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J Virol, July 1998, p. 5654-5660, Vol. 72, No. 7
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

NF-kappa B-Mediated Inhibition of Apoptosis Is Required for Encephalomyocarditis Virus Virulence: a Mechanism of Resistance in p50 Knockout Mice

Edward M. Schwarz,1,dagger Cornel Badorff,2 Timothy S. Hiura,2 Rainer Wessely,2 Annette Badorff,2 Inder M. Verma,1 and Kirk U. Knowlton2,*

Laboratory of Genetics, The Salk Institute, San Diego, California 92186-5800,1 and Department of Medicine, University of California, San Diego, California 92093-06132

Received 25 November 1997/Accepted 23 March 1998

Apoptosis is a central host defense mechanism to eliminate virus-infected cells. Activation of NF-kappa B suppresses apoptosis following some types of stimulation in vitro. To test the physiological importance of this pathway in vivo, we studied murine encephalomyocarditis virus (EMCV) infection in mice and cell lines defective in NF-kappa B1 (p50) signaling. As previously reported, we find that all p50 knockout (p50 -/-) mice survive an EMCV infection that readily kills normal mice. By introducing the p50 mutation into interferon (IFN) type I receptor knockout (IFNRI -/-) mice, we find that this resistance is not mediated by IFN-beta as previously thought. While no IFNRI -/- mice survive, the double-knockout mice survive 60% of the time. The survival is tightly linked to the animals' ability to clear the virus from the heart in vivo. Using murine embryonic fibroblasts (MEF) derived from wild-type, p50 -/-, and p65 -/- embryos, we found that NF-kappa B is not required for the replication cycle of EMCV. However, during these experiments we observed that p50 -/- and p65 -/- MEF infected with EMCV undergo enhanced, premature cytotoxicity. Upon examination of this cell death, we found that EMCV infection induced both plasma membrane and nuclear changes typical of apoptosis in all cell lines. These apoptotic processes occurred in an accelerated and pronounced way in the NF-kappa B-defective cells, as soon as 6 h after infection, when virus is beginning to be released. Previously, only the RelA (p65) subunit of NF-kappa B has been shown to play a role in suppressing apoptosis. In our studies, we find that p50 is equally important in suppressing apoptosis during EMCV infection. Additionally, we show that suppression of apoptosis by NF-kappa B1 is required for EMCV virulence in vivo. The attenuation in p50 -/- mice can be explained by rapid apoptosis of infected cells which allows host phagocytes to clear infected cells before the viral burst leading to a reduction of the viral burden and survival of the mice.

* Corresponding author. Mailing address: Department of Medicine, 0613c, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0613. Phone: (619) 822-1363. Fax: (619) 822-1365. E-mail: kknowlton{at}ucsd.edu.

dagger Present address: Immunology/Rheumatology Unit, University of Rochester, Rochester, NY 14642.

J Virol, July 1998, p. 5654-5660, Vol. 72, No. 7
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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