Diabetogenic potential of human pathogens uncovered in experimentally permissive beta-cells.
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.
Flodström
Malin
M
Department of Immunology, the Scripps Research Institute, La Jolla, California, USA.
Tsai
Devin
D
Fine
Cody
C
Maday
Amy
A
Sarvetnick
Nora
N
D000208:Acute Disease; D000818:Animals; D001117:Arenaviridae Infections / Q000150:complications / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics; D003586:Cytomegalovirus Infections / Q000150:complications* / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000821:virology*; D006566:Herpesviridae Infections / Q000150:complications / Q000276:immunology; D006801:Humans; D007372:Interferons / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000276:immunology / Q000821:virology*; D008217:Lymphocytic choriomeningitis virus; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D018146:Muromegalovirus; D009205:Myocarditis / Q000821:virology; D010195:Pancreatitis / Q000276:immunology / Q000821:virology; D012097:Repressor Proteins; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013601:T-Lymphocytes / Q000276:immunology
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D012097:Repressor Proteins; C108944:SOCS1 protein, human; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007372:Interferons