TLR3 signaling is either protective or pathogenic for the development of TMEV-IDD depending on the time of viral infection (76.5)

We have previously shown that toll-like receptor 3 (TLR3)-mediated signaling plays an important role in the induction of innate cytokine responses to Theiler’s murine encephalomyelitis virus (TMEV) infection. In addition, cytokine levels produced after TMEV infection are significantly higher in the glial cells of susceptible SJL mice compared to those of resistant C57BL/6 mice. However, it is not known whether TLR3-mediated signaling plays a protective or pathogenic role in the development of demyelinating disease. In this study, we investigated the role of TLR3-mediated signaling in the protection and pathogenesis of TMEV-induced demyelinating disease. Our results indicate that TLR3-mediated signaling plays an important role in protecting mice from the development of disease during viral infection, as a lack of TLR3 signals in TLR3-deficient mice exacerbates the disease. However, activation of TLR3 with poly IC prior to viral infection also exacerbated disease development, whereas administration of poly IC after viral infection restrained disease development. These results suggest that TLR3-mediated signaling during viral infection protects against demyelinating disease by reducing the viral load and modulating immune responses. In contrast, premature activation of TLR3 signal transduction during early viral infection may lead to pathogenesis via over-activation of the pathogenic immune response.