Viral encephalitis 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. Novel and broadly applicable strategies for the treatment of neurotropic viral infections are desperately needed. Using microarray analysis we identified death receptor signaling and peroxisome proliferator-activated receptor gamma (PPAR3) signaling as cellular signaling pathways that are significantly represented by the pattern of differential gene expression following infection of the brain with reovirus and West Nile virus (WNV), neurotropic viruses from different viral families. Preliminary data suggests that these pathways modulate virus- induced neuronal cell death and disease and provide novel therapeutic targets for viral encephalitis. In the proposed studies we will investigate the activation of these pathways following infection of the brain with reovirus, WNV and herpes simplex virus (HSV). Reovirus represents a """"""""classic"""""""" in vivo experimental model of viral encephalitis. Complementary experiments using our recently developed ex vivo model of reovirus encephalitis and in vitro experiments with primary neuronal cultures provide an unmatched experimental system for the rapid evaluation of therapeutic targets for virus-induced CNS disease. To increase the impact and significance of our proposal we will perform parallel experiments with the clinically important encephalitic viruses, WNV and HSV. In order to identify novel cellular genes and pathways that can be used as therapeutic targets for viral encephalitis we will perform an inventive microarray approach using pairs of neurovirulent and neuroattenuated strains of reovirus, WNV and HSV. It is expected that genes and signaling pathways that are differentially regulated or activated following infection with neurovirulent and neuroattenuated viral strains will be directly involved in viral pathogenesis within the brain. Our experiments will thus identify a restricted set cellular genes and signaling pathways that will be evaluated as therapeutic targets for viral encephalitis. Identified genes and signaling pathways may be applicable as therapeutic targets for individual viruses. However, by identifying cellular factors that are differentially regulated following infection with multiple viruses from different families, we also expect to identify cellular targets with broad spectrum therapeutic potential for encephalitis induced by a variety of known and unknown (emerging) viruses. Our studies are also expected to increase our understanding of other human diseases characterized by the onset or disruption of neuronal death signaling.

Public Health Relevance

Virus encephalitis results in significant morbidity and mortality throughout the world. Current treatment strategies which inhibit the replication of individual viruses 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 Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS076512-01
Application #
8215547
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Wong, May
Project Start
2011-09-15
Project End
2015-08-31
Budget Start
2011-09-15
Budget End
2012-08-31
Support Year
1
Fiscal Year
2011
Total Cost
$344,250
Indirect Cost
Name
University of Colorado Denver
Department
Neurology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Dionne, Kalen R; Tyler, Kenneth L (2013) Slice culture modeling of central nervous system (CNS) viral infection. Methods Mol Biol 1078:97-117
Nath, Avindra; Tyler, Kenneth L (2013) Novel approaches and challenges to treatment of central nervous system viral infections. Ann Neurol 74:412-22

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