The goal of Project 4 is to understand the crosstalk between innate immune sensing and regulation of protective T cell immune response during flavivirus infection. West Nile virus (WNV) and Japanese encephalitis virus (JEV) are emerging mosquito-borne flaviviruses that globally cause annual epidemics of virus-induced encephalitis. T here is no approved vaccine or therapy for use in humans to treat WNV infection and the current vaccines to prevent JEV infection do not provide life-long protective immunity. Protection against WNV and JEV is mediated by both innate and adaptive immune responses. The RlG-1 like receptors (RLR) are cytosolic pathogen recognition receptors that recognize non-self RNA and signal through the MAVS adaptor protein to trigger innate antiviral immunity against WNV and JEV. In addition to their role in innate immunity, our laboratory recently discovered that components of the RLR pathway are critical for programming protective adaptive immune responses responsible for clearing virus during the later stages of infection. This includes MAVS-mediated regulation of humoral and cell-mediated immune responses (CD8+, CD4+ and Treg responses) as well as LGP2-mediated regulation of T cell immunity during WNV infection. LGP2 was found to function in a cell-intrinsic manner to control CD8+ T cell survival and effector properties. These findings establish that the RLRs regulate the interface between innate and adaptive immunity during flavivirus infection. However, the immunological mechanism underlying RLR regulation of T cell immunity against flavivirus infection and vaccination are not well understood. Project 4 studies will (1) determine the role of RLR signaling and function in regulating T cell priming;(2) define the Tcell intrinsic function of MAVS and LGP2 in regulating effector and memory T cell responses;(3) determine how MAVS and LGP2 function to regulate memory T cell recall responses. This work will reveal novel insights into innate immune regulation of immunological memory and identify new therapeutic targets and strategies for vaccine protection against flavivirus infection.

Public Health Relevance

): West Nile virus and Japanese Encephalitis virus are neurotopic flaviviruses that cause global epidemics of mosquito-borne encephalitis annually. Our studies are investigate the crosstalk between innate immune sensing and regulation of protective T cell immune response during flavivirus infection. These studies will reveal new therapeutic targets and strategies for vaccine protection against flavivirus infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
2U19AI083019-06
Application #
8675533
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
Pierson, Theodore C; Diamond, Michael S (2018) The emergence of Zika virus and its new clinical syndromes. Nature 560:573-581
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

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