In this center grant we propose to study interactions of Category A, B and C viruses with human primary cells resulting in induction of innate and adaptive immune responses. Our investigations will be focused on viral mechanisms of induction and subversion of 1) type 1 interferon responses and 2) maturation of dendritic cells and the impact that these processes have on adaptive immunity. This will be done through the development of novel technologies that will provide a comprehensive profile of human responses to viral pathogens. Although it has become apparent that most if not all viruses encode gene products implicated in evasion of immunity, very little is known of the impact of these viral genes on the human immune response. We are planning to establish assays that will 1) identify and characterize viral inhibitors of immune function using chimeric viruses expressing such antagonists; 2) generate a molecular depiction of the induction of the human immune response against viruses at three stages: innate immunity, the innate-adaptive interface, and adaptive immunity. This will be done by characterizing the kinetics of the cellular response to viral infection at the levels of gene transcription, IFN signaling, cytokine/cell surface marker expression and peptide presentation; and 3) attempt to identify human gene polymorphisms that impact the levels of transcription of critical genes involved in the induction of the immune response. The technology developed will be utilized by other members of the center to study NIAID priority pathogens. Project 1 investigates the highly lethal Nipah virus, a zoonotic paramyxovirus, to precisely define the mechanisms of action of four viral proteins (P,V,W, and C) shown to inhibit innate immunity. Project 2 investigates the role that different proteins encoded by Ebola virus have on modulation of dendritic cell function, which appears to be affected during natural infections with this hemorrhagic negative strand RNA virus. In Project 3, the IFN antagonist protein NS1 of influenza virus is investigated with respect to its ability to attenuate innate immunity, dendritic cell maturation and stimulation of T cells. Reliable access to human samples required for both the technological and research projects is provided by the clinical core , which in addition will generate a database of patient clinical histories that will be invaluable for interpretation of differences in immune responses among individuals. Administrative core will oversee and coordinate the research projects and technology development components of this application, and organize joint meetings to guarantee a better synergism among these components. The information and resources gathered by our proposed center will be used to facilitate research in human-pathogen interactions, as exemplified by the support of pilot projects on several category A-C pathogens. Our proposed studies will expand our understanding of human immune responses to virus infection at the cellular level and of the mechanism of action and the impact on adaptive immunity and pathogenicity of viral genes that antagonize the type 1 IFN response. In addition, the developed technology will facilitate the analysis of human/pathogen interactions that modulate the innate and adaptive immune response.
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