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Journal of Virology, November 2007, p. 11620-11633, Vol. 81, No. 21
0022-538X/07/$08.00+0     doi:10.1128/JVI.00702-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Severe Acute Respiratory Syndrome Coronavirus Evades Antiviral Signaling: Role of nsp1 and Rational Design of an Attenuated Strain{triangledown}

Marc G. Wathelet,1* Melissa Orr,1 Matthew B. Frieman,2 and Ralph S. Baric2,3

Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, Ohio 45267-0576,1 Departments of Epidemiology and Microbiology and Immunology,2 Carolina Vaccine Institute, University of North Carolina, Chapel Hill, North Carolina 27599-74353

Received 2 April 2007/ Accepted 13 August 2007

The severe acute respiratory syndrome (SARS) epidemic was caused by the spread of a previously unrecognized infectious agent, the SARS-associated coronavirus (SARS-CoV). Here we show that SARS-CoV could inhibit both virus- and interferon (IFN)-dependent signaling, two key steps of the antiviral response. We mapped a strong inhibitory activity to SARS-CoV nonstructural protein 1 (nsp1) and show that expression of nsp1 significantly inhibited the activation of all three virus-dependent signaling pathways. We show that expression of nsp1 significantly inhibited IFN-dependent signaling by decreasing the phosphorylation levels of STAT1 while having little effect on those of STAT2, JAK1, and TYK2. We engineered an attenuated mutant of nsp1 in SARS-CoV through reverse genetics, and the resulting mutant virus was viable and replicated as efficiently as wild-type virus in cells with a defective IFN response. However, mutant virus replication was strongly attenuated in cells with an intact IFN response. Thus, nsp1 is likely a virulence factor that contributes to pathogenicity by favoring SARS-CoV replication.

* Corresponding author. Mailing address: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0576. Phone: (513) 558-4515. Fax: (513) 558-5738. E-mail: marc.wathelet{at}uc.edu

{triangledown} Published ahead of print on 22 August 2007.

Journal of Virology, November 2007, p. 11620-11633, Vol. 81, No. 21
0022-538X/07/$08.00+0     doi:10.1128/JVI.00702-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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