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* Department of Medicine and
Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655
Viral infections are associated epidemiologically with the expression of type 1 diabetes in humans, but the mechanisms underlying this putative association are unknown. To investigate the role of viruses in diabetes, we used a model of viral induction of autoimmune diabetes in genetically susceptible biobreeding diabetes-resistant (BBDR) rats. BBDR rats do not develop diabetes in viral-Ab-free environments, but 
25% of animals infected with the parvovirus Kilham rat virus (KRV) develop autoimmune diabetes via a mechanism that does not involve 
cell infection. Using this model, we recently documented that TLR agonists synergize with KRV infection and increase disease penetrance. We now report that KRV itself activates innate immunity through TLR ligation. We show that KRV infection strongly stimulates BBDR splenocytes to produce the proinflammatory cytokines IL-6 and IL-12p40 but not TNF-
. KRV infection induces high levels of IL-12p40 by splenic B cells and Flt-3-ligand-induced bone marrow-derived dendritic cells (DCs) but only low levels of IL-12p40 production by thioglycolate-elicited peritoneal macrophages or GM-CSF plus IL-4-induced bone marrow-derived DCs. KRV-induced cytokine production is blocked by pharmacological inhibitors of protein kinase R and NF-
B. Genomic KRV DNA also induces BBDR splenocytes and Flt-3L-induced DCs from wild-type but not TLR9-deficient mice to produce IL-12p40; KRV-induced up-regulation of B lymphocytes can be blocked by TLR9 antagonists including inhibitory CpG and chloroquine. Administration of chloroquine to virus-infected BBDR rats decreases the incidence of diabetes and decreases blood levels of IL-12p40. Our data implicate the TLR9-signaling pathway in KRV-induced innate immune activation and autoimmune diabetes in the BBDR rat.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This was supported in part by Grants DK49106, DK36024, DK25306, 1R21AI059414-01, AI057588, and a Diabetes and Endocrinology Research Center Grant DK32520 from the National Institutes of Health, Grant 1-2006-745 from the Juvenile Diabetes Research Foundation, and a grant from the Iacocca Foundation. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Danny Zipris, Diabetes Division, University of Massachusetts Medical School, Two Biotech, Suite 218, 373 Plantation Street, Worcester, MA 01605. E-mail address: danny.zipris{at}umassmed.edu
3 Abbreviations used in this paper: T1D, type 1 diabetes; BBDR, biobreeding diabetes resistant; KRV, Kilham rat virus; Treg, regulatory T cell; DC, dendritic cell; NRK, normal rat kidney; cDMEM, complete DMEM; iCpG, inhibitory CpG; PDTC, pyrrolidine dithiocarbamate; PKR, protein kinase R; 2AP, 2-aminopurine; poly(I:C), polyinosinic:polycytidylic acid; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.
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