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EMBO J. 2017 Sep 15;36(18):2742-2757. doi: 10.15252/embj.201696273. Epub 2017 Aug 29.

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

Author information

1
Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Vic., Australia.
2
Department of Oral and Maxillofacial Surgery, Institute of Dental Medicine, Qilu Hospital of Shandong University, Jinan, China.
3
Department of Molecular and Translational Science, Monash University, Clayton, Vic., Australia.
4
Enteric and Diarrheal Disease, Global Health, Bill and Melinda Gates Foundation, Seattle, WA, USA.
5
Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Vic., Australia.
6
Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Vic., Australia anthony.sadler@hudson.org.au.

Abstract

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 β-cells.

KEYWORDS:

MDA5; inflammation; innate immunity; interferons; type 1 diabetes

PMID:
28851763
PMCID:
PMC5599799
DOI:
10.15252/embj.201696273
[Indexed for MEDLINE]
Free PMC Article

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