Anti-viral responses to diabetogenic viruses are mediated by superoxide production (BA12P.107)

Abstract

Abstract Viral infections may directly trigger the onset of Type 1 diabetes (T1D) by β-cell lysis and/or indirectly via pro-inflammatory cytokines and reactive oxygen species (ROS) by islet-infiltrating leukocytes. We recently demonstrated a crucial role for NADPH oxidase (NOX)-dependent superoxide production in T1D, as NOX-deficient Non-Obese Diabetic (NOD.Ncf1m1J) mice were resistant to autoimmune diabetes, which was partly mediated by diminished pro-inflammatory cytokine and Type I interferon synthesis via dampened macrophage-derived Toll-like receptor (TLR) signaling in response to poly(I:C), a viral RNA mimic. Therefore, we hypothesized that ROS deficiency would diminish anti-viral pro-inflammatory responses and inhibit T1D in response to viral triggers. To define the interplay between redox status and anti-viral responses, we performed infections with Coxsackie B4 (CB4) virus a putative diabetogenic enterovirus associated with T1D induction in both humans and rodents. In the absence of superoxide, NOD.Ncf1m1J macrophages exhibited a 2-fold decrease in TNF-α and IFN-α upon infection due to dampened TLR3 and RIG-I signaling. Corroborating the in vitro results, CB4 infection of NOD.Ncf1m1J mice elicited a 2-fold decrease in TNF-α and IL-1β by pancreas-infiltrating macrophages in contrast to NOD. Future studies will determine if oxidative stress can influence anti-viral responses and uncover novel insights into T1D pathogenesis in response to diabetogenic viruses.