Infection of susceptible mice with mouse hepatitis virus (JHMV, a positive-strand RNA virus) results in an acute encephalomyelitis following by a chronic demyelinating disease that shares many similarities with the human demyelinating disease Multiple Sclerosis (MS). Animals develop ascending hind-limb paralysis accompanied by mononuclear cell infiltration into the central nervous system (CNS) and myelin destruction. As such, the JMHV model of demyelination is a well accepted model to study the immunopathological mechanisms contributing to human demyelinating diseases such as MS. T cells and macrophages are considered important contributors to JHMV-induced demyelination as well as demyelination in MS patients. The long-range goal of this proposal is to better understand the molecular mechanisms governing the trafficking and entry of T cells into the CNS following JMHV infection. To this end, studies outlined in this research proposal are designed to evaluate the contributions of the T cell chemoattractant chemokine IP10 (interferon inducible protein 10 kDa) in the pathogenesis of JHMV-induced demyelination. This is padicularly relevant as recent studies have implicated IP-10 as potentially important in contributing to demye!ination in MS patients by attracting T cells into the CNS. in support of this, repots from this laboratory indicate that IP-10 produced by astrocytes contributes to demyelination in JHMV-infected mice by attracting predominantly CD4+ T cells into the CNS of persistently infected mice. Specifically, antibody-mediated neutralization of IP-10 results in reduced neurologic disease, diminished demyelination, and a marked increase in the number of remyellinated axons which correlated with reduced T cell infiltration. Studies outlined in this proposal are designed to increase our understanding of how IP-10 contributes to disease in JHMV-infected mice. Novel strategies designed to accomplish this goal include (i) examination of the molecular mechanisms contributing to IP-10 expression following either viral infection or cytokine treatment of astrocytes and (ii) examining how anti-IP-10 regulates T cell infiltration into the CNS. Together, these studies will extend our current understanding of how IP-10 controls CNS inflammation and demyelination following viral infection.
