title: Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Center of Biodefense and Emerging Infectious Diseases, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555-1019, USA.
authors.forename: Santhana G
authors.initials: SG
authors.lastname: Devaraj
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.forename: Zhongbin
authors.initials: Z
authors.lastname: Chen
authors.forename: Zihong
authors.initials: Z
authors.lastname: Chen
authors.forename: Monica
authors.initials: M
authors.lastname: Tseng
authors.forename: Naina
authors.initials: N
authors.lastname: Barretto
authors.forename: Rongtuan
authors.initials: R
authors.lastname: Lin
authors.forename: Clarence J
authors.initials: CJ
authors.lastname: Peters
authors.forename: Chien-Te K
authors.initials: CT
authors.lastname: Tseng
authors.forename: Susan C
authors.initials: SC
authors.lastname: Baker
authors.forename: Kui
authors.initials: K
authors.lastname: Li
mesh_terms: D000818:Animals; D001980:Bronchi / Q000166:cytology / Q000276:immunology / Q000821:virology; D002460:Cell Line; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology; D010447:Peptide Hydrolases / Q000737:chemistry / Q000276:immunology*; D017434:Protein Structure, Tertiary; D045473:Severe acute respiratory syndrome-related coronavirus / Q000201:enzymology* / Q000276:immunology*; D045169:Severe Acute Respiratory Syndrome / Q000276:immunology* / Q000821:virology; D014764:Viral Proteins / Q000737:chemistry / Q000276:immunology*
chemical_list: D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D014764:Viral Proteins; D010447:Peptide Hydrolases