1726-P: MDA5, a Janus-Faced dsRNA Sensor in Coxsackievirus-Accelerated Autoimmune Diabetes

While microbial infections can trigger type 1 diabetes (T1D), innate immune activation and the synthesis of free radicals, proinflammatory cytokines, and type 1 interferons contribute to pancreatic β-cell destruction. We previously demonstrated that Coxsackievirus B3 (CB3) infection of Non-Obese Diabetic (NOD) mice can accelerate T1D, partly due to the induction of antiviral signaling pathways including melanoma differentiation-associated protein 5 (MDA5). Single-nucleotide polymorphisms within Ifih1, the gene encoding for MDA5, is associated with multiple autoimmune diseases including T1D, but the molecular mechanism contributing to innate immune dysregulation is not known. Since T1D is a chronic proinflammatory autoimmune disease involving MDA5, we hypothesized that attenuated MDA5 expression and signaling can delay diabetogenic viral-accelerated T1D. We generated NOD mice mutated in Ifih1 that exhibited a delay in spontaneous T1D due to the loss of MDA5 expression (NOD.Ifih1-m1) or an in-frame deletion in the helicase domain that decreased MDA5 synthesis (NOD.Ifih1-m4). Interestingly, CB3-infected NOD and NOD.Ifih1-m1 mice displayed virus-accelerated T1D, but NOD.Ifih1-m4 (n=9 per group) mice were significantly (p < 0.001) delayed. CB3-infected NOD.Ifih1-m4 mice exhibited a 5-fold decrease in IFN-β synthesis in the pancreas, the reduction in inflammation may be a driving factor to prevent the induction of autoimmunity. The Ifih1-m4 mutation did not compromise pancreatic viral clearance, and this was complemented by a ∼34% and ∼32% reduction in pancreas-infiltrating CD8 T cells and activated macrophages (F4/80⁺, I-A^g7+), respectively, in comparison to CB3-infected NOD mice. The protective Ifih1-m4 mutation may establish an acute level of type 1 interferons and islet-infiltrating lymphocytes to sufficiently inhibit CB3 replication without mediating bystander activation of autoreactive T cells, preventing virus-accelerated autoimmune diabetes.