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The innate immune receptor MDA 5 limits rotavirus infection but promotes cell death and pancreatic inflammation
Author(s) -
Dou Yu,
Yim Howard CH,
Kirkwood Carl D,
Williams Bryan RG,
Sadler Anthony J
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201696273
Subject(s) - immune system , rotavirus , innate immune system , inflammation , immunology , biology , autoimmunity , pancreas , programmed cell death , virology , virus , apoptosis , biochemistry
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.