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Journal of Virology, September 2001, p. 8187-8194, Vol. 75, No. 17
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.17.8187-8194.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Expression of Immunoregulatory Cytokines by Recombinant Coxsackievirus B3 Variants Confers Protection against Virus-Caused Myocarditis

Andreas Henke,* Roland Zell, Gunter Ehrlich, and Axel Stelzner

Institute of Virology, Medical Center, Friedrich Schiller University, D-07745 Jena, Germany

Received 12 March 2001/Accepted 29 May 2001

Clinical and laboratory investigations have demonstrated the involvement of viruses and bacteria as potential causative agents in cardiovascular disease and have specifically found coxsackievirus B3 (CVB3) to be a leading cause. Experimental data indicate that cytokines are involved in controlling CVB3 replication. Therefore, recombinant CVB3 (CVB3rec) variants expressing the T-helper-1 (TH1)-specific gamma interferon (IFN-gamma ) or the TH2-specific interleukin-10 (IL-10) as well as the control virus CVB3(muIL-10), which produce only biologically inactive IL-10, were established. Coding regions of murine cytokines were cloned into the 5' end of the CVB3 wild type (CVB3wt) open reading frame and were supplied with an artificial viral 3Cpro-specific Q-G cleavage site. Correct processing releases active cytokines, and the concentration of IFN-gamma and IL-10 was analyzed by enzyme-linked immunosorbent assay and bioassays. In mice, CVB3wt was detectable in pancreas and heart tissue, causing massive destruction of the exocrine pancreas as well as myocardial inflammation and heart cell lysis. Most of the CVB3wt-infected mice revealed virus-associated symptoms, and some died within 28 days postinfection. In contrast, CVB3rec variants were present only in the pancreas of infected mice, causing local inflammation with subsequent healing. Four weeks after the first infection, surviving mice were challenged with the lethal CVB3H3 variant, causing casualties in the CVB3wt- and CVB3(muIL-10)-infected groups, whereas almost none of the CVB3(IFN-gamma )- and CVB3(IL-10)-infected mice died and no pathological disorders were detectable. This study demonstrates that expression of immunoregulatory cytokines during CVB3 replication simultaneously protects mice against a lethal disease and prevents virus-caused tissue destruction.

* Corresponding author. Mailing address: Institute of Virology, Medical Center, Friedrich Schiller University, Winzerlaer Str. 10, D-07745 Jena, Germany. Phone: (49) 3641 657215. Fax: (49) 3641 657202. E-mail: i6hean{at}rz.uni-jena.de.

Journal of Virology, September 2001, p. 8187-8194, Vol. 75, No. 17
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.17.8187-8194.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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