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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI083019-04
Application #
8375811
Study Section
Special Emphasis Panel (ZAI1-BDP-I)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$300,080
Indirect Cost
$105,078
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Bekerman, Elena; Neveu, Gregory; Shulla, Ana et al. (2017) Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects. J Clin Invest 127:1338-1352
Daniels, Brian P; Jujjavarapu, Harsha; Durrant, Douglas M et al. (2017) Regional astrocyte IFN signaling restricts pathogenesis during neurotropic viral infection. J Clin Invest 127:843-856
Da Costa, Andreia; Garza, Esteban; Graham, Jessica B et al. (2017) Extrinsic MAVS signaling is critical for Treg maintenance of Foxp3 expression following acute flavivirus infection. Sci Rep 7:40720
Gorman, Jacquelyn A; Hundhausen, Christian; Errett, John S et al. (2017) The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity. Nat Immunol 18:744-752
Jagger, Brett W; Miner, Jonathan J; Cao, Bin et al. (2017) Gestational Stage and IFN-? Signaling Regulate ZIKV Infection In Utero. Cell Host Microbe 22:366-376.e3
Daniels, Brian P; Snyder, Annelise G; Olsen, Tayla M et al. (2017) RIPK3 Restricts Viral Pathogenesis via Cell Death-Independent Neuroinflammation. Cell 169:301-313.e11
Li, Junwei; Baird, Madison A; Davis, Michael A et al. (2017) Dramatic enhancement of the detection limits of bioassays via ultrafast deposition of polydopamine. Nat Biomed Eng 1:
Luo, Huanle; Winkelmann, Evandro; Xie, Guorui et al. (2017) MAVS Is Essential for Primary CD4+ T Cell Immunity but Not for Recall T Cell Responses following an Attenuated West Nile Virus Infection. J Virol 91:
Tajfirouz, Deena; West, Devin M; Yin, Xiao-Tang et al. (2017) CXCL9 compensates for the absence of CXCL10 during recurrent Herpetic stromal keratitis. Virology 506:7-13
Green, Richard; Wilkins, Courtney; Thomas, Sunil et al. (2017) Oas1b-dependent Immune Transcriptional Profiles of West Nile Virus Infection in the Collaborative Cross. G3 (Bethesda) 7:1665-1682

Showing the most recent 10 out of 120 publications