MDA5 and a type 1 interferon signature in the development of type 1 diabetes

Type 1 diabetes (T1D) is a debilitating disease involving the autoimmune destruction of insulin-producing pancreatic β-cells. The personal and economic burden of this disease is enormous, therefore simpler and more cost effective therapeutic approaches than those currently available must be explored. In children at risk for T1D, a unique type 1 interferon (IFN-I) transcriptional signature precedes islet autoimmunity. Recent onset of T1D strongly associates with infection by RNA viruses like coxsackievirus that induce IFN-I. Importantly, genetic variants in the T1D risk locus IFIH1 are linked to protection from T1D and result in reduced expression of the RNA virus sensor melanoma differentiation-associated protein 5 (MDA5), which is also a critical component in establishing the IFN-I signature. In chapter 2 we describe a novel model where we have translated the reduced MDA5 expression phenotype observed in patients onto the non-obese diabetic (NOD) mouse and established its importance in T1D. We describe the first observations that a reduction in MDA5 in the NOD mouse protects from spontaneous and coxsackievirus B4 (CB4)-induced T1D. We also establish the importance of a specific IFN-I signature in the development of T1D as a result of reduced (not eliminated) MDA5 sensing of CB4 that allows for regulatory T cells (Tregs) at the site of autoimmunity and protects from CB4 induced T1D. In chapter 3 we show that this unique IFN-I signature is limited to MDA5 and disease pathogenesis is linked to the specific IFN-I response induced by the virus as a strain of CB3 failed to modify the IFN-I signature associated with disease. Further RNA sequencing discussed in Chapter 4 demonstrates unique tissue-specific differential gene profiles associated with a reduction in MDA5 following CB4 infection. Our results support our hypothesis that there is a direct correlation between the IFN-I signature induced following environmental challenge with the induction of a strong effector T cell and a matched Treg response. This work demonstrates the essential role of MDA5 signaling in regulating the IFN-I signature, implicates MDA5 in T1D susceptibility and in protection against IFN-I and T1D-inducing agents like CB4 and suggests restricting MDA5 function as a potential T1D therapeutic.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat