The Effect of EBV on Inflammatory Processes in a Type 1 Autoimmune Diabetes Mellitus Mouse Model

Abstract

Introduction: Type 1 diabetes (T1D) is considered a complex heterogeneous autoimmune disease. It occurs due to the destruction of insulin-producing beta cells of the islets of Langerhans of the pancreas. Risk factors of developing T1D include genetic predisposition and environmental challenges such as infectious agents. One such infectious agent is the Epstein-Barr virus (EBV) which establishes latency in B cells but then can reactivate producing viral DNA and resulting in immunomodulation. The association between EBV and T1D is not well investigated. Hence, we aimed at utilizing an EBV/EBV DNA-treated STZ-induced diabetes mouse model to determine the effect of the virus and its DNA on the inflammatory processes in T1D. Methods: Male C57BL/6J mice, 10 weeks of age, were intraperitoneally-administered EBV or EBV DNA followed by streptozotocin (STZ) 7 days later to induce T1D. One group was given only STZ while another was only given the EBV viral particles. Mice were monitored for 4 weeks after STZ administration for any changes in body weight and random blood glucose levels. Four weeks after the administration of STZ, mice were sacrificed, then blood and organs were collected. The length of the excised colon was measured. Sections of the colon and the liver were stained with H&E and then examined for signs of inflammation and infiltration in addition to histological damage grading. Levels of interleukin 17A (IL-17A), the pro-autoimmune cytokine, in plasma samples as well as in pancreatic tissues were determined by enzyme-linked immunosorbent assay (ELISA). Real-time PCR was also performed to determine the relative expression of IFNγ, as well as of Toll-like Receptors (TLRs) 3, 7, and 9. Results: The random blood glucose levels were significantly higher in the group that was administered EBV followed by STZ 7 days later as compared to the group that was only administered STZ. No similar effects were detected for EBV DNA. In addition, a significant increase in both the plasma and pancreatic levels of IL-17A was detected in mice administered EBV and STZ compared to those only given STZ. No significant enhancement of liver or colon tissue damage was observed in the groups treated with viral elements and STZ compared to the group treated only with STZ; similarly, no relevant changes in IFNγ, TLR3, 7, or 9 RNA levels were detected in the groups treated with viral elements and STZ compared to the group treated only with STZ. Conclusion: Our findings indicate that EBV enhances the levels of the proinflammatory IL-17A in the plasma and pancreatic tissues of STZ-induced C57BL/6J male mice. This is accompanied by enhanced blood glucose levels in the STZ-induced diabetes mouse model. A better understanding of the factors involved in the development of T1D and the involvement of EBV in this disease may aid in developing therapeutic interventions that target pro-diabetogenic mediators triggered by this virus.