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

Abstract

The Epstein-Barr virus (EBV), also referred to as Human herpes virus 4 (HHV-4), is a double-stranded virus that belongs to the Herpesviridae family of viruses. It is estimated that this ubiquitous virus has infected more than 90% of the world’s adult population and persists for the lifetime of an individual whereby it undergoes latency in infected memory B cells. EBV has been implicated in several autoimmune diseases notably multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. Therefore, a study conducted by our lab examined the effects of the DNA of EBV on the expression levels of several cytokines. Results revealed higher Interleukin 17A (IL-17A) levels 3,6- and 9 days post-EBV DNA administration to mice. IL-17A is an autoimmune-associated cytokine. With Type 1 Diabetes Mellitus (T1DM) being a chronic autoimmune disease affecting millions worldwide, we aimed at assessing the roles EBV may play in the pathogenesis of T1DM. C57BL/6J male mice were intraperitoneally administered with 144 x 103 EBV particles or DNA on day 0. The induction of T1D was obtained via the intraperitoneal injection of 150 mg/kg streptozotocin (STZ) seven days later. Afterwards, mice were monitored for four weeks for body weight changes and blood glucose levels. The relative concentrations of pancreatic IL-17A and IFN-γ were determined by ELISA. The length of the excised colon was measured. Sections of the colon, pancreas and the liver were stained with H&E and then examined for signs of inflammation and infiltration in addition to histological damage grading. We observed significantly higher average blood glucose levels in week four in EBV-treated STZ-induced diabetic mice compared to the STZ-treated mice. Moreover, the former group had fluctuating average body weights for four weeks. Following week 3, mice in this group continued to exhibit decreased body weights as compared to the group administered with STZ alone. IL-17A and IFN-γ levels were higher in pancreatic tissues from mice treated with EBV followed by STZ compared to those administered with STZ alone. No significant enhancement of colon, pancreas or liver tissue damage was observed in the groups treated with viral elements and STZ compared to the group treated only with STZ. Therefore, our research demonstrates that EBV rather than EBV DNA is exacerbating T1DM pathogenesis. 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.