The duality of MDA5 in Coxsackievirus-accelerated autoimmune diabetes and protection.

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Samuel I. Blum1, Ashley R. Burg1, Yi-Guang Chen2 and Hubert M. Tse1

 1Department of Microbiology, Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL

 2Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI

While microbial infections can trigger autoimmune diabetes, ultimately, innate immune activation and the synthesis of free radicals, proinflammatory cytokines, and Type I interferons contribute to pancreatic ?-cell destruction in Type 1 diabetes (T1D). We previously demonstrated that Coxsackievirus B3 (CB3) infection of Non-Obese Diabetic (NOD) mice can accelerate T1D, partly due to the induction of oxidative stress and antiviral signaling pathways including melanoma differentiation-associated protein 5 (MDA5). Single-nucleotide polymorphisms within Ifih1, the gene encoding for MDA5, is associated with multiple autoimmune diseases including T1D, but the molecular mechanism contributing to innate immune dysregulation is not known. Since T1D is a chronic proinflammatory autoimmune disease involving MDA5, we hypothesized that aberrant MDA5 expression and signaling can contribute to diabetogenic viral-accelerated T1D. NOD mice mutated in Ifih1 that resulted in loss of MDA5 expression (NOD.Ifih1_m1) or an in-frame truncation in the helicase domain of MDA5 (NOD.Ifih1_m4) exhibited a delay in spontaneous T1D. Interestingly, CB3-infected NOD and NOD.Ifih1_m1 mice displayed accelerated virus-induced T1D, but NOD.Ifih1_m4 mice were significantly (p < 0.001) delayed. CB3-infected NOD.Ifih1_m4 mice were efficient in pancreatic viral clearance and exhibited decreases in circulating Type I interferons in contrast to NOD and NOD.Ifih1_m1 mice. The protective Ifih1_m4 mutation may establish an acute level of Type I interferons sufficient to inhibit CB3 replication without mediating bystander activation of autoreactive T cell progression in autoimmune diabetes.

Submission ID :
IDS86198
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University of Alabama at Birmingham
University of Alabama at Birmingham
Medical College of Wisconsin
University of Alabama at Birmingham

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Event dates:
Thursday 25 October - Monday 29 October 2018

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Monday 14 May 2018

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July 2018

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