Project 1 is focused on understanding how Dengue virus (DENV), West Nile virus (WNV), and Japanese encephalitis virus (JEV) are recognized by the host cell to trigger innate immune and inflammatory responses, and on defining how these cell-intrinsic and cell-extrinsic responses synergize to control infection. DENV, WNV, and JEV are genetically related flaviviruses and among the most important arthropod-borne viruses globally. These viruses are continually emerging and can cause severe hemorrhagic (DENV) or neurological disease (WNV and JEV) in humans. There is no approved antiviral therapeutic agent available for treatment of flavivirus infections. Moreover, there are no approved vaccines against DENV or WNV infection forthe billions of at-risk people, and the current JEV vaccines demonstrate limited durability of protection. Our preliminary studies indicate that susceptibility to flavivirus infection is controlled by innate immune/type I interferon (IFN) defenses triggered by pathogen-associated molecular pattern (PAMP) recognition of flavivirus RNA by RlG-l-like receptors (RLRs), RIG-I and MDA5. Additionally, we have identified a major role forthe Nod-like receptor protein (NLRP)3 in inflammasome signaling/IL-lbeta production in the virus-induced inflammatory response. These studies show that viral triggering of RLR and NLRP3 signaling pathways links innate immune and inflammatory responses to suppress flavivirus infection. The studies in this proposal will (1) Identify the viral PAMPs that trigger RLR signaling of innate immunity during DENV, WNV, and JEV infection; (2) Define the trigger(s) of NLRP3 activation and IL-1 D production by the neurotropic flaviviruses, WNV and JEV; and (3) Determine the molecular mechanisms of linkage and effector actions of innate immune/lFN responses and IL-lbeta inflammatory responses that control flavivirus infection

Public Health Relevance

Dengue virus. West Nile virus, and Japanese encephalitis virus are members of a family that are the leading cause of mosquito-transmitted viral disease. These viruses continue to emerge and spread globally. Our studies will assess the virus and host interactions that regulate the innate immune and inflammatory responses to infection, and will reveal novel targets for the development of therapeutics against flaviviruses

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI083019-10
Application #
9655153
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Mallia, Conrad M
Project Start
Project End
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
10
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Adams Waldorf, Kristina M; Nelson, Branden R; Stencel-Baerenwald, Jennifer E et al. (2018) Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain. Nat Med 24:368-374
Hickman, Heather D; Suthar, Mehul S (2018) Editorial overview: Viral immunology: Generating immunity to diverse viral pathogens. Curr Opin Virol 28:viii-x
Chow, Kwan T; Wilkins, Courtney; Narita, Miwako et al. (2018) Differential and Overlapping Immune Programs Regulated by IRF3 and IRF5 in Plasmacytoid Dendritic Cells. J Immunol 201:3036-3050
Bryan, Marianne A; Giordano, Daniela; Draves, Kevin E et al. (2018) Splenic macrophages are required for protective innate immunity against West Nile virus. PLoS One 13:e0191690
Agner, Shannon C; Klein, Robyn S (2018) Viruses have multiple paths to central nervous system pathology. Curr Opin Neurol 31:313-317
Green, Richard; Ireton, ReneƩ C; Gale Jr, Michael (2018) Interferon-stimulated genes: new platforms and computational approaches. Mamm Genome 29:593-602
Walker, Christie L; Merriam, Audrey A; Ohuma, Eric O et al. (2018) Femur-sparing pattern of abnormal fetal growth in pregnant women from New York City after maternal Zika virus infection. Am J Obstet Gynecol 219:187.e1-187.e20
Hahn, William O; Butler, Noah S; Lindner, Scott E et al. (2018) cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses. JCI Insight 3:
Garber, Charise; Vasek, Michael J; Vollmer, Lauren L et al. (2018) Astrocytes decrease adult neurogenesis during virus-induced memory dysfunction via IL-1. Nat Immunol 19:151-161
Bowen, James R; Zimmerman, Matthew G; Suthar, Mehul S (2018) Taking the defensive: Immune control of Zika virus infection. Virus Res 254:21-26

Showing the most recent 10 out of 147 publications