Genetic and transcriptional dysregulation of innate antiviral immune pathways in type 1 diabetes

Innate antiviral immune pathways (InAIPs) are dysregulated in islets of type 1 diabetes (T1D) patients, implying how enterovirus might contribute to beta-cell autoimmunity. However, it is unclear whether similar dysregulation occurs in the intestine, contributing to pathologies like barrier dysfunction. Thus, we used a published genome-wide association study to identify polymorphisms in intestinal permeability and InAIP genes. We compared female prediabetic non-obese diabetic (NOD) and C57BL/6 mice and their jejunal epithelial RNA profile by GeneChip analysis. The potential link between dysregulation of InAIP genes and increased intestinal permeability was assessed by measuring trans-epithelial electrical resistance in intestinal Caco-2 cells upon R837 toll-like receptor 7 stimulation. There was genetic predisposition to T1D among intestinal permeability genes. However, InAIP genes contained more promising T1D-associated polymorphisms, especially for TNFA, OAS3, PIGR, CD55, NOD2, and IFIH1. Comparing prediabetic NOD with C57BL/6 mice revealed age-dependent dysregulation of several InAIP genes (Ifih1, Rnase1 etc.) in jejunum. Lastly, mimicking an enterovirus infection with R837 stimulation of Caco-2 cells increased intestinal permeability. We demonstrate genetic and transcriptional dysregulation of InAIPs in T1D and their potential involvement in intestinal barrier dysfunction, providing new clues to the disease-manifesting mechanisms of enterovirus infection.