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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Wong, May
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University of Colorado Denver
Schools of Medicine
United States
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Zhuang, Yonghua; Berens-Norman, Heather M; Leser, J Smith et al. (2016) Mitochondrial p53 Contributes to Reovirus-Induced Neuronal Apoptosis and Central Nervous System Injury in a Mouse Model of Viral Encephalitis. J Virol 90:7684-91
Quick, Eamon D; Leser, J Smith; Clarke, Penny et al. (2014) Activation of intrinsic immune responses and microglial phagocytosis in an ex vivo spinal cord slice culture model of West Nile virus infection. J Virol 88:13005-14
Clarke, Penny; Leser, J Smith; Quick, Eamon D et al. (2014) Death receptor-mediated apoptotic signaling is activated in the brain following infection with West Nile virus in the absence of a peripheral immune response. J Virol 88:1080-9
Tyler, Kenneth L (2014) Current developments in understanding of West Nile virus central nervous system disease. Curr Opin Neurol 27:342-8
Clarke, Penny; Leser, J Smith; Bowen, Richard A et al. (2014) Virus-induced transcriptional changes in the brain include the differential expression of genes associated with interferon, apoptosis, interleukin 17 receptor A, and glutamate signaling as well as flavivirus-specific upregulation of tRNA synthetases. MBio 5:e00902-14
Dionne, Kalen R; Tyler, Kenneth L (2013) Slice culture modeling of central nervous system (CNS) viral infection. Methods Mol Biol 1078:97-117
Dionne, Kalen R; Zhuang, Yonghua; Leser, J Smith et al. (2013) Daxx upregulation within the cytoplasm of reovirus-infected cells is mediated by interferon and contributes to apoptosis. J Virol 87:3447-60
Nath, Avindra; Tyler, Kenneth L (2013) Novel approaches and challenges to treatment of central nervous system viral infections. Ann Neurol 74:412-22
Tyler, Kenneth L (2013) PML therapy: ""It's Déjà vu all over again"". J Neurovirol 19:311-3
Davis, Larry E; Oyer, Ryan; Beckham, J David et al. (2013) Elevated CSF cytokines in the Jarisch-Herxheimer reaction of general paresis. JAMA Neurol 70:1060-4

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