Poster Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

Viral infections are thought to be a trigger for the onset of Type-1 diabetes (T1D) in human patients. In animal models, virus-induced diabetes can be mediated by direct β-cell lysis, and/or indirectly by the synthesis of damaging pro-inflammatory cytokines and reactive oxygen species (ROS) by islet-infiltrating leukocytes during infection. We recently demonstrated a critical role for ROS production in T1D pathogenesis, as superoxide-deficient Non-Obese Diabetic (NOD.Ncf1^m1J) mice are highly T1D-resistant. Interestingly, bone marrow-derived macrophages (BMMΦ) from these mice have reduced viral RNA sensing capacity in response to the viral dsRNA-mimic, poly(I:C). Therefore, we hypothesized that superoxide deficiency will alter the diabetogenicity of viral infections through diminished innate anti-viral responses. To test this hypothesis, we performed in vitro and in vivo infection studies with diabetogenic Encephalomyocarditis strain D (EMCV-D) and Coxsackie B4 (CB4) viruses to define how superoxide mediates anti-viral responses. In vitro, EMCV-D- and CB4-induced levels of RIG-I were 1.7- and 2-fold lower, respectively, in NOD.Ncf1^m1J BMMΦ than NOD. In addition, CB4-induced TLR3 levels were diminished 1.4-fold in NOD.Ncf1^m1J BMMΦ as compared to NOD. Interestingly, cytokine analysis revealed that EMCV-D-induced IL-1β synthesis in NOD.Ncf1^m1J BMMΦ was reduced by 1.9-fold compared to NOD (6.27 ±0.04 vs. 11.91 ±0.19 pg/mL; p<0.0001), albeit no detectable levels with CB4. Superoxide deficiency similarly hindered TNFα synthesis in both virus infections. NOD.Ncf1^m1J BMMΦ showed a 1.2-fold decreased response to EMCV compared to NOD (4968.0 ±68.7 pg/mL vs. 6011.0 ±154.5 pg/mL; p<0.0035), and a 2-fold decreased response to CB4 (12.44 ±0.91 pg/mL vs. 24.74 ±0.66 pg/mL; p<0.0005). These findings highlight the expansive effect of superoxide deficiency on anti-viral responses. Future studies will further define the role of superoxide in the immune responses that culminate in viral-induced diabetes, and determine if redox modulation of innate immune responses can prevent viral triggers of T1D.