The innate immune receptor MDA5 limits rotavirus infection but promotes cell death and pancreaticￂ inflammation

• Published in: The EMBO journal Vol. 36; no. 18; p. 2742
• Main Authors: Dou, Yu, Yim, Howard CH, Kirkwood, Carl D, Williams, Bryan RG, Sadler, Anthony J
• Format: Journal Article
• Language: English
• Published: Heidelberg Blackwell Publishing Ltd 01.09.2017
• Subjects: Alleles; Apoptosis; Autoimmunity; Beta cells; Cell death; Cytokines; Damage; Diabetes; Diabetes mellitus; Differentiation; Etiology; Functional analysis; Immune response; Immune system; Infections; Inflammation; Innate immunity; Interferon; Melanoma; Mortality; Pancreas; Risk; Rotavirus; Viruses
• DOI: 10.15252/embj.201696273
• ISSN: 0261-4189

Melanoma differentiation-associated protein 5 (MDA5) mediates the innate immune response to viral infection. Polymorphisms in IFIH1, the gene coding for MDA5, correlate with the risk of developing type 1 diabetes (T1D). Here, we demonstrate that MDA5 is crucial for the immune response to enteric rotavirus infection, a proposed etiological agent for T1D. MDA5 variants encoded by minor IFIH1 alleles associated with lower T1D risk exhibit reduced activity against rotavirus infection. We find that MDA5 activity limits rotavirus infection not only through the induction of antiviral interferons and pro-inflammatory cytokines, but also by promoting cell death. Importantly, this MDA5-dependent antiviral response is specific to the pancreas of rotavirus-infected mice, similar to the autoimmunity associated with T1D. These findings imply that MDA5-induced cell death and inflammation in the pancreas facilitate progression to autoimmune destruction of pancreatic [beta]-cells. Synopsis Polymorphisms in the innate immune receptor MDA5 correlate with type I diabetes (T1D). Here, functional analysis of MDA5 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.