West Nile Virus (WNV) is one of the many neurotropic flaviviruses that is widely spread throughout the world, and continues to cause significant morbidity and mortality. In the US alone there were 24,000 cases of human WNV infection and 1000 fatalities since 2006. Both innate and adaptive immune components, including CDS, CD4 T cells and B cells contribute to WNV clearance and prevent infection of neurons. The adaptive immune components also form memory, which is the hall-mark for vaccination strategies. The generation of adaptive immunity is linked to innate activation, primarily via viral sensing by host pattern recognition receptors (PRRs), which in turn lead to ARC activation and generation of inflammatory mediators. One class of these early inflammatory mediators, type-l interferons (IFN-I) induce an anti-viral state in infected and neighboring cells. Many viruses, including WNV, developed potent IFN-I evasive strategies. Recent studies from our and other labs show that IFN-I can also exert profound influence on T cells responses, and generation of immune memory;but very little is known about the roles of specific pattern recognition receptors and the IFN-signaling in generating flavivirus-specific adaptive response. An understanding of this is critical for generating improved vaccines. We hypothesize that IFN-I signaling plays a critical role in generating WNV-specific adaptive immunity and that strategies to interfere with viral IFN-I evasive mechanisms should yield better vaccines.
In Aim 1 we will define the role of dendritic cell signaling via RNA helicases and TLRs for generating WNV-specific CDS T cell responses.
In Aim 2 we will examine the role of IFN-I signaling in the generation of WNV-specific CDS T cell responses.
In Aim 3 we will assess the importance of the timing of IFN-I signals in programming T cell responses. Using the knowledge gained from these and the studies proposed in the other four projects of this U19, in Aim 4 we will modulate IFN-I signaling as means to enhance vaccination. Thus, this proposal will contribute to attainment of multi-project objectives of this U19.

Public Health Relevance

Improved vaccine and therapeutic approaches require critical understanding of the mechanisms by which innate clues of infection fine-tune adaptive immune response in vivo. Our research sheds novel insights into these mechanisms, advances the field and has implications for public health. The knowledge gained from these studies, together with the other projects of this program project, contributes to understanding of the immune mechanisms of viral control and has implications for novel vaccination strategies.

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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