The filoviruses, Ebola and Marburg viruses (EBOV and MARV), are emerging, negative-strand RNA viruses that cause severe viral hemorrhagic fever. The virulence and emerging nature of these zoonotic pathogens makes them a significant threat to human health, potential agents of bioterrorism and NIAID category A priority pathogens. Currently, no approved anti-filovirus therapeutics are available. Filoviral hemorrhagic fever is characterized by uncontrolled, systemic virus replication, excessive inflammation and coagulation, dysregulated dendritic cell (DC) function and lymphocyte apoptosis. We previously identified and structurally characterized filoviral interferon antagonist proteins, including EBOV and MARV VP35, EBOV VP24 and MARV VP40. The VP35s counteract the production of interferon (IFN)-alpha/beta, critical antiviral cytokines. EBOV VP24 and MARV VP40 block the signaling induced by IFN-alpha/beta. We hypothesize that the function of these viral IFN-antagonists will not only counteract the innate antiviral effects of IFN-alpha/beta but, by targeting signaling downstream of pattern recognition, interferon and cytokine receptors, will also be able to disrupt the normal DC maturation process and promote dysregulated DC-T lymphocyte interactions. In this way, the filoviral IFN-antagonists will disrupt both innate and adaptive antiviral immunity. Building on ongoing collaborations between the Basler laboratory at the Icahn School of Medicine at Mt Sinai and the Amarasinghe and Gross laboratories at Washington University, we will characterize the molecular mechanisms of immune disruption by filoviral interferon antagonists. Using in vitro biochemical and structural studies, the Amarasinghe and Gross laboratories at Washington University will define the structural and biochemical basis for how filoviral interferon antagonists interact with host immune system signaling molecules and design loss of function mutants. The Basler laboratory will define the specific signaling pathways affected by each filoviral IFN-antagonist in dendritic cells and macrophages and using the structural and biochemical data provided by Amarasinghe and Gross labs as well as specific knockdown of key signaling molecules will define the impact of filoviral IFN-antagonists on macrophage function and DC cell maturation. The resulting data will generate specific hypotheses regarding the contribution of filoviral IFN-antagonists to EBOV and MARV suppression of DC function (to be tested by Project 2), to promotion of virus replication and induction of IFN and adaptive immune responses in non-human primate models (addressed by Project 3).

Public Health Relevance

Growing concerns of rare but increasing Ebola outbreaks in human populations, coupled with a rising potential of misuse in the form of bioterrorism, underscore the importance of identifying mechanisms of pathogenesis and new therapeutic approaches. Work described in this proposal will characterize how filoviral interferon antagonists modulate host immune mechanisms that control viral replication.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-ZL-I (J1))
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Icahn School of Medicine at Mount Sinai
New York
United States
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Feagins, Alicia R; Basler, Christopher F (2014) The VP40 protein of Marburg virus exhibits impaired budding and increased sensitivity to human tetherin following mouse adaptation. J Virol 88:14440-50
Shabman, Reed S; Jabado, Omar J; Mire, Chad E et al. (2014) Deep sequencing identifies noncanonical editing of Ebola and Marburg virus RNAs in infected cells. MBio 5:e02011
Basler, Christopher F (2014) New hope in the search for Ebola virus treatments. Immunity 41:515-7
Xu, Wei; Edwards, Megan R; Borek, Dominika M et al. (2014) Ebola virus VP24 targets a unique NLS binding site on karyopherin alpha 5 to selectively compete with nuclear import of phosphorylated STAT1. Cell Host Microbe 16:187-200
Basler, Christopher F; Woo, Patrick C Y (2014) Editorial overview: emerging viruses. Curr Opin Virol 5:v-vii
Yen, Benjamin; Mulder, Lubbertus C F; Martinez, Osvaldo et al. (2014) Molecular basis for ebolavirus VP35 suppression of human dendritic cell maturation. J Virol 88:12500-10
Basler, Christopher F (2014) Portrait of a killer: genome of the 2014 EBOV outbreak strain. Cell Host Microbe 16:419-21