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.
|Adams Waldorf, Kristina M; Stencel-Baerenwald, Jennifer E; Kapur, Raj P et al. (2016) Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate. Nat Med 22:1256-1259|
|Miner, Jonathan J; Diamond, Michael S (2016) Mechanisms of restriction of viral neuroinvasion at the blood-brain barrier. Curr Opin Immunol 38:18-23|
|Hare, David N; Collins, Susan E; Mukherjee, Subhendu et al. (2016) Membrane Perturbation-Associated Ca2+ Signaling and Incoming Genome Sensing Are Required for the Host Response to Low-Level Enveloped Virus Particle Entry. J Virol 90:3018-27|
|Pattabhi, Sowmya; Wilkins, Courtney R; Dong, Ran et al. (2016) Targeting Innate Immunity for Antiviral Therapy through Small Molecule Agonists of the RLR Pathway. J Virol 90:2372-87|
|Gorman, Matthew J; Poddar, Subhajit; Farzan, Michael et al. (2016) The Interferon-Stimulated Gene Ifitm3 Restricts West Nile Virus Infection and Pathogenesis. J Virol 90:8212-25|
|Green, Richard; Wilkins, Courtney; Thomas, Sunil et al. (2016) Transcriptional profiles of WNV neurovirulence in a genetically diverse Collaborative Cross population. Genom Data 10:137-140|
|Proenca-Modena, Jose Luiz; Hyde, Jennifer L; Sesti-Costa, Renata et al. (2016) Interferon-Regulatory Factor 5-Dependent Signaling Restricts Orthobunyavirus Dissemination to the Central Nervous System. J Virol 90:189-205|
|Salimi, Hamid; Cain, Matthew D; Klein, Robyn S (2016) Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis. Neurotherapeutics 13:514-34|
|Vasek, Michael J; Garber, Charise; Dorsey, Denise et al. (2016) A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature 534:538-43|
|Zhang, Rong; Miner, Jonathan J; Gorman, Matthew J et al. (2016) A CRISPR screen defines a signal peptide processing pathway required by flaviviruses. Nature 535:164-8|
Showing the most recent 10 out of 96 publications