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Journal of Virology, August 2003, p. 8272-8279, Vol. 77, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.15.8272-8279.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Exogenous Interleukin-12 Protects against Lethal Infection with Coxsackievirus B4

Daniel M. Potvin,1 Dennis W. Metzger,2 William T. Lee,1,3 Doris N. Collins,1 and Arlene I. Ramsingh1,3*

Department of Biomedical Sciences, School of Public Health, State University of New York at Albany, Albany, New York 12237,1 Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208,2 Wadsworth Center, New York State Department of Health, Albany, New York 122013

Received 28 February 2003/ Accepted 6 May 2003

Infections with the group B coxsackieviruses either can be asymptomatic or can lead to debilitating chronic diseases. To elucidate the mechanism by which these viruses cause chronic disease, we developed a mouse model of chronic pancreatitis by using a virulent variant of coxsackievirus B4, CVB4-V. Infection with CVB4-V results in an early, severe pancreatitis, which can lead to mortality or progress to chronic pancreatitis. Chronic pancreatitis, in this model, is due to immunopathological mechanisms. We investigated whether interleukin-12 (IL-12) could modulate the outcome of CVB4-V infection. Eighty-five percent of the infected mice treated with 500 ng of IL-12 survived, whereas all untreated mice succumbed. To understand the mechanism underlying the beneficial effect of IL-12, we investigated the role of gamma interferon (IFN-{gamma}). Three lines of evidence suggest that the protective effect of IL-12 is due to IFN-{gamma}. First, administration of IL-12 increased the production of endogenous IFN-{gamma} in CVB4-V-infected mice. Both NK and NKT cells were identified as the source of IFN-{gamma}. Second, IFN-{gamma} knockout mice treated with IL-12 succumbed to infection with CVB4-V. Third, wild-type mice treated with IFN-{gamma} survived infection with CVB4-V. Due to the antiviral effects of IFN-{gamma}, we examined whether IL-12 treatment affected viral replication. Administration of IL-12 did not decrease viral replication in the pancreas, but it did prevent extensive tissue damage and the subsequent development of chronic pancreatitis. The data suggest that IL-12 treatment during CVB4-V infection is able to suppress the immunopathological mechanisms that lead to chronic disease.

* Corresponding author. Mailing address: Wadsworth Center, New York State Department of Health, Albany, NY 12201. Phone: (518) 474-8634. Fax: (518) 474-3181. E-mail: arlene.ramsingh{at}wadsworth.org.

Journal of Virology, August 2003, p. 8272-8279, Vol. 77, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.15.8272-8279.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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