Abstract
The IFIH1 gene encodes the pattern recognition receptor MDA5. A common polymorphism in IFIH1 (rs1990760, A946T) confers increased risk for autoimmune disease, including type 1-diabetes (T1D). Coxsackievirus infections are linked to T1D and cause beta-cell damage in vitro. Here we demonstrate that the rs1990760 polymorphism regulates the interferon (IFN) signature expressed by human pancreatic islets following Coxsackievirus infection. A strong IFN signature was associated with high expression of IFNλ1 and IFNλ2, linking rs1990760 to the expression of type III IFNs. In the high-responding genotype, IRF-1 expression correlated with that of type III IFN, suggesting a positive-feedback on type III IFN transcription. In summary, our study uncovers an influence of rs1990760 on the canonical effector function of MDA5 in response to an acute infection of primary human parenchymal cells with a clinically relevant virus linked to human T1D. It also highlights a previously unrecognized connection between the rs1990760 polymorphism and the expression level of type III IFNs.
Highlights
The interferon-induced helicase-1 (IFIH1) gene encodes the melanoma differentiation associated protein 5 (MDA5), an intracellular pattern recognition receptor (PRR) of importance for the recognition of certain viruses
We have shown that human pancreatic islets express MDA526, and together with others demonstrated that MDA5 is important in the host immune response to CVBs27,28
The present study uncovers a connection between the rs1990760 polymorphism and the magnitude of the innate immune response to a virus associated with human disease
Summary
The interferon-induced helicase-1 (IFIH1) gene encodes the melanoma differentiation associated protein 5 (MDA5), an intracellular pattern recognition receptor (PRR) of importance for the recognition of certain viruses. Type I and III IFNs have potent antiviral activities; they act in an auto- and paracrine manner to induce the expression of interferon-stimulated genes (ISGs) leading to an antiviral state in uninfected cells. They promote innate and adaptive immune responses[1,2,3,4,5]. (d) Pie chart showing the enrichment of process networks based on the 166 DEGs identified by RNAseq. (g) Venn diagrams showing the number of ISGs (upper diagram, yellow) and non-ISGs (including IFNs, lower diagram, red) commonly or differentially expressed in the two rs1990760 genotype populations (TT and TCs). Little is known on how this nsSNP regulates risk for development of these inflammatory diseases, and information on the biological effects of this nsSNP may provide useful insights
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