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

National Institute of Health (NIH)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
United States
Zip Code
Pinto, Amelia K; Ramos, Hilario J; Wu, Xiaobo et al. (2014) Deficient IFN signaling by myeloid cells leads to MAVS-dependent virus-induced sepsis. PLoS Pathog 10:e1004086
Ireton, ReneƩ C; Gale Jr, Michael (2014) Pushing to a cure by harnessing innate immunity against hepatitis C virus. Antiviral Res 108:156-64
Graham, Jessica B; Da Costa, Andreia; Lund, Jennifer M (2014) Regulatory T cells shape the resident memory T cell response to virus infection in the tissues. J Immunol 192:683-90
Hyde, Jennifer L; Gardner, Christina L; Kimura, Taishi et al. (2014) A viral RNA structural element alters host recognition of nonself RNA. Science 343:783-7
Zhao, Jincun; Li, Kun; Wohlford-Lenane, Christine et al. (2014) Rapid generation of a mouse model for Middle East respiratory syndrome. Proc Natl Acad Sci U S A 111:4970-5
Hussmann, Katherine L; Vandergaast, Rianna; Ochsner, Susan Park et al. (2014) In vitro and in vivo characterization of a West Nile virus MAD78 infectious clone. Arch Virol 159:3113-8
Suthar, Mehul S; Pulendran, Bali (2014) Systems analysis of West Nile virus infection. Curr Opin Virol 6:70-5
Diamond, Michael S (2014) IFIT1: A dual sensor and effector molecule that detects non-2'-O methylated viral RNA and inhibits its translation. Cytokine Growth Factor Rev 25:543-50
Thackray, Larissa B; Shrestha, Bimmi; Richner, Justin M et al. (2014) Interferon regulatory factor 5-dependent immune responses in the draining lymph node protect against West Nile virus infection. J Virol 88:11007-21
Durrant, Douglas M; Daniels, Brian P; Klein, Robyn S (2014) IL-1R1 signaling regulates CXCL12-mediated T cell localization and fate within the central nervous system during West Nile Virus encephalitis. J Immunol 193:4095-106

Showing the most recent 10 out of 38 publications