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 wil 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.
Virus encephalitis, including encephalitis induced by the arboviruses West Nile virus, Japanese encephalitis virus and Venezuelan equine encephalitis 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.
|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:|
|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|
|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|
|Nath, Avindra; Tyler, Kenneth L (2013) Novel approaches and challenges to treatment of central nervous system viral infections. Ann Neurol 74:412-22|
|Beatman, Erica; Oyer, Ryan; Shives, Katherine D et al. (2012) West Nile virus growth is independent of autophagy activation. Virology 433:262-72|