Diabetogenic Potential of Human Pathogens Uncovered in Experimentally Permissive β-Cells

Abstract

Pancreatic β-cell antiviral defense plays a critical role in protection from coxsackievirus B4 (CVB4)-induced diabetes. In the present study, we tested the hypothesis that interferon (IFN)-induced antiviral defense determines β-cell survival after infection by the human pathogen CVB3, cytomegalovirus (CMV), and lymphocytic choriomeningitis virus (LCMV). We demonstrated that mice harboring β-cells that do not respond to IFN because of the expression of the suppressor of cytokine signaling-1 (SOCS-1) succumb to an acute form of type 1 diabetes after infection with CVB3. Interestingly, the tropism of the virus was altered in SOCS-1 transgenic (Tg) mice, and CVB3 was detected in islet cells of SOCS-1–Tg mice before β-cell loss and the onset of diabetes. Furthermore, insulitis was increased in SOCS-1–Tg mice after infection with murine CMV, and a minority of the mice developed overt diabetes. However, infection with LCMV failed to cause β-cell destruction in SOCS-1 Tg mice. These findings suggest that CVB3 can cause diabetes in a host lacking adequate β-cell antiviral defense, and that incomplete target cell antiviral defense may enhance susceptibility to diabetes triggered by CMV. In conclusion, suppressed β-cell antiviral defense reveals the diabetogenic potential of two pathogens previously linked to the onset of type 1 diabetes in humans.