Aberrant MDA5 signaling and IFN-β synthesis elicit protection from Coxsackievirus-accelerated Type 1 diabetes

Abstract Viral infections can trigger the synthesis of proinflammatory cytokines and free radicals that contribute to pancreatic β-cell destruction leading to Type 1 diabetes (T1D). We previously demonstrated that Coxsackievirus B3 (CB3) infection of Non-Obese Diabetic (NOD) mice can accelerate T1D, due to the induction of antiviral signaling pathways including melanoma differentiation-associated protein 5 (MDA5). SNPs within Ifih1, the gene encoding for MDA5, is associated with T1D pathogenesis, but the molecular mechanism contributing to innate immune dysregulation is not known. We hypothesized that attenuated MDA5 expression and signaling can delay diabetogenic viral-accelerated T1D. We generated NOD mice mutated in Ifih1 that displayed a loss in 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 delayed in both spontaneous and CB3-accelerated T1D (p=0.0036 and p=0.0004, respectively). CB3-infected NOD.Ifih1-m4 mice exhibited a 4-fold decrease in pancreas IFN-β levels and may partly explain the delay in CB3-induction of T1D. 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-Ag7+), respectively, in comparison to CB3-infected NOD mice. The protective Ifih1-m4 mutation may establish an acute level of IFN-β and islet-infiltrating lymphocytes to inhibit CB3 replication without mediating bystander activation and virus-accelerated autoimmune diabetes.