): Multiple sclerosis (MS) is the most common autoimmune neurodegenerative disease of adults in the United States, affecting approximately 250,000 individuals. Available evidence suggests that MS etiology and pathogenesis may involve two events, the first being exposure to an environmental agent, likely a virus, early in life, followed by a second event in early adulthood which triggers disease. Links with host genetics, particularly MHC-class II antigens and gender have been shown, but a definitive pathogenetic sequence linking the early and late events has not been shown, therefore animal model systems are of value in providing insight into the pathogenesis of MS. This project seeks to understand the mechanisms of CD4+ T cell mediated immune responses in the pathogenesis of CNS demyelinating disease, the signals which trigger influx of inflammatory cells, and the state and sites of virus persistence within the CNS. Intracerebral inoculation of C57B1/6 mice with the neurotropic murine coronavirus MHV-JHM and variants such as V5A13.1 derived from it results in a reproducible encephalomyelitis which usually resolves within 7-14 days but is followed by acute or chronic episodes of demyelination. Restriction of virus replication and spread within the brain is controlled by elements of the T cell response, and is accompanied by induction of multiple cytokine and chemokine mRNAs in the CNS compartment. Evidence suggests that CD4+ T cell responses are central to both control of infection and demyelinating disease, hence Dr. Buchmeier proposes three specific aims to elucidate details of this virus-host interaction. These are: 1) to investigate in CD4 knockout mice the requirements for demyelination; 2) to investigate in C57B1/6 and B6CD4 knockout mice the pathogenesis of virus-induced acute and chronic demyelinating disease and to seek evidence of an antiself response against components of the myelin sheath triggered by virus infection; and 3) to analyze by in situ hybridization, immunohistochemistry and PCR the state and cellular sites of viral persistence within the CNS following infection. Coronaviruses are widespread upper respiratory and enteric pathogens in man and animals, and coronavirus RNA has recently been described in the brains of human multiple sclerosis patients. The studies proposed will reveal basic information in interpreting the host-virus relationship in coronavirus infections, how they cause persistent infections, and the mechanisms of pathogenesis of demyelinating disease.
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