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)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-BDP-I)
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