The innate immune receptor MDA 5 limits rotavirus infection but promotes cell death and pancreatic inflammation

Abstract

Melanoma differentiation‐associated protein 5 ( MDA 5) mediates the innate immune response to viral infection. Polymorphisms in IFIH1 , the gene coding for MDA 5, correlate with the risk of developing type 1 diabetes (T1D). Here, we demonstrate that MDA 5 is crucial for the immune response to enteric rotavirus infection, a proposed etiological agent for T1D. MDA 5 variants encoded by minor IFIH1 alleles associated with lower T1D risk exhibit reduced activity against rotavirus infection. We find that MDA 5 activity limits rotavirus infection not only through the induction of antiviral interferons and pro‐inflammatory cytokines, but also by promoting cell death. Importantly, this MDA 5‐dependent antiviral response is specific to the pancreas of rotavirus‐infected mice, similar to the autoimmunity associated with T1D. These findings imply that MDA 5‐induced cell death and inflammation in the pancreas facilitate progression to autoimmune destruction of pancreatic β‐cells. image Polymorphisms in the innate immune receptor MDA 5 correlate with type I diabetes (T1D). Here, functional analysis of MDA 5 activity identifies a pancreas‐specific pathology that may account for the genetic association with T1D. Rotavirus infection, which has been proposed as an etiological agent of T1D, activates MDA5. Activation of MDA5 induces damaging inflammation and cell death. MDA5 activity is tissue specific and is particular to the pancreas. The minor alleles of the gene encoding MDA5, which are associated with reduce risk for T1D, have reduced function.