P101 The role of MDA5 and the effect of rotavirus in type 1 diabetes

Abstract

Introduction The melanoma differentiation associated factor 5 (MDA5) is a member of the RIG- like helicase family that function in the antiviral response. MDA5 is a cytoplasmic sensor of viral RNAs that regulates the activity of the interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NFκB) transcription factors [1] . It has been reported that polymorphisms in the gene that encodes MDA5 (ifih1) correlate with the risk for developing Type 1 Diabetes (T1D) [2] . Although the triggers for this autoimmune disease are unknown, it is believed that both genetic and environmental factors are involved. Viral infection has been proposed as an important environmental trigger for T1D. We test the role of MDA5 in the antiviral response to rotavirus, which has been proposed as a likely environmental trigger, and test the different responsiveness of protein polymorphs that have been associated with T1D [3] . Methods (1) Induction of type-I interferon (IFN) and cytokines and replications of rotavirus were investigated in Mda5 wild type and knock out MEFs infected with rotavirus. (2) Point mutations of Mda5 polymorphisms associated with the risk of developing T1D were cloned. IRF3 and NFkB pathways were investigated in Hela cells transfected with Mda5 polymorphisms in response to double stranded RNA. (3) Glucose tolerant tests and levels of insulitis are investigated in Mda5 wild type and knock out mice inoculated with rotavirus. Results (1) We confirm that MDA5 is important in the immune response to rotavirus infection. The type-I IFN and cytokine responses are diminished in MDA5-ablated cells. And rotavirus replication is increased in the absence of MDA5. (2) Point mutations in MDA5 associated with the risk of developing T1D respond differentially to double stranded RNA. MDA5 polymorphisms show diminished capacity to induce IRF3 and NFkB. (3) We are currently investigating the role of MDA5 in insulitis initiated by rotavirus infection in vivo. Conclusion MDA5 is shown to be important for the immune response to a virus infection that has been proposed to be causal in T1D. Furthermore, polymorphisms associated with the risk of developing T1D are shown to have reduced antiviral function. Hence, our findings are consistent with a direct role for MDA5 in the development of the autosomal conditions that cause T1D.