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Journal of Virology, July 2008, p. 6139-6149, Vol. 82, No. 13
0022-538X/08/$08.00+0     doi:10.1128/JVI.00597-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Rotavirus Infection Accelerates Type 1 Diabetes in Mice with Established Insulitis

Kate L. Graham,^1,, Natalie Sanders,^1,, Yan Tan,^1, Janette Allison,^1,2 Thomas W. H. Kay,² and Barbara S. Coulson^1*

Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia,¹ St. Vincent's Institute, Fitzroy, Victoria 3065, Australia²

Received 18 March 2008/ Accepted 9 April 2008

Infection modulates type 1 diabetes, a common autoimmune disease characterized by the destruction of insulin-producing islet β cells in the pancreas. Childhood rotavirus infections have been associated with exacerbations in islet autoimmunity. Nonobese diabetic (NOD) mice develop lymphocytic islet infiltration (insulitis) and then clinical diabetes, whereas NOD8.3 TCR mice, transgenic for a T-cell receptor (TCR) specific for an important islet autoantigen, show more rapid diabetes onset. Oral infection of infant NOD mice with the monkey rotavirus strain RRV delays diabetes development. Here, the effect of RRV infection on diabetes development once insulitis is established was determined. NOD and NOD8.3 TCR mice were inoculated with RRV aged 12 and 5 weeks, respectively. Diabetes onset was significantly accelerated in both models (P < 0.024), although RRV infection was asymptomatic and confined to the intestine. The degree of diabetes acceleration was related to the serum antibody titer to RRV. RRV-infected NOD mice showed a possible trend toward increased insulitis development. Infected males showed increased CD8⁺ T-cell proportions in islets. Levels of β-cell major histocompatibility complex class I expression and islet tumor necrosis factor alpha mRNA were elevated in at least one model. NOD mouse exposure to mouse rotavirus in a natural experiment also accelerated diabetes. Thus, rotavirus infection after β-cell autoimmunity is established affects insulitis and exacerbates diabetes. A possible mechanism involves increased exposure of β cells to immune recognition and activation of autoreactive T cells by proinflammatory cytokines. The timing of infection relative to mouse age and degree of insulitis determines whether diabetes onset is delayed, unaltered, or accelerated.

Published ahead of print on 16 April 2008.

K.L.G. and N.S. contributed equally to this study.

Present address: St. Vincent's Institute, Fitzroy, Victoria 3065, Australia.

Present address: Department of Dentistry, The University of Melbourne, Victoria 3010, Australia.