title: Severe acute respiratory syndrome coronavirus evades antiviral signaling: role of nsp1 and rational design of an attenuated strain.
abstract: 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.
authors: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0576, USA. marc.wathelet@uc.edu
authors: Marc G
authors: MG
authors: Wathelet
authors: Melissa
authors: M
authors: Orr
authors: Matthew B
authors: MB
authors: Frieman
authors: Ralph S
authors: RS
authors: Baric
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D024882:Drug Resistance, Viral; D017930:Genes, Reporter; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism; D007372:Interferons / Q000378:metabolism; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D012324:RNA-Dependent RNA Polymerase / Q000378:metabolism*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; D016899:Interferon-beta; D007372:Interferons; C521592:Nsp1 protein, SARS coronavirus; D012324:RNA-Dependent RNA Polymerase
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