Demyelinating Disease-Viral and Cellular Function

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DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). The etiology and pathogenesis of MS have yet to be elucidated but are probably multifactorial, involving both genetic and environmental factors. Several viruses including coronavirus have been associated with demyelinating processes and represent candidate environmental triggers of MS. The murine coronavirus (MHV) can induce an MS-like disease in rodents. The long-term goal of this research is to elucidate the mechanisms of virus-induced demyelinating diseases of the CNS by using MHV as a model. While a large body of evidence has revealed an important role of the immune system in the onset and development of MHV-induced demyelination, it has remained unclear until recently whether the immune system is absolutely required for triggering the disease. Recently, studies using RAG1 knockout mice demonstrated that MHV infection induced demyelination in the absence of mature T and B cells, indicating that both T and B cells are not required for MHV-induced CNS demyelination. This finding leads us to hypothesize that MHV infection in the CNS results in the destruction of the myelin sheath by direct viral killing of oligodendrocytes. This hypothesis is supported by previous observation that a significant number of apoptotic oligodendrocytes were detected in CNS of MHV-infected rat with subacute encephalomyelitis. It is also substantiated by our recent findings that MHV infection induced apoptosis in cultured rat oligodendrocytes. However, the underlying mechanisms by which MHV infection causes apoptosis and destruction of oligodendrocytes are not known. We propose two specific aims to address these questions. We will first determine what viral factors induce apoptosis in cultured oligodendrocytes. We will then elucidate the molecular mechanisms underlying MHV-induced apoptosis in oligodendrocytes. These studies will identify the components and biochemical pathways that are involved in regulation of oligodendrocyte apoptosis by MHV infection, and will provide insights into the mechanisms of virus-induced demyelinating diseases of the CNS. Findings from these studies will be helpful for the development of effective therapeutic intervention for demyelinating diseases such as MS.