JVI Accepts, published online ahead of print on 16 April 2008

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J. Virol. doi:10.1128/JVI.00597-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Rotavirus Infection Accelerates Type 1 Diabetes in Mice with Established Insulitis

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

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

^* To whom correspondence should be addressed. Email: barbarac{at}unimelb.edu.au.

Infection modulates type 1 diabetes, a common autoimmune disease characterized by destruction of insulin-producing islet cells in the pancreas. Childhood rotavirus infections have been associated with exacerbations in islet autoimmunity. Non-obese diabetic (NOD) mice develop lymphocytic islet infiltration (insulitis) then clinical diabetes, whereas NOD8.3 TCR mice, transgenic for a T cell receptor specific for an important islet autoantigen, show more rapid diabetes onset. Oral infection of infant NOD mice with monkey rotavirus 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 titre to RRV. RRV-infected NOD mice showed a possible trend towards increased insulitis development. Infected males showed increased CD8+ T cell proportions in islets. Levels of cell MHC class I expression and islet TNF 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 cell autoimmunity is established affects insulitis and exacerbates diabetes. A possible mechanism involves increased exposure of 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.