DA strain of Theiler's murine encephalomyelitis virus (TMEV) causes TMEV-induced demyelinating disease (TMEV-IDD), which serves as an experimental model of multiple sclerosis (MS): both diseases have similar immune-mediated demyelinating pathology. In contrast, GDVII strain of TMEV causes a fatal encephalomyelitis without demyelination or virus persistence. Both DA L and GDVII L protein block IFN-? transcription, however, they do so at different sites in the IRF-3 pathway. DA L, and therefore DA virus infection, blocks the activation of IRF-3, while GDVII L, and therefore GDVII virus infection (as well as infection by a mutant virus called DALGDVII, in which DA L is replaced by GDVII L), activates IRF-3, but blocks the binding of IRF-3 to the IFN-? promoter. Of note, activated IRF-3: is critical for IL-27 synthesis, which inhibits Th17 cells; decreases IL-17 secretion by CD4+ memory cells; is important in the differentiation of IL-10- secreting Tr1 cells, a regulatory T cell that can resolve inflammation and restore tolerance; negatively regulates granulocyte-macrophage-colony stimulating factor (GM-CSF) expression in T cells, which is important in mediating experimental allergic encephalomyelitis (EAE). Activated IRF-3 also interferes with production of IL- 12p40, a subunit of IL-12 and IL-23, preventing polarization of nave T cells into proinflammatory Th1 cells (induced by IL-12) and Th17 cells (induced by IL-23). In the present proposal, we hypothesize that the activation or the failure of activation of IRF-3 (and the balance of IL-27/Th17) is important in the demyelination induced by TMEV, and in (partly) determining the two TMEV subgroup disease phenotypes. Antagonism of the IFN-? response because of a failure to activate IRF-3 may occur following infections with varied pathogens, and this may be the reason that the initiation of MS and/or an MS attack (or of another autoimmune disease) occurs after infection with these pathogens. A better understanding of these activities of the innate immune system in TMEV-IDD may clarify its pathogenesis and open up new therapeutic directions in MS.
Certain strains of Theiler's murine encephalomyelitis virus (TMEV) induce a persistent virus infection of the central nervous system associated with a chronic inflammatory immune-mediated demyelinating disease, which serves as an excellent model of multiple sclerosis (MS). We plan to investigate immunologic factors that lead to the demyelination. These studies may elucidate mechanisms of virus persistence and virus-induced demyelination, increase our understanding of other virus-induced autoimmune diseases (e.g., diabetes, cardiomyopathy), and also clarity the role of immune factors in the demyelination seen in MS.
