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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants Phase II (R33)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Repik, Patricia M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
United States
Zip Code
Seitz, Scott; Clarke, Penny; Tyler, Kenneth L (2018) Pharmacologic Depletion of Microglia Increases Viral Load in the Brain and Enhances Mortality in Murine Models of Flavivirus-Induced Encephalitis. J Virol 92:
Messacar, Kevin; Fischer, Marc; Dominguez, Samuel R et al. (2018) Encephalitis in US Children. Infect Dis Clin North Am 32:145-162
Quick, Eamon D; Seitz, Scott; Clarke, Penny et al. (2017) Minocycline Has Anti-inflammatory Effects and Reduces Cytotoxicity in an Ex Vivo Spinal Cord Slice Culture Model of West Nile Virus Infection. J Virol 91:
Hixon, Alison M; Yu, Guixia; Leser, J Smith et al. (2017) A mouse model of paralytic myelitis caused by enterovirus D68. PLoS Pathog 13:e1006199
White, Martyn K; Wollebo, Hassen S; David Beckham, J et al. (2016) Zika virus: An emergent neuropathological agent. Ann Neurol 80:479-89
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
Wilson, Michael; Tyler, Kenneth L (2016) Emerging Diagnostic and Therapeutic Tools for Central Nervous System Infections. JAMA Neurol 73:1389-1390
Tyler, Kenneth L (2015) Rationale for the evaluation of fluoxetine in the treatment of enterovirus D68-associated acute flaccid myelitis. JAMA Neurol 72:493-4
Tyler, Kenneth L (2014) Current developments in understanding of West Nile virus central nervous system disease. Curr Opin Neurol 27:342-8
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