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Journal of Virology, March 1999, p. 1756-1766, Vol. 73, No. 3
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Protection from Lethal Coxsackievirus-Induced Pancreatitis by Expression of Gamma Interferondagger

Marc S. Horwitz, Troy Krahl, Cody Fine, Jae Lee, and Nora Sarvetnick*

Department of Immunology, The Scripps Research Institute, La Jolla, California 92037

Received 19 October 1998/Accepted 12 November 1998

Coxsackievirus infection causes severe pancreatitis and myocarditis in humans, often leading to death in young or immunocompromised individuals. In susceptible strains of mice, coxsackievirus strain CB4 causes lethal hypoglycemia. To investigate the potential of gamma interferon (IFN-gamma ) in protection and clearance of the viral infection, IFN-gamma knockout mice and transgenic (Tg) mice specifically expressing IFN-gamma in their pancreatic beta  cells were infected with CB4. Lack of IFN-gamma in mice normally resistant to CB4-mediated disease resulted in hypoglycemia and rapid death. However, expression of IFN-gamma in the beta  cells of Tg mice otherwise susceptible to lethal infection allowed for survival and protected them from developing the accompanying hypoglycemia. While all the mice had high levels of viral replication in their pancreata and comparable tissue pathology following viral infection, the Tg mice had significantly lower levels of virus at the peak of infection, significantly higher numbers of activated macrophages before and after infection, and less damage to their acinar tissue. Additionally, despite having increased levels of inducible nitric oxide synthetase (iNOS) expression, treatment of Tg mice with the iNOS inhibitor aminoguanidine did not alter the level of protection afforded by IFN-gamma expression. In conclusion, IFN-gamma protects from lethal coxsackievirus infection by activating macrophages in an iNOS-independent manner.

* Corresponding author. Mailing address: Department of Immunology (IMM-23), The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (619) 784-9066. Fax: (619) 784-9083. E-mail: noras{at}scripps.edu.

dagger This is manuscript number 11674-IMM from The Scripps Research Institute.

Journal of Virology, March 1999, p. 1756-1766, Vol. 73, No. 3
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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