Molecular Mechanisms of Filoviral-host Interactions

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Overall Project Summary/Abstract: Molecular mechanisms of filoviral-host interactions The family Filoviridae, which includes Ebola virus (EBOV) and Marburg virus (MARV), are zoonotic pathogens that cause outbreaks of severe human disease and require biosafety level 4 (BSL4) containment for study. Recent approval of a vaccine and antibody-based therapies against an EBOV represent progress towards medical countermeasures. However, the family is comprised of multiple antigenically distinct species, making identification of pan-filoviral therapeutic approaches desirable. Furthermore, the molecular mechanisms required for replication and pathogenesis are incompletely understood. Defining key filovirus-host interactions and the mechanisms by which they promote viral growth and disease will provide important insight into viral biology and suggest new therapeutic approaches. Existing data, including our own, have identified key host-viral interactions that likely play important roles in the pathogenesis of filovirus disease. Our overarching goal is to address this gap in knowledge by building and expanding upon the strong foundational knowledge on EBOV to define molecular mechanisms at the host-pathogen interface and to identify EBOV-specific and pan-filoviral interactions that contribute to pathogenesis. To achieve our goals, we have assembled a highly accomplished team with track records of effective synergistic collaboration and expertise ranging from molecular biochemistry, structural biology and mass spectrometry to cell biology, virology, and work at BSL4. In the current funding period, we identified multiple host pathways that impact EBOV infection and defined key interactions at the viral-host interface. In our proposed studies, we use a reductionist approach to define molecular mechanisms by biochemical and structural methods (Project 1; RP01), determine the cellular impact and contributions of viral proteins such as VP30 and VP24 in immune response, viral replication, assembly and egress (Project 2; RP02), and evaluate the impact of specific interactions with EBOV and MARV virus in cell culture and in vivo, including specific subnetworks that regulate filoviral entry and replication (Project 3; RP03). Recognizing the complexity of the data being generated we have recruited new expertise in proteomics and genetic network analysis to provide a deeper understanding of host-virus protein connectivity and interaction. These efforts will be further supported by two scientific cores, the Antibody and Reagent Development Core B and the BSL4/ABSL4 laboratory Core C. This work will be guided by an active Administrative Core A that will receive critical input from the Core A Advisory Group (CAAG) and the External Advisory Board (EAB). Each is comprised of preeminent scientists in academia and industry with strong productivity in emerging infectious diseases and immunology and significant advisory experience. Building on our productive initial work, we are poised to define a comprehensive host interaction network, validate regulatory mechanisms that drive viral infection, and identify targets for therapeutic intervention. Our unique innovative experimental framework and highly interactive scientific approach provides a blueprint to tackle other emerging and reemerging pathogens.