Establishing a Role for Intrinsic Immunity to Influenza A Virus Infection PDF Download
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Author: Matthew Charman
Publisher:
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Languages : en
Pages :
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Author: Matthew Charman
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Languages : en
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Author: Ann Arvin
Publisher: Cambridge University Press
ISBN: 1139461648
Category : Medical
Languages : en
Pages : 1325
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This comprehensive account of the human herpesviruses provides an encyclopedic overview of their basic virology and clinical manifestations. This group of viruses includes human simplex type 1 and 2, Epstein–Barr virus, Kaposi's Sarcoma-associated herpesvirus, cytomegalovirus, HHV6A, 6B and 7, and varicella-zoster virus. The viral diseases and cancers they cause are significant and often recurrent. Their prevalence in the developed world accounts for a major burden of disease, and as a result there is a great deal of research into the pathophysiology of infection and immunobiology. Another important area covered within this volume concerns antiviral therapy and the development of vaccines. All these aspects are covered in depth, both scientifically and in terms of clinical guidelines for patient care. The text is illustrated generously throughout and is fully referenced to the latest research and developments.
Author: François Coulombe
Publisher:
ISBN:
Category :
Languages : en
Pages :
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"Influenza virus infection causes a complex respiratory disease inflicting a persistent threat to human health worldwide and presenting challenges to clinicians who are left with no available therapeutic interventions. The broad complexity of the disease is the consequence of host-pathogen interactions, which may result in severe influenza- associated illness and death. Severity of influenza infections correlates with the ability of the virus to reach and replicate within the lower respiratory tract, where it encounters alveolar macrophages. These cells reside in close contact with the respiratory epithelium of the lower airways and are the first immune cells to make contact with the influenza virus. Despite evidence showing their critical role in anti-viral immunity and in the maintenance of pulmonary homeostasis, the regulatory mechanisms that drive macrophage function during severe influenza virus infection are poorly defined.The first part of the work presented herein focuses on the function of host-derived lipid mediators, known as eicosanoids, in the regulation of macrophage function during influenza virus infection. Using mice deficient in various components of the eicosanoid biosynthesis pathways, we first established that influenza virus specifically hijacks the prostaglandin E2 pathway to subvert macrophage function and suppress both innate and adaptive immune responses. We identified two distinct pathways through which prostaglandin E2 paralyzed macrophage anti-viral immunity: type I interferon and apoptosis. The impairment of these two pathways severely hinders the innate immune response as type I interferon directly counteracts viral replication, while apoptosis blocks the cellular machinery crucial for viral amplification/dissemination. In addition, we found that prostaglandin E2 suppresses adaptive immunity to influenza virus infection. Importantly, prostaglandin E2-deficient mice were more protected against influenza and pharmacological inhibition of prostaglandin E2 recapitulated this protective effect against the virus.Next, we demonstrated that mice deficient in the 5-lipoxygenase pathway showed remarkable protection against influenza infection. This protection was associated with a concomitant lack of lipoxin A4 up-regulation in infected mice, as well as early expansion of granulocyte macrophage-colony stimulating factor (GM-CSF)-secreting alveolar macrophages in the airways. GM-CSF has a well-established protective role against pulmonary viral infection and specific inhibition of GM-CSF in 5-lipoxygenase deficient mice abrogated their protection against influenza.The second part of this thesis focuses on the consequences of macrophage death modality during the course of influenza virus infection. While host-induced apoptosis of infected cells is a mechanism to restrict viral replication, influenza virus paradoxically has been shown to induce early apoptosis in immune cells, especially in monocytes/macrophages, via its PB1-F2 accessory protein. Here, we demonstrate that the host NLRX1 receptor can effectively interact with the influenza virus pro-apoptotic protein PB1-F2 in macrophage mitochondria, thereby preventing PB1-F2-induced apoptosis and leading to increased type I interferon production by macrophages. The interaction between host NLRX1 and viral PB1-F2 in macrophages was furthermore critical for the control of influenza virus replication.Taken together, our results suggest that eicosanoids and apoptosis act in concert as critical regulators of macrophage-mediated immunity against severe influenza virus infection. We propose that macrophages act as the cellular switch initiating the pulmonary anti-viral responses by monitoring the balance between virus-triggered or host-triggered production of eicosanoids and induction of apoptosis. We further envision that immunotherapies targeting specific eicosanoids offer promising avenues for treatment of influenza and potentially other viral infections." --
Author: Jing Guan
Publisher:
ISBN: 9781361368121
Category :
Languages : en
Pages :
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This dissertation, "The Role of Virus-specific Human T Cells in Influenza A Virus Infection" by Jing, Guan, 管静, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Influenza A virus infection is a major cause of human morbidity and mortality. T cell immunity is believed to play critical roles for host defenses against influenza A infection. Once intracellular influenza A infection is established, viral clearance is mainly dependent on virus-specific CD8+ T cells. CD4+ T cells are important for adaptive immunity to natural influenza A infection or vaccination by providing help to B cells for antibody production and also providing help to CD8+ T cells for the generation of cytotoxicity. In addition, virusspecific CD4+ and CD8+ T cells are rich sources of effector cytokines, such as IFN-and TNF-, which can promote the function of antigen presenting cells and have direct antiviral activity. Cross-subtype reactive CD4+ and CD8+ memory T cells also affect the clearance of virus infection even in those who lack virus-specific antibodies. Therefore, the aim of our study is to assess the influenza virus-specific T cell responses and define their possible protective role in pandemic H1N1 virus and seasonal influenza infection in human. First we determined whether healthy adults have the cross-reactivity of memory CD4+ and CD8+ T cells against pandemic virus. In April of 2009, 7 pandemic H1N1 infected patients and 17 their healthy contacts who had no pandemic influenza infection were recruited in this study. By using intracellular IFN-staining and flow cytometry, we examined their pandemic H1N1 virus and seasonal influenza H1N1-specific CD4+ and CD8+ T cell responses. Healthy contacts did have measurable but low frequencies of cross-reactive influenza-specific CD4+ and CD8+ T cells, though the frequencies of these T cells specific to pandemic H1N1 virus were slightly lower than that specific to seasonal H1N1 virus. Furthermore, when compared the pandemic H1N1-specific T cell responses between healthy contacts and patients with pandemic H1N1 infection, we can found that the healthy contacts have higher pandemic H1N1 specific-T cell responses than patients, suggesting these pre-existing pandemic H1N1 specific-T cells may have protection from pandemic influenza virus infection. In addition, we conducted a prospective T cell immunity and influenza surveillance study in a cohort of more than 200 healthy volunteers before the influenza season and investigated whether the pre-existing T cell immunity is related to the protection from influenza infection in the next coming influenza season. Using intracellular IFN-staining assay, we examined their pre-existing seasonal influenza H1N1, H3N2, seasonal influenza B virus-specific CD4+ and CD8+ T cell responses. Due to the small number of cases of influenza infection in the coming influenza season, the results only showed a trend that the subjects who have higher frequency of influenza virus strain-specific T cells may have lower chance to suffer from same strain of influenza infection, which to some extent, reflect the pre-exist memory T cells have association with the protection in the coming influenza season. In conclusion, T cells play an important role in defensing against influenza infection. The higher influenza virus specific-T cells response activity in healthy adu
Author: David S. Hui
Publisher: European Respiratory Society
ISBN: 1849840709
Category : Medical
Languages : en
Pages : 148
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Viral respiratory tract infections are important and common causes of morbidity and mortality worldwide. In the past two decades, several novel viral respiratory infections have emerged with epidemic potential that threaten global health security. This Monograph aims to provide an up-to-date and comprehensive overview of severe acute respiratory syndrome, Middle East respiratory syndrome and other viral respiratory infections, including seasonal influenza, avian influenza, respiratory syncytial virus and human rhinovirus, through six chapters written by authoritative experts from around the globe.
Author: Heather M. Machkovech
Publisher:
ISBN:
Category :
Languages : en
Pages : 148
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There are numerous factors that direct and constrain influenza evolution. On the one hand influenza virus is constrained to encode proteins that allow it to complete the viral life cycle, but the immune system also recognizes those same viral proteins to mount an immune response. The interplay between selection for viral propagation and escape from immunity shapes the rapid evolution of influenza virus. In Chapter 2, I explore one of the immune pressures that drives influenza evolution. It is well known that antibodies are a driver of the rapid evolution of influenza. However, it was unknown whether CD8 T-cells, which are also a component of adaptive immunity to influenza, also shape influenza evolution. There is experimental support that CD8 T-cells help control influenza infection and there are even documented instances of mutations that confer escape from CD8 T-cells. However, conventional tests of selection consistently fail to find evidence that CD8 T-cells drive influenza evolution. Since CD8 T-cells tend to be found in regions that are fairly conserved in influenza, I hypothesized that CD8 T-cells are a selective pressure but that functional constraint masked our ability to detect such selection by conventional means. I therefore employed two novel statistical methods that have increased sensitivity to detect selection in influenza. I leveraged the existence of parallel lineages of influenza that infect different hosts with varying immune pressures to examine whether CD8 T-cells drive influenza evolution. I find statistical support that one influenza protein, nucleoprotein, is under selective pressure to evade the CD8 T-cell response. This means that the role of CD8 T-cells is sufficiently strong to shape the evolutionary trajectory of influenza virus. There is strong interest in generating vaccines with broad responses to influenza. Since T-cells are capable of eliciting broad responses, the finding that the biological role of T-cells is strong enough to shape influenza evolution validates the use of T-cells in the development of broad-acting vaccines. In Chapter 3, I explore translation initiation in the context of influenza virus infection. Because CD8 T-cells shape influenza evolution and non-canonical translation initiation can generate novel CD8 T-cell epitopes, I examined whether there was an evolutionary signature consistent with selection against alternate translation initiation in influenza virus. I find evolutionary support that is consistent with selection against alternate translation initiation of CTG codons in mammalian lineages of influenza. I then performed ribosome profiling, a deep sequencing technique that enables capture of ribosome protected frag- ments, to annotate sites of translation initiation in the influenza genome. I did not find evidence of CTG initiation in the influenza viral genome, but I did find a small number of alternate translation initiation sites at ATG codons in the influenza viral genome. One of these alternate initiation sites generates an N-terminally truncated form of neuraminidase (NA), the influenza protein that mediates viral egress. This N-terminally truncated NA lacks the first fourteen amino acids, but is enzymatically active, supports viral growth, and is broadly conserved in the N1 lineage. In the Discussion, I speculate about the possible discordance of the evolutionary results and ribosome profiling data. Overall, this work in- creases our understanding of the range of viral proteins that are generated in the compact influenza genome and uncovers new evolutionary signatures of influenza virus.
Author: Paula Maguire
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Influenza A virus (IAV) infection predisposes individuals to severe infections with bacteria such as Streptococcus pneumoniae (S.p.). Research shows that influenza infection impairs the T helper 17 (Th17) immune response, which is critical in the clearance of S.p. infections. Studies have demonstrated a role for type I Interferons in the impaired Th17 immunity associated with IAV. The results presented in this thesis demonstrate that IAV infection significantly impairs S.p. driven innate and adaptive cytokines. However, this inhibition occurred in the absence of type I Interferons, suggesting an additional mechanism of Th17 immunomodulation associated with IAV. To establish how IAV inhibits these responses, we investigated the effect of IAV infection on specific innate immune Toll Like Receptors (TLRs), which are triggered by S.p. infection. We have identified that IAV targets TLRs (TLR2, TLR4, TLR9) in human monocytes, resulting in a reduction in TLR-induced cytokines. The effect of IAV is more profound on the TLR2 and TLR9 pathways. We established IAV may be inhibiting the TLR9 pathway by targeting RORC, a Th17-specific transcription factor. We investigated if TLR5 agonism could restore IAV-inhibited immune responses. Levels of pneumococcus driven cytokines, which had previously been inhibited by IAV were not reduced in the presence of the TLR5 agonist, suggesting this may restore immune responses despite IAV inhibition. Finally, we sought to investigate the role of the influenza surface glycoprotein, haemagglutinin (HA) in innate and adaptive responses to S.p. and innate responses to TLR agonism. Pneumococcus driven innate and adaptive cytokines were significantly inhibited by HA, whilst certain TLR agonist driven cytokines were also inhibited by HA. Novel findings include determining that immune inhibition by IAV is not solely due to type I IFNs, and demonstrating that TLR5 agonism may be beneficial in circumventing immune inhibition by IAV and restoring Th17 responses.
Author: R. Ahmed
Publisher: Wiley-Blackwell
ISBN:
Category : Medical
Languages : en
Pages : 754
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Persistent Viral Infections Edited by Rafi Ahmed Emory Vaccine Center, Atlanta, USA and Irvin S. Y. Chen UCLA School of Medicine, Los Angeles, USA During the past decade much of our attention has focused on diseases associated with viral persistence. Major breakthroughs in immunology, and the advent of molecular approaches to study pathogenesis have increased our understanding of the complex virus-host interactions that occur during viral persistence. Persistent Viral Infections focuses on: * The pathogenesis and immunology of chronic infections * Animal models that provide, or have the potential to provide, major insights This volume will be essential reading for virologists, immunologists, oncologists and neurologists.
Author: Hiroshi Kiyono
Publisher: Elsevier
ISBN: 0080537057
Category : Medical
Languages : en
Pages : 501
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This comprehensive, authoritative treatise covers all aspects of mucosal vaccines including their development, mechanisms of action, molecular/cellular aspects, and practical applications. The contributing authors and editors of this one-of-a-kind book are very well known in their respective fields. Mucosal Vaccines is organized in a unique format in which basic, clinical, and practical aspects of the mucosal immune system for vaccine development are described and discussed. This project is endorsed by the Society for Mucosal Immunology. Provides the latest views on mucosal vaccines Applies basic principles to the development of new vaccines Links basic, clinical, and practical aspects of mucosal vaccines to different infectious diseases Unique and user-friendly organization
Author: Morris Pollard
Publisher:
ISBN:
Category : Medical
Languages : en
Pages : 322
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