Project 1 is focused on understanding how virus and host control innate immune defenses and the outcome of West Nile (WNV) virus infection. West Nile virus is a model flavivirus. Its replication program, host immune induction, and innate immune evasion strategies, are representative of other members of the flavivirus family. WNV is emerging in the Western hemisphere, and is now a contemporary public health threat. Our studies have defined specific pathogen recognition (PRR) pathways and interferon regulatory factors (IRFs) as key features of immune triggering and programming during WNV infection. We hypothesize that viral triggering and control of PRR signaling programs and innate immune defenses of the host cell defines the tissue tropism and virulence properties of WNV infection. To investigate this hypothesis we will conduct in vitro and in vivo studies to 1) Define the cell-specific PRR pathways that trigger innate immunity against WNV infection;2) Identify the interferon-stimulated innate immune effector genes that control WNV replication, and 3) Determine the molecular mechanisms by which pathogenic WNV evades the innate immune actions of alpha/beta interferons. In collaboration with Projects 2-5 and the Virology Core, we will define the role of the innate immune response in governing immunity and the outcome of WNV infection. These studies will define the virus/host interface of WNV infection that controls immunity, and will provide novel insights to guide vaccine and therapeutic strategies aimed at modulating WNV and flavivirus infection.

Public Health Relevance

Flavivruses, including West Nile virus, are major and emerging human pathogens. Our studies will use West Nile virus as a model system to define the processes by which flaviviruses trigger and control innate immunity to infection. These studies will provide insights to direct therapeutic and vaccine strategies aimed at limiting flavivirus infection and disease.

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-BDP-I)
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University of Washington
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Adams Waldorf, Kristina M; Stencel-Baerenwald, Jennifer E; Kapur, Raj P et al. (2016) Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate. Nat Med 22:1256-1259
Miner, Jonathan J; Diamond, Michael S (2016) Mechanisms of restriction of viral neuroinvasion at the blood-brain barrier. Curr Opin Immunol 38:18-23
Hare, David N; Collins, Susan E; Mukherjee, Subhendu et al. (2016) Membrane Perturbation-Associated Ca2+ Signaling and Incoming Genome Sensing Are Required for the Host Response to Low-Level Enveloped Virus Particle Entry. J Virol 90:3018-27
Pattabhi, Sowmya; Wilkins, Courtney R; Dong, Ran et al. (2016) Targeting Innate Immunity for Antiviral Therapy through Small Molecule Agonists of the RLR Pathway. J Virol 90:2372-87
Gorman, Matthew J; Poddar, Subhajit; Farzan, Michael et al. (2016) The Interferon-Stimulated Gene Ifitm3 Restricts West Nile Virus Infection and Pathogenesis. J Virol 90:8212-25
Green, Richard; Wilkins, Courtney; Thomas, Sunil et al. (2016) Transcriptional profiles of WNV neurovirulence in a genetically diverse Collaborative Cross population. Genom Data 10:137-140
Proenca-Modena, Jose Luiz; Hyde, Jennifer L; Sesti-Costa, Renata et al. (2016) Interferon-Regulatory Factor 5-Dependent Signaling Restricts Orthobunyavirus Dissemination to the Central Nervous System. J Virol 90:189-205
Salimi, Hamid; Cain, Matthew D; Klein, Robyn S (2016) Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis. Neurotherapeutics 13:514-34
Vasek, Michael J; Garber, Charise; Dorsey, Denise et al. (2016) A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature 534:538-43
Zhang, Rong; Miner, Jonathan J; Gorman, Matthew J et al. (2016) A CRISPR screen defines a signal peptide processing pathway required by flaviviruses. Nature 535:164-8

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