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Journal of Virology, October 2000, p. 9580-9585, Vol. 74, No. 20
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The Murine Double-Stranded RNA-Dependent Protein Kinase PKR Is Required for Resistance to Vesicular Stomatitis Virus

David F. Stojdl,1,2 Ninan Abraham,3 Shane Knowles,1 Ricardo Marius,1 Ann Brasey,4 Brian D. Lichty,1 Earl G. Brown,2 Nahum Sonenberg,4 and John C. Bell1,2,*

Ottawa Regional Cancer Centre Research Laboratories, Ottawa, Ontario K1H 8L6,1 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5,2 and Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6,4 Canada, and Gladstone Institute of Virology and Immunology, San Francisco, California 94141-91003

Received 31 March 2000/Accepted 25 July 2000

Interferon (IFN)-induced antiviral responses are mediated through a variety of proteins, including the double-stranded RNA-dependent protein kinase PKR. Here we show that fibroblasts derived from PKR-/- mice are more permissive for vesicular stomatitis virus (VSV) infection than are wild-type fibroblasts and demonstrate a deficiency in alpha/beta-IFN-mediated protection. We further show that mice lacking PKR are extremely susceptible to intranasal VSV infection, succumbing within days after instillation with as few as 50 infectious viral particles. Again, alpha/beta-IFN was unable to rescue PKR-/- mice from VSV infection. Surprisingly, intranasally infected PKR-/- mice died not from pathology of the central nervous system but rather from acute infection of the respiratory tract, demonstrating high virus titers in the lungs compared to similarly infected wild-type animals. These results confirm the role of PKR as the major component of IFN-mediated resistance to VSV infection. Since previous reports have shown PKR to be nonessential for survival in animals challenged with encephalomyocarditis virus, influenza virus, and vaccinia virus (N. Abraham et al., J. Biol. Chem. 274:5953-5962, 1999; Y. Yang et al., EMBO J. 14:6095-6106, 1995), our findings serve to highlight the premise that host dependence on the various mediators of IFN-induced antiviral defenses is pathogen specific.

* Corresponding author. Mailing address: Ottawa Regional Cancer Centre Research Laboratories, 501 Smyth Rd., Ottawa, Ontario K1H 8L6, Canada. Phone: (613) 737-7700, ext. 6893. Fax: (613) 247-3524. E-mail: jbell{at}med.uottawa.ca.

Journal of Virology, October 2000, p. 9580-9585, Vol. 74, No. 20
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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