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J. Biol. Chem., Vol. 282, Issue 44, 32208-32221, November 2, 2007
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From the
Department of Microbiology and Immunology and the ||Center of Biodefense and Emerging Infectious Diseases, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas 77555-1019, the Department of Microbiology and Immunology, Loyola University of Chicago, Maywood, Illinois 60153, and ¶Lady Davis Institute for Medical Research, Montreal, Quebec H3T 1E2, Canada
Severe acute respiratory syndrome coronavirus (SARS-CoV) is a novel coronavirus that causes a highly contagious respiratory disease, SARS, with significant mortality. Although factors contributing to the highly pathogenic nature of SARS-CoV remain poorly understood, it has been reported that SARS-CoV infection does not induce type I interferons (IFNs) in cell culture. However, it is uncertain whether SARS-CoV evades host detection or has evolved mechanisms to counteract innate host defenses. We show here that infection of SARS-CoV triggers a weak IFN response in cultured human lung/bronchial epithelial cells without inducing the phosphorylation of IFN-regulatory factor 3 (IRF-3), a latent cellular transcription factor that is pivotal for type I IFN synthesis. Furthermore, SARS-CoV infection blocked the induction of IFN antiviral activity and the up-regulation of protein expression of a subset of IFN-stimulated genes triggered by double-stranded RNA or an unrelated paramyxovirus. In searching for a SARS-CoV protein capable of counteracting innate immunity, we identified the papain-like protease (PLpro) domain as a potent IFN antagonist. The inhibition of the IFN response does not require the protease activity of PLpro. Rather, PLpro interacts with IRF-3 and inhibits the phosphorylation and nuclear translocation of IRF-3, thereby disrupting the activation of type I IFN responses through either Toll-like receptor 3 or retinoic acid-inducible gene I/melanoma differentiation-associated gene 5 pathways. Our data suggest that regulation of IRF-3-dependent innate antiviral defenses by PLpro may contribute to the establishment of SARS-CoV infection.
Received for publication, June 13, 2007 , and in revised form, August 27, 2007.
* This work was supported in part by National Institutes of Health Grants AI069285, DA018054 (to K. L.), AI45798, AI060915 (to S. C. B.), and AI30039 and Western Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Career Development Grant AI057156 (to C. T. K. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The on-line version of this article (available at http://www.jbc.org) contains supplemental text and Figs. 1 and 2.
1 To whom correspondence should be addressed: 4.142G Blocker Medical Research Bldg., University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1019. Tel.: 409-772-4934; Fax: 409-772-5065; E-mail: kuli{at}utmb.edu.
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