A study of the molecular pathogenesis of Murray Valley encephalitis virus in mice using infectious clone-derived virus

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The significance of this project derives primarily from the public health problem posed by epidemics of Murray Valley encephalitis in Australia and, more importantly, by the very much larger and more frequent epidemics of Japanese encephalitis in southeast Asia. Reported case fatality rates of Murray Valley encephalitis and of Japanese encephalitis range from 20 to 40%. Rates of neurological sequelae (motor deficits, mental retardation, convulsions, memory loss) are high among survivors and impose a considerable burden on affected individuals and on community health and rehabilitation services. Currently there are no effective treatments, other than supportive measures, available for acute flavivirus encephalitis. The research outlined in this grant application is designed to understand the complex interaction between a pathogenic virus and it's mammalian host at the molecular, cellular and whole animal level. To achieve this aim, we have developed an infectious cDNA clone of Murray Valley encephalitis virus, allowing us to create genetically defined attenuated viruses containing single or limited amino acid differences from the virulent wild-type virus. This research will allow us to achieve a comprehensive understanding of how single or limited nucleotide changes in the genomes of laboratory-derived mutants result in attenuation of virulence in a mammalian host . This research has important implications for the development of genetically defined, live-attenuated flavivirus vaccines engineered from infectious cDNA clones. We have recently shown that the pathogenesis of Murray Valley encephalitis in mice results, in part, from host inflammatory responses. Thus, we plan to rigorously analyze the inflammatory responses to MVE infection in mice and to assess the ability of several anti-inflammatory agents to alleviate the clinical manifestations of acute Murray Valley encephalitis or it's neurological sequelae in mice.