Viral encephalitis, including encephalitis induced by the arboviruses West Nile virus (WNV) and Japanese encephalitis virus (JEV), is a major source of morbidity and mortality both in the U.S. and throughout the world. Proven treatments for viral encephalitis are limited to only a few viruses and even when treatments exist (e.g. acyclovir for herpes simplex encephalitis) disability and death remain significant. There are currently no effective treatments for arbovirus-induced encephalitis. Novel and broadly applicable strategies for the treatment of neurotropic viral infections are desperately needed. We will perform microarray analysis on RNA extracted from the brains of mice infected with WNV or JEV in order to identify novel cellular genes and pathways that are differentially regulated in the brain following virus infection and which may provide therapeutic targets for viral encephalitis. Genes and pathways that are differentially regulated in the brains of mice infected with both viruses will be preferentially used as identified targets. We then propose to perform an inventive PCR approach using pairs of neurovirulent and neuroattenuated viral strains, different treatment conditions and additional encephalitis viruses to identify pathogenic genes and signaling pathways which have the highest likelihood of providing therapeutic targets for viral encephalitis. In the final part of this proposal we will evaluate these targets in in vivo and ex vivo models of viral pathogenesis using genetic, pharmacologic and siRNA directed approaches. It is expected that these studies will identify and evaluate novel therapeutic targets for virus encephalitis. Although the main goal of the proposal to identify novel therapeutic targets for WNV and JEV the inclusion of additional encephalitic viruses may identify broad spectrum therapeutic targets for encephalitis induced by a wide variety of different viruses. Our studies may also have relevance for other diseases of the central nervous system.

Public Health Relevance

Virus encephalitis, including encephalitis induced by the arboviruses West Nile virus, Japanese encephalitis virus and Venezualen equine encephailtits virus result in significant morbidity and mortality throughout the world. Current treatment strategies are inadequate. We propose an alternate strategy to identify and evaluate novel therapeutic targets for virus-induced CNS disease from cellular genes and signaling pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
4R33AI101064-03
Application #
8841447
Study Section
Special Emphasis Panel (NSS)
Program Officer
Repik, Patricia M
Project Start
2012-06-01
Project End
2017-05-31
Budget Start
2014-06-10
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
$464,574
Indirect Cost
$164,768
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045