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Diabetogenic potential of human pathogens uncovered in experimentally permissive beta-cells
Malin Flodström1, Devin Tsai, Cody Fine
1Department of Immunology, the Scripps Research Institute, La Jolla, California, USA.
Abstract:
Pancreatic beta-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 beta-cell survival after infection by the human pathogen CVB3, cytomegalovirus (CMV), and lymphocytic choriomeningitis virus (LCMV). We demonstrated that mice harboring beta-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 beta-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 beta-cell destruction in SOCS-1 Tg mice. These findings suggest that CVB3 can cause diabetes in a host lacking adequate beta-cell antiviral defense, and that incomplete target cell antiviral defense may enhance susceptibility to diabetes triggered by CMV. In conclusion, suppressed beta-cell antiviral defense reveals the diabetogenic potential of two pathogens previously linked to the onset of type 1 diabetes in humans.
Insights
Impaired pancreatic beta-cell antiviral defense increases type 1 diabetes risk. Suppressed interferon responses to viruses like coxsackievirus B3 and cytomegalovirus enhance susceptibility to virus-induced diabetes.
Area of Science:
- Immunology
- Virology
- Endocrinology
Background:
- Pancreatic beta-cell antiviral defense is crucial for preventing virus-induced diabetes.
- Interferon (IFN)-mediated signaling pathways are key components of this defense mechanism.
Purpose of the Study:
- To investigate the role of IFN-induced antiviral defense in beta-cell survival against viral infections.
- To determine if impaired antiviral defense influences susceptibility to diabetes induced by Coxsackievirus B3 (CVB3), cytomegalovirus (CMV), and lymphocytic choriomeningitis virus (LCMV).
Main Methods:
- Utilized a transgenic mouse model expressing Suppressor of Cytokine Signaling-1 (SOCS-1) in beta-cells, leading to impaired IFN response.
- Infected SOCS-1 transgenic (Tg) mice and control mice with CVB3, murine CMV, and LCMV.
- Assessed viral tropism, insulitis, beta-cell destruction, and onset of diabetes.
Main Results:
- SOCS-1 Tg mice infected with CVB3 developed acute type 1 diabetes, with altered viral tropism and early detection in islet cells.
- Murine CMV infection in SOCS-1 Tg mice led to increased insulitis and a subset developed diabetes.
- LCMV infection did not cause beta-cell destruction in SOCS-1 Tg mice.
Conclusions:
- Inadequate beta-cell antiviral defense, particularly impaired IFN signaling, reveals the diabetogenic potential of CVB3 and CMV.
- These findings highlight the critical role of robust beta-cell antiviral immunity in preventing virus-triggered type 1 diabetes.