Theiler's murine encephalomyelitis virus (TMEV) establishes a persistent central nervous system (CNS) infection, leading to the development of an autoimmune demyelinating disease. Because of its autoimmune nature and the prominent infiltration of CD4+ T cells and phagocytes, TMEV-induced demyelinating disease (TMEV-IDD) is considered a highly relevant animal model for multiple sclerosis. The innate immune response is the host first line of defense and leads to activation of antigen presenting cell (APC) functions and production of immune effector molecules. In the CNS glial cells (microglia and astrocytes) can respond vigorously to infection and are the major cells in which TMEV persists. Activation of innate immune responses in these cells may contribute directly to demyelination or to epitope spreading of the immune response to myelin antigens. Preliminary data shows that astrocytes express Toll like receptors (TLRs) important in activating innate anti-viral responses and that ligation of these receptors can result in the upregulation of inflammatory cytokines and APC functions of astrocytes. This proposal will thus test the overall hypothesis that astrocytes can respond to TMEV infection through the activation of TLRs by upregulating innate immune, APC and effector functions, and that this activation plays a significant role in the chronic pathogenesis of TMEV-IDD.