Project Description. Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease characterized by selective destruction of the insulin secreting b-cells found in pancreatic islets of Langerhans. While T-lymphocytes are the primary mediators of b-cell destruction during disease development, the pathways that initiate this autoimmune attack are unknown. There is a genetic predisposition for diabetes development, but the low concordance rate among identical twins (less than 40%) suggest that environmental factors participate in the induction of autoimmune diabetes. While virus infection is one environmental factor that has been proposed to initiate b-cell damage during the development of diabetes, the effects of infection on b-cell function and viability as well as the activation of b-cell defense responses to infection are poorly understood. The broad goals of this research program are to define the biochemical mechanisms by which environmental factors, specifically virus infection, contribute to disease development. Much of the focus of this competitive renewal application is on the mechanisms by which b-cells participate in disease tolerance to virus infection. Disease tolerance is an evolutionary conserved defense strategy that limits the impact of a pathogen on host fitness without directly modifying the pathogen. Using a mouse tropic enterovirus that is known to infect and replicate in b-cells and that induces diabetes in susceptible strains of mice (Encephalomyocarditis virus, EMCV), we have identified a novel pathway by which b-cell resist EMCV infection. This protective pathway is mediated by nitric oxide, the same free radical produced by b-cell following cytokine stimulated inducible nitric oxide synthase (NOS) expression. We show that nitric oxide, in b- cell selective manner, enhances b-cell fitness by limiting virus replication and we hypothesize that it is when this disease tolerance is broken that diabetes ensues.