Numerous restrictions are placed on immune-mediated clearance of viral infections of the central nervous system (CNS). Not only is immune cell access to the CNS limited, immune-mediated antiviral strategies must avoid lysis of infected neurons, as CNS neurons are generally non-renewable. While non-cytolytic immune-mediated viral clearance in the CNS has been observed, the mechanisms of such clearance are not understood. Using a transgenic mouse model of neuron-restricted measles virus (MV) infection, our laboratory demonstrated that viral clearance i) required both CD4+ and CD8+ (CTL) T lymphocytes; ii) was not associated with immune-mediated neuronal death; and iii) depended on the Th1 cytokine interferon gamma (IFNgamma). However, as CNS neurons are thought to express little or no class I major histocompatibility complex (MHCI), whether CTL-neuron contact is required for MV clearance, and the mechanism by which IFNgamma, clears MV from infected neurons, are unknown. The goal of the proposed research is to define the mechanisms of T cell-mediated noncytolytic viral clearance in CNS neurons by 1) examining whether contact between CTL and neurons is required for MV clearance, and whether MHCI expression mediates this contact; and ii) characterizing the antiviral response of MV-infected neurons stimulated by IFNgamma by examining signal transduction and IFNgamma-responsive gene upregulation. A better understanding of noncytolytic MV clearance in neurons will undoubtedly also be applicable to other neurotropic viruses, and may ultimately provide important insights into the development of novel antiviral approaches to fight chronic infections of the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS051024-02
Application #
7106553
Study Section
Special Emphasis Panel (ZRG1-F07 (20))
Program Officer
Wong, May
Project Start
2005-07-21
Project End
2006-08-31
Budget Start
2006-07-21
Budget End
2006-08-31
Support Year
2
Fiscal Year
2006
Total Cost
$11,825
Indirect Cost
Name
Institute for Cancer Research
Department
Type
DUNS #
064367329
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Rose, R Wesley; Vorobyeva, Anna G; Skipworth, Jason D et al. (2007) Altered levels of STAT1 and STAT3 influence the neuronal response to interferon gamma. J Neuroimmunol 192:145-56