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.
Highlights
32208 JOURNAL OF BIOLOGICAL CHEMISTRY tion of type I interferons (IFN2-␣ and -)
To ensure that these findings generally reflect SARSCoV infection and were not a cell-type specific phenomenon, we conducted similar experiments in an African green monkey kidney cell line MA104. These cells have been reported to be permissive for SARS-CoV infection [55], and we have found that MA104 cells supported SARS-CoV replication with faster kinetics than Calu-3 cells, with cytopathic effect (CPE) seen as early as 28 h postinfection
We found that infection of MA104 cells with SARS-CoV up-regulated IFN- mRNA by 12- and 49-fold, respectively, at 20 and 30 h postinfection, the induction of IFN mRNA was significantly weaker than that (409-fold) triggered by transfection of a synthetic dsRNA analog, poly(I-C) (Fig. 1B, right panel)
Summary
32208 JOURNAL OF BIOLOGICAL CHEMISTRY tion of type I interferons (IFN2-␣ and -). IFN induces the expression of hundreds of IFN-stimulated genes (ISGs) that establish an antiviral state, thereby limiting viral replication and spread [1,2,3,4,5]. A similar inhibition of poly(I-C)-induced ISG56 expression by PLpro-TM was observed in these cells, regardless of the delivery route, i.e. poly(I-C) being added to culture medium or introduced into cells by transfection, which engage the TLR3 and MDA5 pathways [10, 11], respectively (Fig. 5A, ISG56 panel, compare lane 6 versus 2, and data not shown).
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