Innate Viral Sensor MDA5 and Coxsackievirus Interplay in Type 1 Diabetes Development

Type 1 diabetes (T1D) is a polygenic autoimmune disease characterized by immune-mediated destruction of insulin-producing beta-cells. The concordance rate for T1D in monozygotic twins is approximate to 30-50%, indicating that environmental factors also play a role in T1D development. Previous studies have demonstrated that enterovirus infections such as coxsackievirus type B (CVB) are associated with triggering T1D. Prior to autoantibody development in T1D, viral RNA and antibodies against CVB can be detected within the blood, stool, and pancreata. An innate pathogen recognition receptor, melanoma differentiation-associated protein 5 (MDA5), which is encoded by theIFIH1gene, has been associated with T1D onset. It is unclear how single nucleotide polymorphisms inIFIH1alter the structure and function of MDA5 that may lead to exacerbated antiviral responses contributing to increased T1D-susceptibility. Binding of viral dsRNA via MDA5 induces synthesis of antiviral proteins such as interferon-alpha and -beta (IFN-alpha/beta). Viral infection and subsequent IFN-alpha/beta synthesis can lead to ER stress within insulin-producing beta-cells causing neo-epitope generation, activation of beta-cell-specific autoreactive T cells, and beta-cell destruction. Therefore, an interplay between genetics, enteroviral infections, and antiviral responses may be critical for T1D development.