovanna; Morone, Diego; Mantovani, Alberto; Garlanda, Cecilia

    2017-01-01

    Innate immunity is involved in regulating inflammatory and tissue repair responses to injury. In particular, humoral innate immunity plays functions related to wound clearance from tissue debris, and regulation of macrophage and stromal cell activities. PTX3, a component of humoral innate immunity, orchestrates tissue repair by interacting with plasminogen and fibrin. Fluid-phase molecules of innate immunity interact with elements of the extracellular matrix, and some of the latter display opsonic activity against certain bacterial species. Thus, recognition of extracellular matrix and microbial components is a recurrent theme in the humoral arm of the innate immune system. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. 31 CFR 585.216 - Expenses of maintaining blocked property; liquidation into blocked account.

    Science.gov (United States)

    2010-07-01

    ... property; liquidation into blocked account. 585.216 Section 585.216 Money and Finance: Treasury Regulations... blocked property; liquidation into blocked account. (a) Except as otherwise authorized, and... expenses incident to the blocking and maintenance of property blocked pursuant to § 585.201 or § 585.215(a...

  14. On the Eigenvalues and Eigenvectors of Block Triangular Preconditioned Block Matrices

    KAUST Repository

    Pestana, Jennifer

    2014-01-01

    Block lower triangular matrices and block upper triangular matrices are popular preconditioners for 2×2 block matrices. In this note we show that a block lower triangular preconditioner gives the same spectrum as a block upper triangular preconditioner and that the eigenvectors of the two preconditioned matrices are related. © 2014 Society for Industrial and Applied Mathematics.

  15. Block-Matching Based Multifocus Image Fusion

    Directory of Open Access Journals (Sweden)

    Feng Zhu

    2015-01-01

    Full Text Available A new multifocus image fusion method is proposed. Two image blocks are selected by sliding the window from the two source images at the same position, discrete cosine transform (DCT is implemented, respectively, on these two blocks, and the alternating component (AC energy of these blocks is then calculated to decide which is the well-focused one. In addition, block matching is used to determine a group of image blocks that are all similar to the well-focused reference block. Finally, all the blocks are returned to their original positions through weighted average. The weight is decided with the AC energy of the well-focused block. Experimental results demonstrate that, unlike other spatial methods, the proposed method effectively avoids block artifacts. The proposed method also significantly improves the objective evaluation results, which are obtained by some transform domain methods.

  16. Blocking incidental frustration during bargaining.

    Science.gov (United States)

    Vargas, Maria Esperanza S; Brown, Anna-Leigh; Durkee, Cassandra M; Sim, Hoeun

    2018-02-08

    The current study examined the effects of an intervention aimed at blocking the transfer of frustration from a previous experience (i.e. recall task) to a subsequent and unrelated task (i.e. ultimatum bargaining task). Participants who went through the intervention were more likely to accept unfair offers in the ultimatum bargaining task than those who did not go through the intervention. These results show that participants who were blocked from transferring their feelings of frustration from the recall task to the subsequent bargaining task (no-transfer condition) more likely accepted unfair offers than those who inadvertently transferred their feelings of frustration (transfer condition). The effect of conditions on accept-reject decisions in the ultimatum bargaining was mediated by reported feelings of frustration.

  17. The Innate Immune System in Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Allal Boutajangout

    2013-01-01

    Full Text Available Alzheimer’s disease (AD is the leading cause for dementia in the world. It is characterized by two biochemically distinct types of protein aggregates: amyloid β (Aβ peptide in the forms of parenchymal amyloid plaques and congophilic amyloid angiopathy (CAA and aggregated tau protein in the form of intraneuronal neurofibrillary tangles (NFT. Several risk factors have been discovered that are associated with AD. The most well-known genetic risk factor for late-onset AD is apolipoprotein E4 (ApoE4 (Potter and Wisniewski (2012, and Verghese et al. (2011. Recently, it has been reported by two groups independently that a rare functional variant (R47H of TREM2 is associated with the late-onset risk of AD. TREM2 is expressed on myeloid cells including microglia, macrophages, and dendritic cells, as well as osteoclasts. Microglia are a major part of the innate immune system in the CNS and are also involved in stimulating adaptive immunity. Microglia express several Toll-like receptors (TLRs and are the resident macrophages of the central nervous system (CNS. In this review, we will focus on the recent advances regarding the role of TREM2, as well as the effects of TLRs 4 and 9 on AD.

  18. The image schema and innate archetypes: theoretical and clinical implications.

    Science.gov (United States)

    Merchant, John

    2016-02-01

    Based in contemporary neuroscience, Jean Knox's 2004 JAP paper 'From archetypes to reflective function' honed her position on image schemas, thereby introducing a model for archetypes which sees them as 'reliably repeated early developmental achievements' and not as genetically inherited, innate psychic structures. The image schema model is used to illustrate how the analyst worked with a patient who began life as an unwanted pregnancy, was adopted at birth and as an adult experienced profound synchronicities, paranormal/telepathic phenomena and visions. The classical approach to such phenomena would see the intense affectivity arising out of a ruptured symbiotic mother-infant relationship constellating certain archetypes which set up the patient's visions. This view is contrasted with Knox's model which sees the archetype an sich as a developmentally produced image schema underpinning the emergence of later imagery. The patient's visions can then be understood to arise from his psychoid body memory related to his traumatic conception and birth. The contemporary neuroscience which supports this view is outlined and a subsequent image schema explanation is presented. Clinically, the case material suggests that a pre-birth perspective needs to be explored in all analytic work. Other implications of Knox's image schema model are summarized. © 2016, The Society of Analytical Psychology.

  19. Lanosterol Modulates TLR4-Mediated Innate Immune Responses in Macrophages

    Directory of Open Access Journals (Sweden)

    Elisa Araldi

    2017-06-01

    Full Text Available Macrophages perform critical functions in both innate immunity and cholesterol metabolism. Here, we report that activation of Toll-like receptor 4 (TLR4 in macrophages causes lanosterol, the first sterol intermediate in the cholesterol biosynthetic pathway, to accumulate. This effect is due to type I interferon (IFN-dependent histone deacetylase 1 (HDAC1 transcriptional repression of lanosterol-14α-demethylase, the gene product of Cyp51A1. Lanosterol accumulation in macrophages, because of either treatment with ketoconazole or induced conditional disruption of Cyp51A1 in mouse macrophages in vitro, decreases IFNβ-mediated signal transducer and activator of transcription (STAT1-STAT2 activation and IFNβ-stimulated gene expression. These effects translate into increased survival to endotoxemic shock by reducing cytokine secretion. In addition, lanosterol accumulation increases membrane fluidity and ROS production, thus potentiating phagocytosis and the ability to kill bacteria. This improves resistance of mice to Listeria monocytogenes infection by increasing bacterial clearance in the spleen and liver. Overall, our data indicate that lanosterol is an endogenous selective regulator of macrophage immunity.

  20. Memorizing innate instructions requires a sufficiently specific adaptive immune system.

    Science.gov (United States)

    Borghans, José A M; De Boer, Rob J

    2002-05-01

    During its primary encounter with a pathogen, the immune system has to decide which type of immune response is most appropriate. Based on signals from the innate immune system and the immunological context in which the pathogen is presented, responding lymphocytes will adopt a particular phenotype, e.g. secrete a particular profile of cytokines. Once stimulated, lymphocytes store the appropriate type of response by differentiating from a naive to a memory phenotype. This allows the appropriate type of immune reaction to be regenerated upon re-stimulation of those memory clones. We developed a computer simulation model in which cross-reacting effector/memory clones contribute to the immunological context of pathogens. If a pathogen is recognized by both naive clones and pre-existing effector/memory clones, the naive lymphocytes adopt the effector mechanism of the memory clone. The adaptive immune system thereby stores immunological decisions and somatically learns to induce the right type of immune response to pathogens sharing epitopes. The influence of effector/memory lymphocytes may be detrimental when they cross-react to new pathogens that require a different kind of immune response. Here, we show that the immune system needs to be sufficiently specific to avoid such mistakes and to profit from the information that is stored in effector/memory lymphocytes. Repertoire diversity is required to reconcile this specificity with reactivity against many pathogens.

  1. Regulation of Innate Lymphoid Cells by Aryl Hydrocarbon Receptor

    Directory of Open Access Journals (Sweden)

    Shiyang Li

    2018-01-01

    Full Text Available With striking similarity to their adaptive T helper cell counterparts, innate lymphoid cells (ILCs represent an emerging family of cell types that express signature transcription factors, including T-bet+ Eomes+ natural killer cells, T-bet+ Eomes− group 1 ILCs, GATA3+ group 2 ILCs, RORγt+ group 3 ILCs, and newly identified Id3+ regulatory ILC. ILCs are abundantly present in barrier tissues of the host (e.g., the lung, gut, and skin at the interface of host–environment interactions. Active research has been conducted to elucidate molecular mechanisms underlying the development and function of ILCs. The aryl hydrocarbon receptor (Ahr is a ligand-dependent transcription factor, best known to mediate the effects of xenobiotic environmental toxins and endogenous microbial and dietary metabolites. Here, we review recent progresses regarding Ahr function in ILCs. We focus on the Ahr-mediated cross talk between ILCs and other immune/non-immune cells in host tissues especially in the gut. We discuss the molecular mechanisms of the action of Ahr expression and activity in regulation of ILCs in immunity and inflammation, and the interaction between Ahr and other pathways/transcription factors in ILC development and function with their implication in disease.

  2. Crosstalk between the circadian clock and innate immunity in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Chong Zhang

    Full Text Available The circadian clock integrates temporal information with environmental cues in regulating plant development and physiology. Recently, the circadian clock has been shown to affect plant responses to biotic cues. To further examine this role of the circadian clock, we tested disease resistance in mutants disrupted in CCA1 and LHY, which act synergistically to regulate clock activity. We found that cca1 and lhy mutants also synergistically affect basal and resistance gene-mediated defense against Pseudomonas syringae and Hyaloperonospora arabidopsidis. Disrupting the circadian clock caused by overexpression of CCA1 or LHY also resulted in severe susceptibility to P. syringae. We identified a downstream target of CCA1 and LHY, GRP7, a key constituent of a slave oscillator regulated by the circadian clock and previously shown to influence plant defense and stomatal activity. We show that the defense role of CCA1 and LHY against P. syringae is at least partially through circadian control of stomatal aperture but is independent of defense mediated by salicylic acid. Furthermore, we found defense activation by P. syringae infection and treatment with the elicitor flg22 can feedback-regulate clock activity. Together this data strongly supports a direct role of the circadian clock in defense control and reveal for the first time crosstalk between the circadian clock and plant innate immunity.

  3. Differences in innate cytokine responses between European and African children.

    Science.gov (United States)

    Labuda, Lucja A; de Jong, Sanne E; Meurs, Lynn; Amoah, Abena S; Mbow, Moustapha; Ateba-Ngoa, Ulysse; van der Ham, Alwin J; Knulst, André C; Yazdanbakhsh, Maria; Adegnika, Ayola A

    2014-01-01

    Although differences in immunological responses between populations have been found in terms of vaccine efficacy, immune responses to infections and prevalence of chronic inflammatory diseases, the mechanisms responsible for these differences are not well understood. Therefore, innate cytokine responses mediated by various classes of pattern-recognition receptors including Toll-like receptors (TLR), C-type lectin receptors (CLRs) and nucleotide-binding oligomerisation domain-like receptors (NLRs) were compared between Dutch (European), semi-urban and rural Gabonese (African) children. Whole blood was stimulated for 24 hours and the pro-inflammatory tumor necrosis factor (TNF) and the anti-inflammatory/regulatory interleukin-10 (IL-10) cytokines in culture supernatant were measured by enzyme-linked immunosorbent assay (ELISA). Gabonese children had a lower pro-inflammatory response to poly(I:C) (TLR3 ligand), but a higher pro-inflammatory response to FSL-1 (TLR2/6 ligand), Pam3 (TLR2/1 ligand) and LPS (TLR4 ligand) compared to Dutch children. Anti-inflammatory responses to Pam3 were also higher in Gabonese children. Non-TLR ligands did not induce substantial cytokine production on their own. Interaction between various TLR and non-TLR receptors was further assessed, but no differences were found between the three populations. In conclusion, using a field applicable assay, significant differences were observed in cytokine responses between European and African children to TLR ligands, but not to non-TLR ligands.

  4. Differences in innate cytokine responses between European and African children.

    Directory of Open Access Journals (Sweden)

    Lucja A Labuda

    Full Text Available Although differences in immunological responses between populations have been found in terms of vaccine efficacy, immune responses to infections and prevalence of chronic inflammatory diseases, the mechanisms responsible for these differences are not well understood. Therefore, innate cytokine responses mediated by various classes of pattern-recognition receptors including Toll-like receptors (TLR, C-type lectin receptors (CLRs and nucleotide-binding oligomerisation domain-like receptors (NLRs were compared between Dutch (European, semi-urban and rural Gabonese (African children. Whole blood was stimulated for 24 hours and the pro-inflammatory tumor necrosis factor (TNF and the anti-inflammatory/regulatory interleukin-10 (IL-10 cytokines in culture supernatant were measured by enzyme-linked immunosorbent assay (ELISA. Gabonese children had a lower pro-inflammatory response to poly(I:C (TLR3 ligand, but a higher pro-inflammatory response to FSL-1 (TLR2/6 ligand, Pam3 (TLR2/1 ligand and LPS (TLR4 ligand compared to Dutch children. Anti-inflammatory responses to Pam3 were also higher in Gabonese children. Non-TLR ligands did not induce substantial cytokine production on their own. Interaction between various TLR and non-TLR receptors was further assessed, but no differences were found between the three populations. In conclusion, using a field applicable assay, significant differences were observed in cytokine responses between European and African children to TLR ligands, but not to non-TLR ligands.

  5. Modeling Innate Immune Response to Early Mycobacterium Infection

    Directory of Open Access Journals (Sweden)

    Rafael V. Carvalho

    2012-01-01

    Full Text Available In the study of complex patterns in biology, mathematical and computational models are emerging as important tools. In addition to experimental approaches, these modeling tools have recently been applied to address open questions regarding host-pathogen interaction dynamics, including the immune response to mycobacterial infection and tuberculous granuloma formation. We present an approach in which a computational model represents the interaction of the Mycobacterium infection with the innate immune system in zebrafish at a high level of abstraction. We use the Petri Net formalism to model the interaction between the key host elements involved in granuloma formation and infection dissemination. We define a qualitative model for the understanding and description of causal relations in this dynamic process. Complex processes involving cell-cell or cell-bacteria communication can be modeled at smaller scales and incorporated hierarchically into this main model; these are to be included in later elaborations. With the infection mechanism being defined on a higher level, lower-level processes influencing the host-pathogen interaction can be identified, modeled, and tested both quantitatively and qualitatively. This systems biology framework incorporates modeling to generate and test hypotheses, to perform virtual experiments, and to make experimentally verifiable predictions. Thereby it supports the unraveling of the mechanisms of tuberculosis infection.

  6. Malarial Pigment Hemozoin and the Innate Inflammatory Response

    Directory of Open Access Journals (Sweden)

    Martin eOlivier

    2014-02-01

    Full Text Available Malaria is a deadly infectious disease caused by the intraerythrocytic protozoan parasite Plasmodium. The four species of Plasmodium known to affect humans all produce an inorganic crystal called hemozoin (HZ during the heme detoxification process. HZ is released from the food vacuole into circulation during erythrocyte lysis, while the released parasites further infect additional naive red blood cells. Once in circulation, HZ is rapidly taken up by circulating monocytes and tissue macrophages, inducing the production of pro-inflammatory mediators, such as interleukin-1β (IL-1β. Over the last few years, it has been reported that HZ, similar to uric acid crystals, asbestos and silica, is able to trigger IL-1β production via the activation of the NOD-like receptor containing pyrin domain 3 (NLRP3 inflammasome complex. Additionally, recent findings have shown that host factors, such as fibrinogen, have the ability to adhere to free HZ and modify its capacity to activate host immune cells. Although much has been discovered regarding NLRP3 inflammasome induction, the mechanism through which this intracellular multimolecular complex is activated remains unclear. In the present review, the most recent discoveries regarding the capacity of HZ to trigger this innate immune complex will be discussed, as well as the impact of HZ on several other inflammatory signalling pathways.

  7. The innate immune response of the respiratory epithelium.

    Science.gov (United States)

    Diamond, G; Legarda, D; Ryan, L K

    2000-02-01

    The respiratory epithelium maintains an effective antimicrobial environment to prevent colonization by microorganisms in inspired air. In addition to constitutively present host defenses which include antimicrobial peptides and proteins, the epithelial cells respond to the presence of microbes by the induction two complementary parts of an innate immune response. The first response is the increased production of antimicrobial agents, and the second is the induction of a signal network to recruit phagocytic cells to contain the infection. Inflammatory mediators released by the recruited cells as well as from the epithelium itself further induce the expression of the antimicrobial agents. The result is an effective prevention of microbial colonization. The epithelial cells recognize the pathogen-associated patterns on microbes by surface receptors such as CD14 and Toll-like receptors. Subsequent signal transduction pathways have been identified which result in the increased transcription of host defense response genes. Diseases such as cystic fibrosis, or environmental exposures such as the inhalation of air pollution particles, may create an environment that impairs the expression or activity of the host defenses in the airway. This can lead to increased susceptibility to airway infections.

  8. Bridging Innate and Adaptive Antitumor Immunity Targeting Glycans

    Directory of Open Access Journals (Sweden)

    Anastas Pashov

    2010-01-01

    Full Text Available Effective immunotherapy for cancer depends on cellular responses to tumor antigens. The role of major histocompatibility complex (MHC in T-cell recognition and T-cell receptor repertoire selection has become a central tenet in immunology. Structurally, this does not contradict earlier findings that T-cells can differentiate between small hapten structures like simple glycans. Understanding T-cell recognition of antigens as defined genetically by MHC and combinatorially by T cell receptors led to the “altered self” hypothesis. This notion reflects a more fundamental principle underlying immune surveillance and integrating evolutionarily and mechanistically diverse elements of the immune system. Danger associated molecular patterns, including those generated by glycan remodeling, represent an instance of altered self. A prominent example is the modification of the tumor-associated antigen MUC1. Similar examples emphasize glycan reactivity patterns of antigen receptors as a phenomenon bridging innate and adaptive but also humoral and cellular immunity and providing templates for immunotherapies.

  9. UAV PHOTOGRAMMETRY: BLOCK TRIANGULATION COMPARISONS

    Directory of Open Access Journals (Sweden)

    R. Gini

    2013-08-01

    Full Text Available UAVs systems represent a flexible technology able to collect a big amount of high resolution information, both for metric and interpretation uses. In the frame of experimental tests carried out at Dept. ICA of Politecnico di Milano to validate vector-sensor systems and to assess metric accuracies of images acquired by UAVs, a block of photos taken by a fixed wing system is triangulated with several software. The test field is a rural area included in an Italian Park ("Parco Adda Nord", useful to study flight and imagery performances on buildings, roads, cultivated and uncultivated vegetation. The UAV SenseFly, equipped with a camera Canon Ixus 220HS, flew autonomously over the area at a height of 130 m yielding a block of 49 images divided in 5 strips. Sixteen pre-signalized Ground Control Points, surveyed in the area through GPS (NRTK survey, allowed the referencing of the block and accuracy analyses. Approximate values for exterior orientation parameters (positions and attitudes were recorded by the flight control system. The block was processed with several software: Erdas-LPS, EyeDEA (Univ. of Parma, Agisoft Photoscan, Pix4UAV, in assisted or automatic way. Results comparisons are given in terms of differences among digital surface models, differences in orientation parameters and accuracies, when available. Moreover, image and ground point coordinates obtained by the various software were independently used as initial values in a comparative adjustment made by scientific in-house software, which can apply constraints to evaluate the effectiveness of different methods of point extraction and accuracies on ground check points.

  10. [THE TECHNOLOGY "CELL BLOCK" IN CYTOLOGICAL PRACTICE].

    Science.gov (United States)

    Volchenko, N N; Borisova, O V; Baranova, I B

    2015-08-01

    The article presents summary information concerning application of "cell block" technology in cytological practice. The possibilities of implementation of various modern techniques (immune cytochemnical analysis. FISH, CISH, polymerase chain reaction) with application of "cell block" method are demonstrated. The original results of study of "cell block" technology made with gelatin, AgarCyto and Shadon Cyoblock set are presented. The diagnostic effectiveness of "cell block" technology and common cytological smear and also immune cytochemical analysis on samples of "cell block" technology and fluid cytology were compared. Actually application of "cell block" technology is necessary for ensuring preservation of cell elements for subsequent immune cytochemical and molecular genetic analysis.

  11. Muller glia in retinal innate immunity: a perspective on their roles in endophthalmitis.

    Science.gov (United States)

    Kumar, Ashok; Pandey, Rajeev K; Miller, Lindsay J; Singh, Pawan K; Kanwar, Mamta

    2013-01-01

    Muller cells are the predominant glial cell type in the retina and have a unique anatomy, with processes that span the entire retinal thickness. Although extensive morphological and physiological studies of Muller glia have been performed, much less is known about their role in retinal innate immunity, specifically in infectious endophthalmitis. They were found to express toll-like receptors (TLRs), a major family of pattern recognition receptors that mediate innate responses and provide an important mechanism by which Muller glia are able to sense both pathogen- and host-derived ligands in the vitreous and the retina. An increasing body of evidence suggests that TLR-signaling mediates beneficial effects in the retina via production of proinflammatory cytokines/chemokines, antimicrobial peptides, and neuroprotective growth factors to restore tissue homeostasis. In this review, we discussed retinal innate immunity in general with emphasis on the role of Muller glia in initiating retinal innate defense.

  12. Innate and discretionary accruals quality and corporate governance: A case study of Tehran Stock Exchange

    Directory of Open Access Journals (Sweden)

    Hossein Panahian

    2012-09-01

    Full Text Available In this paper, we present an empirical study to find the relationship between discretionary accruals quality as well as innate accruals quality and portion of non-executive board of directors, concentration of ownership ratio and board size in Tehran Stock Exchange. The survey selects 118 qualified stocks from this exchange and using a random technique chooses 42 firms. The study implements two linear regression techniques to estimate the first part of the information and then using structural equation modeling examines six hypotheses. Based on the results of this survey we can conclude that an increase on non-executive members positively influences on discretionary accruals quality and negatively influences innate accruals quality. Concentration of ownership ratio positively influences on discretionary accruals quality and negatively impacts on innate accruals quality. Finally, size of board of directors negatively impacts discretionary accruals quality and positively influences on innate accruals quality.

  13. Innate immune evasion strategies against Cryptococcal meningitis caused byCryptococcus neoformans.

    Science.gov (United States)

    Yang, Cheng-Liang; Wang, Jun; Zou, Li-Li

    2017-12-01

    As an infectious fungus that affects the respiratory tract, Cryptococcus neoformans ( C. neoformans ) commonly causes asymptomatic pulmonary infection. C. neoformans may target the brain instead of the lungs and cross the blood-brain barrier (BBB) in the early phase of infection; however, this is dependent on successful evasion of the host innate immune system. During the initial stage of fungal infection, a complex network of innate immune factors are activated. C. neoformans utilizes a number of strategies to overcome the anti-fungal mechanisms of the host innate immune system and cross the BBB. In the present review, the defensive mechanisms of C. neoformans against the innate immune system and its ability to cross the BBB were discussed, with an emphasis on recent insights into the activities of anti-phagocytotic and anti-oxidative factors in C. neoformans .

  14. Aging and innate immunity in the mouse: impact of intrinsic and extrinsic factors

    Science.gov (United States)

    Kovacs, Elizabeth J.; Palmer, Jessica L.; Fortin, Carl F.; Fülöp, Tamas; Goldstein, Daniel R.; Linton, Phyllis-Jean

    2010-01-01

    Aging affects every innate immune cell, including changes in cell numbers and function. Defects in the function of some cells are intrinsic, whereas for other cells, defects are extrinsic and possibly the consequence of the complex interactions with other cell types or the environmental milieu that is altered with aging. Abnormal function contributes to worsened outcomes after injury or infection and leads to diseases observed in the elderly. Knowing the mechanisms responsible for the aberrant function of innate immune cells might lead to the development of therapeutic strategies designed to improve innate immunity in aged individuals. Herein, advances in the field of innate immunity and aging with a focus on neutrophils, macrophages and dendritic cells in laboratory animals are discussed. PMID:19541536

  15. Microarray expression analysis of genes involved in innate immune memory in peritoneal macrophages

    Directory of Open Access Journals (Sweden)

    Keisuke Yoshida

    2016-03-01

    Full Text Available Immunological memory has been believed to be a feature of the adaptive immune system for long period, but recent reports suggest that the innate immune system also exhibits memory-like reaction. Although evidence of innate immune memory is accumulating, no in vivo experimental data has clearly implicated a molecular mechanism, or even a cell-type, for this phenomenon. In this study of data deposited into Gene Expression Omnibus (GEO under GSE71111, we analyzed the expression profile of peritoneal macrophages isolated from mice pre-administrated with toll-like receptor (TLR ligands, mimicking pathogen infection. In these macrophages, increased expression of a group of innate immunity-related genes was sustained over a long period of time, and these genes overlapped with ATF7-regulated genes. We conclude that ATF7 plays an important role in innate immune memory in macrophages.

  16. No compensatory relationship between the innate and adaptive immune system in wild-living European badgers

    NARCIS (Netherlands)

    Sin, Yung Wa; Newman, Chris; Dugdale, Hannah L.; Buesching, Christina; Mannarelli, Maria Elena; Annavi, Geetha; Burke, Terry; MacDonald, David W.

    2016-01-01

    The innate immune system provides the primary vertebrate defence system against pathogen invasion, but it is energetically costly and can have immune pathological effects. A previous study in sticklebacks found that intermediate major histocompatibility complex (MHC) diversity correlated with a

  17. Meningococcal outer membrane vesicle composition-dependent activation of the innate immune response

    NARCIS (Netherlands)

    Zariri, Afshin; Beskers, Joep; van de Waterbeemd, Bas; Hamstra, Hendrik Jan; Bindels, Tim H E; van Riet, Elly; van Putten, Jos P M; van der Ley, Peter

    2016-01-01

    Meningococcal outer membrane vesicles (OMVs) have been extensively investigated and successfully implemented as vaccines. They contain pathogen associated molecular patterns including lipopolysaccharide (LPS), capable of triggering innate immunity. However, Neisseria meningitidis contains an

  18. Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines.

    Science.gov (United States)

    Blok, Bastiaan A; Arts, Rob J W; van Crevel, Reinout; Benn, Christine Stabell; Netea, Mihai G

    2015-09-01

    An increasing body of evidence shows that the innate immune system has adaptive characteristics that involve a heterologous memory of past insults. Both experimental models and proof-of-principle clinical trials show that innate immune cells, such as monocytes, macrophages, and NK cells, can provide protection against certain infections in vaccination models independently of lymphocytes. This process is regulated through epigenetic reprogramming of innate immune cells and has been termed "trained immunity." It has been hypothesized that induction of trained immunity is responsible for the protective, nonspecific effects induced by vaccines, such as BCG, measles vaccination, and other whole-microorganism vaccines. In this review, we will present the mechanisms of trained immunity responsible for the long-lasting effects of vaccines on the innate immune system. © Society for Leukocyte Biology.

  19. Silencing the alarms: innate immune antagonism by rotavirus NSP1 and VP3

    Science.gov (United States)

    Morelli, Marco; Ogden, Kristen M.; Patton, John T.

    2016-01-01

    The innate immune response involves a broad array of pathogen sensors that stimulate the production of interferons (IFN) to induce an antiviral state. Rotavirus, a significant cause of childhood gastroenteritis and a member of the Reoviridae family of segmented, double-stranded RNA viruses, encodes at least two direct antagonists of host innate immunity: NSP1 and VP3. NSP1, a putative E3 ubiquitin ligase, mediates the degradation of cellular factors involved in both IFN induction and downstream signaling. VP3, the viral capping enzyme, utilizes a 2H-phosphodiesterase domain to prevent activation of the cellular oligoadenylate synthase (OAS)-RNase L pathway. Computational, molecular, and biochemical studies have provided key insights into the structural and mechanistic basis of innate immune antagonism by NSP1 and VP3 of group A rotaviruses (RVA). Future studies with non-RVA isolates will be essential to understand how other RV species evade host innate immune responses. PMID:25724417

  20. Plant phosphatidylinositol-specific phospholipase C at the center of plant innate immunity

    NARCIS (Netherlands)

    Abd-El-Haliem, Ahmed M.; Joosten, Matthieu H.A.J.

    2017-01-01

    Understanding plant resistance to pathogenic microbes requires detailed information on the molecular mechanisms controlling the execution of plant innate immune responses. A growing body of evidence places phosphoinositide-specific phospholipase C (PI-PLC) enzymes immediately downstream of activated

  1. Evasion and interactions of the humoral innate immune response in pathogen invasion, autoimmune disease, and cancer.

    Science.gov (United States)

    Rettig, Trisha A; Harbin, Julie N; Harrington, Adelaide; Dohmen, Leonie; Fleming, Sherry D

    2015-10-01

    The humoral innate immune system is composed of three major branches, complement, coagulation, and natural antibodies. To persist in the host, pathogens, such as bacteria, viruses, and cancers must evade parts of the innate humoral immune system. Disruptions in the humoral innate immune system also play a role in the development of autoimmune diseases. This review will examine how Gram positive bacteria, viruses, cancer, and the autoimmune conditions systemic lupus erythematosus and anti-phospholipid syndrome, interact with these immune system components. Through examining evasion techniques it becomes clear that an interplay between these three systems exists. By exploring the interplay and the evasion/disruption of the humoral innate immune system, we can develop a better understanding of pathogenic infections, cancer, and autoimmune disease development. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Müller Glia in Retinal Innate Immunity: A perspective on their roles in endophthalmitis

    OpenAIRE

    Kumar, Ashok; Pandey, Rajeev K; Miller, Lindsay J; Singh, Pawan K; Kanwar, Mamta

    2013-01-01

    Müller cells are the predominant glial cell type in the retina and have a unique anatomy, with processes that span the entire retinal thickness. Although extensive morphological and physiological studies of Müller glia have been performed, much less is known about their role in retinal innate immunity, specifically in infectious endophthalmitis. They were found to express Toll-like receptors (TLRs), a major family of pattern recognition receptors (PRRs) that mediate innate responses and provi...

  3. MicroRNAs, Innate Immunity and Ventricular Rupture in Human Myocardial Infarction

    Directory of Open Access Journals (Sweden)

    Nina Zidar

    2011-01-01

    Full Text Available MicroRNAs are non-coding RNAs, functionioning as post-transcriptional regulators of gene expression. Some microRNAs have been demonstrated to play a role in regulation of innate immunity. After myocardial infarction (MI, innate immunity is activated leading to an acute inflammatory reaction. There is evidence that an intense inflammatory reaction might contribute to the development of ventricular rupture (VR after MI.

  4. Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism.

    OpenAIRE

    Slack Emma; Hapfelmeier Siegfried; Stecher Bärbel; Velykoredko Yuliya; Stoel Maaike; Lawson Melissa A E; Geuking Markus B; Beutler Bruce; Tedder Thomas F; Hardt Wolf-Dietrich; Bercik Premysl; Verdu Elena F; McCoy Kathy D; Macpherson Andrew J

    2009-01-01

    Commensal bacteria in the lower intestine of mammals are 10 times as numerous as the body's cells. We investigated the relative importance of different immune mechanisms in limiting the spread of the intestinal microbiota. Here we reveal a flexible continuum between innate and adaptive immune function in containing commensal microbes. Mice deficient in critical innate immune functions such as Toll like receptor signaling or oxidative burst production spontaneously produce high titer serum ant...

  5. Transgenerational epigenetic effects on innate immunity in broilers: an underestimated field to be explored?

    Science.gov (United States)

    Berghof, T V L; Parmentier, H K; Lammers, A

    2013-11-01

    Transgenerational epigenetics is becoming more and more important for understanding the variation of physiological responses of individuals to the environment and the inheritance of these responses based on all mechanisms other than the actual DNA nucleotide sequence. Transgenerational epigenetics is the phenomenon that the information of the environment of (usually) a female animal is translated into memory-like responses preparing the offspring. As a consequence, individuals of the next generation may show different phenotypic traits depending whether their mothers were kept under different environmental conditions. This may result in either positive or negative effects on the next-generation individuals, which is different from individuals from mothers that have been kept in a different environment. Transgenerational epigenetic effects have been proposed and indicated for specific immune (T cell and antibody) responses (especially in mammals, but also in birds) and innate immunity (nonvertebrates), but surprisingly very little is known of transgenerational effects on innate immunity in chickens. Given the short lifespan of the chicken and therefore the likely dependence of chicken on innate immune mechanisms, more attention should be given to this arm of immunity and mechanisms of inheritance including transgenerational effects that can be initiated in the breeder generation. In addition, it is becoming evident that innate immunity also underlies metabolic disorders in broilers. In the current paper, we will argue that although very little is known of transgenerational effects of innate immunity in poultry, more attention should be given to this type of study. We will illustrate examples of transgenerational epigenetics, and finally propose strategies that should reveal the presence of transgenerational epigenetic effects on innate immunity in chickens and strategies to modulate breeder birds such that these effects positively affect innate immunity of broilers

  6. Regulation of Aeroallergen Immunity by the Innate Immune System: Laboratory Evidence for a New Paradigm

    OpenAIRE

    Horner, Anthony A.

    2009-01-01

    Over the last decade, it has become increasingly clear that innate responses to microbes are mediated largely by toll-like receptors (TLRs), which recognize a diverse family of molecules produced by viruses, bacteria and fungi. This article will present evidence that TLRs also play a dominant role in innate responses to non-infectious immunostimulatory materials present in house dust extracts (HDEs) and the living environments they represent. However, our investigations challenge the commonly...

  7. Evasion of Influenza A Viruses from Innate and Adaptive Immune Responses

    OpenAIRE

    van de Sandt, Carolien E.; Kreijtz, Joost H. C. M.; Rimmelzwaan, Guus F.

    2012-01-01

    textabstractThe influenza A virus is one of the leading causes of respiratory tract infections in humans. Upon infection with an influenza A virus, both innate and adaptive immune responses are induced. Here we discuss various strategies used by influenza A viruses to evade innate immune responses and recognition by components of the humoral and cellular immune response, which consequently may result in reduced clearing of the virus and virus-infected cells. Finally, we discuss how the curren...

  8. Exploring Anopheles gut bacteria for Plasmodium blocking activity

    Science.gov (United States)

    Bahia, Ana C; Dong, Yuemei; Blumberg, Benjamin J; Mlambo, Godfree; Tripathi, Abhai; BenMarzouk-Hidalgo, Omar J; Chandra, Ramesh; Dimopoulos, George

    2014-01-01

    SUMMARY Malaria parasite transmission requires the successful development of Plasmodium gametocytes into flagellated microgametes upon mosquito blood ingestion, and the subsequent fertilization of microgametes and macrogametes for the development of motile zygotes, called ookinetes, which invade and transverse the Anopheles vector mosquito midgut at around 18-36 h after blood ingestion. Within the mosquito midgut, the malaria parasite has to withstand the mosquito's innate immune response and the detrimental effect of its commensal bacterial flora. We have assessed the midgut colonization capacity of 5 gut bacterial isolates from field-derived, and 2 from laboratory colony, mosquitoes and their effect on Plasmodium development in vivo and in vitro, along with their impact on mosquito survival. Some bacterial isolates activated the mosquito's immune system, affected the mosquito's life span, and were capable of blocking Plasmodium development. We have also shown that the ability of these bacteria to inhibit the parasites is likely to involve different mechanisms and factors. A Serratia marcescens isolate was particularly efficient in colonizing the mosquitoes’ gut, compromising mosquito survival, and inhibiting both sexual- and asexual-stage Plasmodium through secreted factors, thereby rendering it a potential candidate for the development of a malaria transmission intervention strategy. PMID:24428613

  9. MicroRNA in innate immunity and autophagy during mycobacterial infection.

    Science.gov (United States)

    Kim, Jin Kyung; Kim, Tae Sung; Basu, Joyoti; Jo, Eun-Kyeong

    2017-01-01

    The fine-tuning of innate immune responses is an important aspect of host defenses against mycobacteria. MicroRNAs (miRNAs), small non-coding RNAs, play essential roles in regulating multiple biological pathways including innate host defenses against various infections. Accumulating evidence shows that many miRNAs regulate the complex interplay between mycobacterial survival strategies and host innate immune pathways. Recent studies have contributed to understanding the role of miRNAs, the levels of which can be modulated by mycobacterial infection, in tuning host autophagy to control bacterial survival and innate effector function. Despite considerable efforts devoted to miRNA profiling over the past decade, further work is needed to improve the selection of appropriate biomarkers for tuberculosis. Understanding the roles and mechanisms of miRNAs in regulating innate immune signaling and autophagy may provide insights into new therapeutic modalities for host-directed anti-mycobacterial therapies. Here, we present a comprehensive review of the recent literature regarding miRNA profiling in tuberculosis and the roles of miRNAs in modulating innate immune responses and autophagy defenses against mycobacterial infections. © 2016 John Wiley & Sons Ltd.

  10. The Role of TOX in the Development of Innate Lymphoid Cells

    Directory of Open Access Journals (Sweden)

    Corey R. Seehus

    2015-01-01

    Full Text Available TOX, an evolutionarily conserved member of the HMG-box family of proteins, is essential for the development of various cells of both the innate and adaptive immune system. TOX is required for the development of CD4+ T lineage cells in the thymus, including natural killer T and T regulatory cells, as well as development of natural killer cells and fetal lymphoid tissue inducer cells, the latter required for lymph node organogenesis. Recently, we have identified a broader role for TOX in the innate immune system, demonstrating that this nuclear protein is required for generation of bone marrow progenitors that have potential to give rise to all innate lymphoid cells. Innate lymphoid cells, classified according to transcription factor expression and cytokine secretion profiles, derive from common lymphoid progenitors in the bone marrow and require Notch signals for their development. We discuss here the role of TOX in specifying CLP toward an innate lymphoid cell fate and hypothesize a possible role for TOX in regulating Notch gene targets during innate lymphoid cell development.

  11. Trade-offs between acquired and innate immune defenses in humans

    Science.gov (United States)

    McDade, Thomas W.; Georgiev, Alexander V.; Kuzawa, Christopher W.

    2016-01-01

    Immune defenses provide resistance against infectious disease that is critical to survival. But immune defenses are costly, and limited resources allocated to immunity are not available for other physiological or developmental processes. We propose a framework for explaining variation in patterns of investment in two important subsystems of anti-pathogen defense: innate (non-specific) and acquired (specific) immunity. The developmental costs of acquired immunity are high, but the costs of maintenance and activation are relatively low. Innate immunity imposes lower upfront developmental costs, but higher operating costs. Innate defenses are mobilized quickly and are effective against novel pathogens. Acquired responses are less effective against novel exposures, but more effective against secondary exposures due to immunological memory. Based on their distinct profiles of costs and effectiveness, we propose that the balance of investment in innate versus acquired immunity is variable, and that this balance is optimized in response to local ecological conditions early in development. Nutritional abundance, high pathogen exposure and low signals of extrinsic mortality risk during sensitive periods of immune development should all favor relatively higher levels of investment in acquired immunity. Undernutrition, low pathogen exposure, and high mortality risk should favor innate immune defenses. The hypothesis provides a framework for organizing prior empirical research on the impact of developmental environments on innate and acquired immunity, and suggests promising directions for future research in human ecological immunology. PMID:26739325

  12. Does baseline innate immunity change with age? A multi-year study in great tits.

    Science.gov (United States)

    Vermeulen, Anke; Eens, Marcel; Van Dongen, Stefan; Müller, Wendt

    2017-06-01

    Throughout their life animals progressively accumulate mostly detrimental changes in cells, tissues and their functions, causing a decrease in individual performance and ultimately an increased risk of death. The latter may be amplified if it also leads to a deterioration of the immune system which forms the most important protection against the permanent threat of pathogens and infectious diseases. Here, we investigated how four baseline innate immune parameters (natural antibodies, complement activity, concentrations of haptoglobin and concentrations of nitric oxide) changed with age in free-living great tits (Parus major). We applied both cross-sectional and longitudinal approaches as birds were sampled for up to three years of their lives. Three out of the four selected innate immune parameters were affected by age. However, the shape of the response curves differed strongly among the innate immune parameters. Natural antibody levels increased during early life until mid-age to decrease thereafter when birds aged. Complement activity was highest in young birds, while levels slightly decreased with increasing age. Haptoglobin levels on the other hand, showed a linear, but highly variable increase with age, while nitric oxide concentrations were unaffected by age. The observed differences among the four studied innate immune traits not only indicate the importance of considering several immune traits at the same time, but also highlight the complexity of innate immunity. Unraveling the functional significance of the observed changes in innate immunity is thus a challenging next step. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Blocking device especially for circulating pumps

    International Nuclear Information System (INIS)

    Susil, J.; Vychodil, V.; Lorenc, P.

    1976-01-01

    The claim of the invention is a blocking device which blocks reverse flow occurring after the shutdown of circulating pumps, namely in the operation of nuclear power plants or in pumps with a high delivery head. (F.M.)

  14. Demographic Data - MDC_BlockGroup

    Data.gov (United States)

    NSGIC Local Govt | GIS Inventory — A polygon feature class of Miami-Dade County Census 2000 Block Groups. A census Block Group is a statistical subdivision of a census Tract consisting of a cluster of...

  15. Dissecting Phaseolus vulgaris Innate Immune System against Colletotrichum lindemuthianum Infection

    Science.gov (United States)

    Chowdhury, Bablu; Caldas, Danielle Gregório Gomes; Tsai, Siu Mui; Camargo, Luis Eduardo Aranha; Melotto, Maeli

    2012-01-01

    the molecular components of the bean innate immune system regulated upon pathogen attack. PMID:22912818

  16. Targeting the innate repair receptor to treat neuropathy

    Directory of Open Access Journals (Sweden)

    Albert Dahan

    2016-07-01

    Full Text Available Abstract. The innate repair receptor (IRR is a heteromer of the erythropoietin receptor and the β-common (CD131 receptor, which simultaneously activates anti-inflammatory and tissue repair pathways. Experimental data suggest that after peripheral nerve injury, the IRR is upregulated in the spinal cord and modulates the neurogenic inflammatory response. The recently introduced selective IRR agonist ARA290 is an 11-amino acid peptide initially tested in animal models of neuropathy. After sciatic nerve injury, ARA290 produced a rapid and long-term relief of mechanical and cold allodynia in normal mice, but not in animals with a β-common receptor knockout phenotype. In humans, ARA290 has been evaluated in patients with small fiber neuropathy associated with sarcoidosis or type 2 diabetes (T2D mellitus. In patients with sarcoidosis, ARA290 significantly improved neuropathic and autonomic symptoms, as well as quality of life as assessed by the small fiber neuropathy screening list questionnaire. In addition, ARA290 treatment for 28 days initiated a regrowth of small nerve fibers in the cornea, but not in the epidermis. In patients with T2D, the results were similar to those observed in patients with sarcoidosis along with an improved metabolic profile. In both populations, ARA290 lacked significant adverse effects. These experimental and clinical studies show that ARA290 effectively reprograms a proinflammatory, tissue-damaging milieu into one of healing and tissue repair. Further clinical trials with long-term treatment and follow-up are needed to assess the full potential of IRR activation by ARA290 as a disease-modifying therapy in neuropathy of various etiologies.

  17. Escherichia coli ghosts promote innate immune responses in human keratinocytes.

    Science.gov (United States)

    Abtin, Arby; Kudela, Pavol; Mayr, Ulrike Beate; Koller, Verena Juliana; Mildner, Michael; Tschachler, Erwin; Lubitz, Werner

    2010-09-10

    Bacterial ghosts (BGs) as non-living bacterial envelopes devoid of cytoplasmic content with preserved and intact inner and outer membrane structures of their living counterparts have been used to study the ability of their surface components for the induction of antimicrobial peptides and pro-inflammatory cytokines in human primary keratinocytes (KCs). Quantitative real-time PCR analysis revealed that incubation of KCs with BGs generated from wild-type Escherichia coli induced the mRNA expression of antimicrobial psoriasin (S100A7c) in a BGs particle concentration-dependent manner. Using immunoblot analysis we showed that BGs generated from the flagellin-deficient (ΔFliC) E. coli strain NK9375 were as effective as its isogenic wild-type (wt) E. coli strain NK9373 to induce psoriasin expression when normalized to BG particles being taken up by KCs. However, results obtained from endocytic activity of KCs reflect that internalization of BGs is greatly dependent on the presence of flagellin on the surface of BGs. Moreover, BGs derived from wt E. coli NK9373 strongly induced the release of the pro-inflammatory cytokines IL-6 and IL-8, compared to ΔFliC E. coli NK9375 BGs. Taken together, obtained data demonstrate that non-living BGs possessing all bacterial bio-adhesive surface properties in their original state while not posing any infectious threat have the capacity to induce the expression of innate immune modulators and that these responses are partially dependent on the presence of flagellin. Copyright © 2010 Elsevier Inc. All rights reserved.

  18. Mechanisms by which Porphyromonas gingivalis evades innate immunity.

    Directory of Open Access Journals (Sweden)

    Kaveh Abdi

    Full Text Available The oral cavity is home to unique resident microbial communities whose interactions with host immunity are less frequently studied than those of the intestinal microbiome. We examined the stimulatory capacity and the interactions of two oral bacteria, Porphyromonas gingivalis (P. gingivalis and Fusobacterium nucleatum (F. nucleatum, on Dendritic Cell (DC activation, comparing them to the effects of the well-studied intestinal microbe Escherichia coli (E. coli. Unlike F. nucleatum and E. coli, P. gingivalis failed to activate DCs, and in fact silenced DC responses induced by F. nucleatum or E. coli. We identified a variant strain of P. gingivalis (W50 that lacked this immunomodulatory activity. Using biochemical approaches and whole genome sequencing to compare the two substrains, we found a point mutation in the hagA gene. This protein is though to be involved in the alteration of the PorSS/gingipain pathway, which regulates protein secretion into the extracellular environment. A proteomic comparison of the secreted products of the two substrains revealed enzymatic differences corresponding to this phenotype. We found that P. gingivalis secretes gingipain(s that inactivate several key proinflammatory mediators made by DCs and/or T cells, but spare Interleukin-1 (IL-1 and GM-CSF, which can cause capillary leaks that serve as a source of the heme that P. gingivalis requires for its survival, and GM-CSF, which can cause epithelial-cell growth. Taken together, our results suggest that P. gingivalis has evolved potent mechanisms to modulate its virulence factors and dampen the innate immune response by selectively inactivating most proinflammatory cytokines.

  19. Of pheromones and kairomones: what receptors mediate innate emotional responses?

    Science.gov (United States)

    Fortes-Marco, Lluis; Lanuza, Enrique; Martinez-Garcia, Fernando

    2013-09-01

    Some chemicals elicit innate emotionally laden behavioral responses. Pheromones mediate sexual attraction, parental care or agonistic confrontation, whereas predators' kairomones elicit defensive behaviors in their preys. This essay explores the hypothesis that the detection of these semiochemicals relies on highly specific olfactory and/or vomeronasal receptors. The V1R, V2R, and formyl-peptide vomeronasal receptors bind their ligands in highly specific and sensitive way, thus being good candidates for pheromone- or kairomone-detectors (e.g., secreted and excreted proteins, peptides and lipophilic volatiles). The olfactory epithelium also expresses specific receptors, for example trace amine-associated receptors (TAAR) and guanylyl cyclase receptors (GC-D and other types), some of which bind kairomones and putative pheromones. However, most of the olfactory neurons express canonical olfactory receptors (ORs) that bind many ligands with different affinity, being not suitable for mediating responses to pheromones and kairomones. In this respect, trimethylthiazoline (TMT) is considered a fox-derived kairomone for mice and rats, but it seems to be detected by canonical ORs. Therefore, we have reassessed the kairomonal nature of TMT by analyzing the behavioral responses of outbred (CD1) and inbred mice (C57BL/J6) to TMT. Our results confirm that both mouse strains avoid TMT, which increases immobility in C57BL/J6, but not CD1 mice. However, mice of both strains sniff at TMT throughout the test and show no trace of TMT-induced contextual conditioning (immobility or avoidance). This suggests that TMT is not a kairomone but, similar to a loud noise, in high concentrations it induces aversion and stress as unspecific responses to a strong olfactory stimulation. Copyright © 2013 Wiley Periodicals, Inc.

  20. Innate Synchronous Oscillations in Freely-Organized Small Neuronal Circuits

    Science.gov (United States)

    Shein Idelson, Mark; Ben-Jacob, Eshel; Hanein, Yael

    2010-01-01

    Background Information processing in neuronal networks relies on the network's ability to generate temporal patterns of action potentials. Although the nature of neuronal network activity has been intensively investigated in the past several decades at the individual neuron level, the underlying principles of the collective network activity, such as the synchronization and coordination between neurons, are largely unknown. Here we focus on isolated neuronal clusters in culture and address the following simple, yet fundamental questions: What is the minimal number of cells needed to exhibit collective dynamics? What are the internal temporal characteristics of such dynamics and how do the temporal features of network activity alternate upon crossover from minimal networks to large networks? Methodology/Principal Findings We used network engineering techniques to induce self-organization of cultured networks into neuronal clusters of different sizes. We found that small clusters made of as few as 40 cells already exhibit spontaneous collective events characterized by innate synchronous network oscillations in the range of 25 to 100 Hz. The oscillation frequency of each network appeared to be independent of cluster size. The duration and rate of the network events scale with cluster size but converge to that of large uniform networks. Finally, the investigation of two coupled clusters revealed clear activity propagation with master/slave asymmetry. Conclusions/Significance The nature of the activity patterns observed in small networks, namely the consistent emergence of similar activity across networks of different size and morphology, suggests that neuronal clusters self-regulate their activity to sustain network bursts with internal oscillatory features. We therefore suggest that clusters of as few as tens of cells can serve as a minimal but sufficient functional network, capable of sustaining oscillatory activity. Interestingly, the frequencies of these

  1. The Behavioural Biogeosciences: Moving Beyond Evolutionary Adaptation and Innate Reasoning

    Science.gov (United States)

    Glynn, P. D.

    2014-12-01

    Human biases and heuristics reflect adaptation over our evolutionary past to frequently experienced situations that affected our survival and that provided sharp distinguished feedbacks at the level of the individual. Human behavior, however, is not well adapted to the more diffusely experienced (i.e. less immediately/locally acute) problems and issues that scientists and society often seek to address today. Several human biases are identified that affect how science is conducted and used. These biases include an innate discounting of less visible phenomena/systems and of long-term perspectives; as well as a general lack of consideration of the coupling between the resources that we use and the waste that we consequently produce. Other biases include strong beliefs in human exceptionalism and separatedness from "nature". Francis Bacon (The New Organon, 1620) provided a classification of the factors, of the "idols of the mind", that bias pursuit of greater knowledge. How can we address these biases and the factors that affect behaviour and pursuit of knowledge; and ultimately impact the sustainability and resilience of human societies, resources and environments? A process for critical analysis is proposed that solicits explicit accounting and cognizance of these potential human biases and factors. Seeking a greater diversity of independant perspectives is essential: in both the conduct of science and in its application to the management of natural resources and environments. Accountability, traceability and structured processes are critical in this endeavor. The scientific methods designed during the industrial revolution are necessary, but insufficient, in addressing the issues of today. A new area of study in "the behavioral biogeosciences" is suggested that counters, or at least closely re-evaluates, our normal (i.e. adapted) human priorities of observation and study, as well as our judgements and decision-making.

  2. Used, Blocking and Sleeping Patents

    DEFF Research Database (Denmark)

    Torrisi, Salvatore; Gambardella, Alfonso; Giuri, Paola

    2016-01-01

    patents are being utilized. A substantial share of patents is neither used internally nor for market transactions, which confirms the importance of strategic patenting and inefficiency in the management of intellectual property. We investigate different types of unused patents—unused blocking patents...... and sleeping patents. We also examine the association between used and unused patents and their characteristics such as family size, scope, generality and overlapping claims, technology area, type of applicant, and the competitive environment from where these patents originate. We discuss our results...

  3. Large block test status report

    International Nuclear Information System (INIS)

    Wilder, D.G.; Lin, W.; Blair, S.C.

    1997-01-01

    This report is intended to serve as a status report, which essentially transmits the data that have been collected to date on the Large Block Test (LBT). The analyses of data will be performed during FY98, and then a complete report will be prepared. This status report includes introductory material that is not needed merely to transmit data but is available at this time and therefore included. As such, this status report will serve as the template for the future report, and the information is thus preserved

  4. Micellization and Dynamics of a Block Copolymer

    DEFF Research Database (Denmark)

    Hvidt, Søren

    2006-01-01

    Triblock copolymers of the type EPE, where E and P denote ethylene oxide and propylene oxide blocks, respectively, are industrially important copolymers often called Pluronics or Poloxamers. EPE copolymers form micelles with a core of P blocks and different micellar shapes depending on block leng...

  5. 31 CFR 515.319 - Blocked account.

    Science.gov (United States)

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Blocked account. 515.319 Section 515... § 515.319 Blocked account. The term blocked account shall mean an account in which any designated national has an interest, with respect to which account payments, transfers or withdrawals or other...

  6. 31 CFR 500.319 - Blocked account.

    Science.gov (United States)

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Blocked account. 500.319 Section 500... § 500.319 Blocked account. The term blocked account shall mean an account in which any designated national has an interest, with respect to which account payments, transfers or withdrawals of other...

  7. Bullet-Block Science Video Puzzle

    Science.gov (United States)

    Shakur, Asif

    2015-01-01

    A science video blog, which has gone viral, shows a wooden block shot by a vertically aimed rifle. The video shows that the block hit dead center goes exactly as high as the one shot off-center. (Fig. 1). The puzzle is that the block shot off-center carries rotational kinetic energy in addition to the gravitational potential energy. This leads a…

  8. 21 CFR 882.5070 - Bite block.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Bite block. 882.5070 Section 882.5070 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES NEUROLOGICAL DEVICES Neurological Therapeutic Devices § 882.5070 Bite block. (a) Identification. A bite block...

  9. Isostatic compression of buffer blocks. Middle scale

    International Nuclear Information System (INIS)

    Ritola, J.; Pyy, E.

    2012-01-01

    Manufacturing of buffer components using isostatic compression method has been studied in small scale in 2008 (Laaksonen 2010). These tests included manufacturing of buffer blocks using different bentonite materials and different compression pressures. Isostatic mould technology was also tested, along with different methods to fill the mould, such as vibration and partial vacuum, as well as a stepwise compression of the blocks. The development of manufacturing techniques has continued with small-scale (30 %) blocks (diameter 600 mm) in 2009. This was done in a separate project: Isostatic compression, manufacturing and testing of small scale (D = 600 mm) buffer blocks. The research on the isostatic compression method continued in 2010 in a project aimed to test and examine the isostatic manufacturing process of buffer blocks at 70 % scale (block diameter 1200 to 1300 mm), and the aim was to continue in 2011 with full-scale blocks (diameter 1700 mm). A total of nine bentonite blocks were manufactured at 70 % scale, of which four were ring-shaped and the rest were cylindrical. It is currently not possible to manufacture full-scale blocks, because there is no sufficiently large isostatic press available. However, such a compression unit is expected to be possible to use in the near future. The test results of bentonite blocks, produced with an isostatic pressing method at different presses and at different sizes, suggest that the technical characteristics, for example bulk density and strength values, are somewhat independent of the size of the block, and that the blocks have fairly homogenous characteristics. Water content and compression pressure are the two most important properties determining the characteristics of the compressed blocks. By adjusting these two properties it is fairly easy to produce blocks at a desired density. The commonly used compression pressure in the manufacturing of bentonite blocks is 100 MPa, which compresses bentonite to approximately

  10. Coastal protection using topological interlocking blocks

    Science.gov (United States)

    Pasternak, Elena; Dyskin, Arcady; Pattiaratchi, Charitha; Pelinovsky, Efim

    2013-04-01

    The coastal protection systems mainly rely on the self-weight of armour blocks to ensure its stability. We propose a system of interlocking armour blocks, which form plate-shape assemblies. The shape and the position of the blocks are chosen in such a way as to impose kinematic constraints that prevent the blocks from being removed from the assembly. The topological interlocking shapes include simple convex blocks such as platonic solids, the most practical being tetrahedra, cubes and octahedra. Another class of topological interlocking blocks is so-called osteomorphic blocks, which form plate-like assemblies tolerant to random block removal (almost 25% of blocks need to be removed for the assembly to loose integrity). Both classes require peripheral constraint, which can be provided either by the weight of the blocks or post-tensioned internal cables. The interlocking assemblies provide increased stability because lifting one block involves lifting (and bending) the whole assembly. We model the effect of interlocking by introducing an equivalent additional self-weight of the armour blocks. This additional self-weight is proportional to the critical pressure needed to cause bending of the interlocking assembly when it loses stability. Using beam approximation we find an equivalent stability coefficient for interlocking. It is found to be greater than the stability coefficient of a structure with similar blocks without interlocking. In the case when the peripheral constraint is provided by the weight of the blocks and for the slope angle of 45o, the effective stability coefficient for a structure of 100 blocks is 33% higher than the one for a similar structure without interlocking. Further increase in the stability coefficient can be reached by a specially constructed peripheral constraint system, for instance by using post-tension cables.

  11. Isostatic compression of buffer blocks. Middle scale

    Energy Technology Data Exchange (ETDEWEB)

    Ritola, J.; Pyy, E. [VTT Technical Research Centre of Finland, Espoo (Finland)

    2012-01-15

    Manufacturing of buffer components using isostatic compression method has been studied in small scale in 2008 (Laaksonen 2010). These tests included manufacturing of buffer blocks using different bentonite materials and different compression pressures. Isostatic mould technology was also tested, along with different methods to fill the mould, such as vibration and partial vacuum, as well as a stepwise compression of the blocks. The development of manufacturing techniques has continued with small-scale (30 %) blocks (diameter 600 mm) in 2009. This was done in a separate project: Isostatic compression, manufacturing and testing of small scale (D = 600 mm) buffer blocks. The research on the isostatic compression method continued in 2010 in a project aimed to test and examine the isostatic manufacturing process of buffer blocks at 70 % scale (block diameter 1200 to 1300 mm), and the aim was to continue in 2011 with full-scale blocks (diameter 1700 mm). A total of nine bentonite blocks were manufactured at 70 % scale, of which four were ring-shaped and the rest were cylindrical. It is currently not possible to manufacture full-scale blocks, because there is no sufficiently large isostatic press available. However, such a compression unit is expected to be possible to use in the near future. The test results of bentonite blocks, produced with an isostatic pressing method at different presses and at different sizes, suggest that the technical characteristics, for example bulk density and strength values, are somewhat independent of the size of the block, and that the blocks have fairly homogenous characteristics. Water content and compression pressure are the two most important properties determining the characteristics of the compressed blocks. By adjusting these two properties it is fairly easy to produce blocks at a desired density. The commonly used compression pressure in the manufacturing of bentonite blocks is 100 MPa, which compresses bentonite to approximately

  12. Characterization of Ixodes ricinus Fibrinogen-Related Proteins (Ixoderins Discloses Their Function in the Tick Innate Immunity

    Directory of Open Access Journals (Sweden)

    Helena Honig Mondekova

    2017-12-01

    Full Text Available Ticks are important vectors of serious human and animal disease-causing organisms, but their innate immunity can fight invading pathogens and may have the ability to reduce or block transmission to mammalian hosts. Lectins, sugar-binding proteins, can distinguish between self and non-self-oligosaccharide motifs on pathogen surfaces. Although tick hemolymph possesses strong lectin activity, and several lectins have already been isolated and characterized, little is known about the implementation of these molecules in tick immunity. Here, we have described and functionally characterized fibrinogen-related protein (FReP lectins in Ixodes ticks. We have shown that the FReP family contains at least 27 genes (ixoderins, ixo that could, based on phylogenetic and expression analyses, be divided into three groups with differing degrees of expansion. By using RNA interference-mediated gene silencing (RNAi we demonstrated that IXO-A was the main lectin in tick hemolymph. Further, we found that ixoderins were important for phagocytosis of Gram-negative bacteria and yeasts by tick hemocytes and that their expression was upregulated upon injection of microbes, wounding, or after blood feeding. However, although the tick hemocytes could swiftly phagocytose Borrelia afzelii spirochetes, their transmission and burst of infection in mice was not altered. Our results demonstrate that tick ixoderins are crucial immune proteins that work as opsonins in the tick hemolymph, targeting microbes for phagocytosis or lysis.

  13. ICOS:ICOS-ligand interaction is required for type 2 innate lymphoid cell function, homeostasis, and induction of airway hyperreactivity.

    Science.gov (United States)

    Maazi, Hadi; Patel, Nisheel; Sankaranarayanan, Ishwarya; Suzuki, Yuzo; Rigas, Diamanda; Soroosh, Pejman; Freeman, Gordon J; Sharpe, Arlene H; Akbari, Omid

    2015-03-17

    Allergic asthma is caused by Th2-cell-type cytokines in response to allergen exposure. Type 2 innate lymphoid cells (ILC2s) are a newly identified subset of immune cells that, along with Th2 cells, contribute to the pathogenesis of asthma by producing copious amounts of IL-5 and IL-13, which cause eosinophilia and airway hyperreactivity (AHR), a cardinal feature of asthma. ILC2s express ICOS, a T cell costimulatory molecule with a currently unknown function. Here we showed that a lack of ICOS on murine ILC2s and blocking the ICOS:ICOS-ligand interaction in human ILC2s reduced AHR and lung inflammation. ILC2s expressed both ICOS and ICOS-ligand, and the ICOS:ICOS-ligand interaction promoted cytokine production and survival in ILC2s through STAT5 signaling. Thus, ICOS:ICOS-ligand signaling pathway is critically involved in ILC2 function and homeostasis. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Live imaging of innate immune cell sensing of transformed cells in zebrafish larvae: parallels between tumor initiation and wound inflammation.

    Directory of Open Access Journals (Sweden)

    Yi Feng

    Full Text Available It has not previously been possible to live image the earliest interactions between the host environment and oncogene-transformed cells as they initiate formation of cancers within an organism. Here we take advantage of the translucency of zebrafish larvae to observe the host innate immune cell response as oncogene-transformed melanoblasts and goblet cells multiply within the larval skin. Our studies indicate activation of leukocytes at very early stages in larvae carrying a transformed cell burden. Locally, we see recruitment of neutrophils and macrophages by 48 h post-fertilization, when transformed cells are still only singletons or doublets, and soon after this we see intimate associations between immune and transformed cells and frequent examples of cytoplasmic tethers linking the two cell types, as well as engulfment of transformed cells by both neutrophils and macrophages. We show that a major component of the signal drawing inflammatory cells to oncogenic HRAS(G12V-transformed cells is H(2O(2, which is also a key damage cue responsible for recruiting neutrophils to a wound. Our short-term blocking experiments show that preventing recruitment of immune cells at these early stages results in reduced growth of transformed cell clones and suggests that immune cells may provide a source of trophic support to the transformed cells just as they do at a site of tissue repair. These parallels between the inflammatory responses to transformed cells and to wounds reinforce the suggestion by others that cancers resemble non-healing wounds.

  15. Randomized Block Cubic Newton Method

    KAUST Repository

    Doikov, Nikita

    2018-02-12

    We study the problem of minimizing the sum of three convex functions: a differentiable, twice-differentiable and a non-smooth term in a high dimensional setting. To this effect we propose and analyze a randomized block cubic Newton (RBCN) method, which in each iteration builds a model of the objective function formed as the sum of the natural models of its three components: a linear model with a quadratic regularizer for the differentiable term, a quadratic model with a cubic regularizer for the twice differentiable term, and perfect (proximal) model for the nonsmooth term. Our method in each iteration minimizes the model over a random subset of blocks of the search variable. RBCN is the first algorithm with these properties, generalizing several existing methods, matching the best known bounds in all special cases. We establish ${\\\\cal O}(1/\\\\epsilon)$, ${\\\\cal O}(1/\\\\sqrt{\\\\epsilon})$ and ${\\\\cal O}(\\\\log (1/\\\\epsilon))$ rates under different assumptions on the component functions. Lastly, we show numerically that our method outperforms the state-of-the-art on a variety of machine learning problems, including cubically regularized least-squares, logistic regression with constraints, and Poisson regression.

  16. ALS insertion device block measurement and inspection

    International Nuclear Information System (INIS)

    Marks, S.; Carrieri, J.; Cook, C.; Hassenzahl, W.V.; Hoyer, E.; Plate, D.

    1991-05-01

    The performance specifications for ALS insertion devices require detailed knowledge and strict control of the Nd-Fe-B permanent magnet blocks incorporated in these devices. This paper describes the measurement and inspection apparatus and the procedures designed to qualify and characterize these blocks. A detailed description of a new, automated Helmholtz coil facility for measurement of the three components of magnetic moment is included. Physical block inspection and magnetic moment measurement procedures are described. Together they provide a basis for qualifying blocks and for specifying placement of blocks within an insertion devices' magnetic structures. 1 ref., 4 figs

  17. Adaptive motion compensation without blocking artifacts

    Science.gov (United States)

    Terriberry, Timothy B.

    2015-03-01

    The Block Matching Algorithms used in most popular video codec standards introduce blocking artifacts which must be removed via residual coding or deblocking filters. Alternative transform stages that do not cause blocking artifacts, such as lapped transforms or wavelets, require motion compensation methods that do not produce blocking artifacts, since they are expensive to remove. We design a new Overlapped Block Motion Compensation (OBMC) scheme that avoids these artifacts while allowing adaptive blending window sizes. This has the potential to show significant visual quality improvements over traditional OBMC.

  18. Misgivings about the Matching Familiar Figures Test: A Brief Reply to Block, Gjerde, and Block (1986).

    Science.gov (United States)

    Kagan, Jerome

    1987-01-01

    Reply by Jerome Kagan to a recent article by Block, Gjerde, and Block (1986) which questions the validity of the construct of reflection-impulsivity. Kagan alleges flaws in the logic of the authors' (Block, Gjerde, Block) position and in the inferences drawn from their data. (Author/RWB)

  19. 31 CFR 544.204 - Expenses of maintaining blocked physical property; liquidation of blocked property.

    Science.gov (United States)

    2010-07-01

    ... physical property; liquidation of blocked property. 544.204 Section 544.204 Money and Finance: Treasury... maintaining blocked physical property; liquidation of blocked property. (a) Except as otherwise authorized..., all expenses incident to the maintenance of physical property blocked pursuant to § 544.201(a) shall...

  20. 31 CFR 547.204 - Expenses of maintaining blocked physical property; liquidation of blocked property.

    Science.gov (United States)

    2010-07-01

    ... physical property; liquidation of blocked property. 547.204 Section 547.204 Money and Finance: Treasury... maintaining blocked physical property; liquidation of blocked property. (a) Except as otherwise authorized..., all expenses incident to the maintenance of physical property blocked pursuant to § 547.201(a) shall...