MHV INDUCED APOPTOSIS AND RESISTANCE TO LETHAL HEPATITIS

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We proposes to utilize the mouse hepatitis virus model of fulminant hepatitis In fully susceptible strains of mice, mouse hepatitis virus, strain 3(MHV-3) produces a lethal fulminant hepatitis characterized by massive hepatocellular necrosis. In contrast, resistant strains of mice survive the infection without detectable evidence of hepatic injury. We have recently observed that MHV-3 induces the rapid induction of apoptosis in infected macrophages derived from strain A/J mice, while replicating rapidly and efficiently in Balb/c derived macrophages. This rapid onset of apoptosis is correlated with inhibition of MHV induced syncytia formation and thus virus spread. We proposed to determine if the rapid induction of apoptosis by MHV-3 is confined to macrophages or also occurs in other cell types, and to delineate pathways and regulators of MHV-3 induce apoptosis using biochemical, pharmacologic, and genetic approaches. Specifically the role of caspases, bc1-2, p53, TNFa, Fas-FasL, and the dsRNA activated protein kinase PKR, in regulating MHV-3 triggered cell suicide will he studied. Furthermore it is proposed to investigate the role of the apoptotic response to resistance to lethal hepatitis by manipulating the apoptotic pathways triggered by MHV-3 we propose to investigate the role of the apoptotic response to resistance to lethal hepatitis.