CNS Damage from Theiler's Virus Persistence: MS Model - Core C

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a neurological disease of major socioeconomic importance in which a viral etiology is strongly suspected. Because of the historical importance of experimental animal models to understanding human disease, investigation of MS models can be expected to lead to clearer insights into the pathogenesis of this human disease. Of the few available experimental animal models of virus-induced demyelination, Theiler's murine encephalomyelitis virus (TMEV) infection in mice is possibly the most relevant to MS. Clearly, a multidisciplinary approach is needed to answer relevant questions about the molecular pathogenesis of TMEV-induced demyelinating disease (TMEV-IDD). This application represents a request for the renewal of a highly successful collaborative research effort examining varying aspects of the pathogenesis and immunoregulation, which has been in effect for the past 16 years. This Program Grant is unique in that it represents a multidisciplinary approach to the study of the molecular pathogenesis of TMEV infection and of its utility as a model of MS. Funding is requested for the continuation of Project 1 (Stephen Miller), Project 2 (Byung Kim) and Project 4 (Howard Lipton), and for the inclusion a new Project 3 directed by William Karpus. Project 1 will determine the mechanisms by which and anatomic location wherein autoreactive myelin-specific T cell responses arise via epitope spreading during persistent CNS TMEV infection, ascertain their functional contribution to chronic disease pathology, define the specificity and mechanisms of specific immunoregulation of TMEV-IDD using peripheral tolerance to virus and myelin antigens, and study endogenous presentation of myelin antigens by peripheral and CNS-resident antigen presenting cells. Project 2 will continue to examine the functional contribution of CD8+ cytotoxic T cells in disease pathogenesis and resistance in susceptible and resistant mouse strains.