Host control of the majority of viral infections requires the interplay of many facets of immunity, ranging from the cell-intrinsic resistance to infection to the production of specific neutralizing antibody by B cells, and the action of specific CD8+ T cells that can eliminate infected cells. The overall goal of the current project is to determine how effectively West Nile virus specific CDS* T cells can limit the replication of virus and prevent neuroinvasive disease. In the natural course of infection, the pathogen enters the skin, replicates there and spreads to the draining lymph nodes. At some stage the blood brain barrier is breached and the virus can infect and lyse neuronal cells. For antigen-inexperienced animals, it takes too long for the nascent T cell response to build up enough effector T cell numbers to impact viral replication during the first five days or so. On the other hand, previously primed animals have a higher frequency of virus specific CD8+ T cells, including effector cells and memory cells, that can access most tissues of the body even in steadystate conditions. In the first Aim we propose a number of approaches that will allow us to generate large numbers of naive, memory and effector virus-specific CD8+ T cells that can be readily tracked, These novel reagents, TCR transgenic mice and recombinant West Nile virus, will be used extensively in the other Projects of this U19 application.
The second Aim will determine whether pre-primed, pre-existing CDS* T cells can limit viral replication at the site of infection (i.e., in the skin) and in the draining lymph nodes. In collaboration with other Projects, factors that control extravasation of effectors to the site of infection will be studied.
The final Aim will focus on the known protective role of CDS immunity in the central nervous system and we devise ways of tracking memory cells in the brain, studying their maintenance and response to infection, and their ability to prevent severe neurologic damage.
West Nile virus is an emergent threat to public health in North America. It also serves as a model pathogen for other flavivirus induced disease. Understanding the host T cell response to infection will aid in our ability to assess and design strategies that protect against exposure to this and other pathogen threats.
|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, Reneé 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