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Journal of Virology, January 2005, p. 1045-1052, Vol. 79, No. 2
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.2.1045-1052.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Diabetes Acceleration or Prevention by a Coxsackievirus B4 Infection: Critical Requirements for both Interleukin-4 and Gamma Interferon

David V. Serreze,1 Clive Wasserfall,2 Eric W. Ottendorfer,2 Michael Stalvey,3,5 Melissa A. Pierce,1 Charles Gauntt,4,5 Brian O'Donnell,5 James B. Flanagan,5 Martha Campbell-Thompson,2 Tamir M. Ellis,2 and Mark A. Atkinson2*

The Jackson Laboratory, Bar Harbor, Maine,1 Department of Pathology,2 Department of Pediatrics,3 Department of Biochemistry, University of Florida, Gainesville, Florida,5 Department of Microbiology, University of Texas, San Antonio, Texas4

Received 23 July 2004/ Accepted 23 August 2004

Type 1 diabetes acceleration in nonobese diabetic (NOD) mice through coxsackievirus B4 (CVB4) infection requires a preexisting critical mass of autoreactive T cells in pancreatic islets, and in the absence of this insulitic threshold, CVB4 infection leads to long-term disease protection. To understand this acceleration and protection process, we challenged 8- and 12-week-old NOD mice containing a disruption in interleukin-4 (IL-4) or gamma interferon (IFN-{gamma}) genes (NOD IL-4–/– and NOD IFN-{gamma}–/–, respectively) with a diabetogenic, pancreatropic Edwards strain of CVB4. The elimination of IL-4 did not alter the rate of insulitis or diabetes development in NOD mice, while the elimination of IFN-{gamma} delayed these events several weeks. CVB4 infection in 8-week-old mice only significantly accelerated the onset of diabetes in a subset of standard, but not IL-4- or IFN-{gamma}-deficient, NOD mice. Long-term diabetes protection was established in standard NOD mice as well as in the NOD IFN-{gamma}–/– mice that did not rapidly develop disease following CVB4 infection at 8 weeks of age. When mice were infected at 12 weeks of age, the onset of diabetes was accelerated in NOD IL-4–/– mice, while neither acceleration nor long-term protection was elicited in NOD IFN-{gamma}–/– mice. No differences were observed in the kinetics of CVB4 clearance in pancreases from NOD, NOD IL-4–/–, and NOD IFN-{gamma}–/– mice. Collectively, these results suggest that at the insulitis threshold at which CVB4 infection can first accelerate the onset of diabetes in NOD mice, IL-4 as well as IFN-{gamma} contributes to this pathogenic process. The protective mechanism against diabetes elicited in NOD mice infected with CVB4 prior to the development of a critical threshold level of insulitis requires neither IL-4 nor IFN-{gamma}.

* Corresponding author. Mailing address: Department of Pathology, University of Florida, Box 100275 JHMHC, 1600 SW Archer Rd., Gainesville, FL 32610. Phone: (352) 392-0048. Fax: (352) 392-8464. E-mail: atkinson{at}ufl.edu.

Journal of Virology, January 2005, p. 1045-1052, Vol. 79, No. 2
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.2.1045-1052.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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