@article{a2f4022d49744b0e88e1c25cd65385fb,
title = "Evasion of Type I Interferon by SARS-CoV-2",
abstract = "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication and host immune response determine coronavirus disease 2019 (COVID-19), but studies evaluating viral evasion of immune response are lacking. Here, we use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. We identify two sets of viral proteins that antagonize IFN-I signaling through blocking signal transducer and activator of transcription 1 (STAT1)/STAT2 phosphorylation or nuclear translocation. Remarkably, SARS-CoV-2 nsp1 and nsp6 suppress IFN-I signaling more efficiently than SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Thus, when treated with IFN-I, a SARS-CoV-2 replicon replicates to a higher level than chimeric replicons containing nsp1 or nsp6 from SARS-CoV or MERS-CoV. Altogether, the study provides insights on SARS-CoV-2 evasion of IFN-I response and its potential impact on viral transmission and pathogenesis.",
keywords = "COVID-19, SARS-CoV-2, coronavirus disease 2019, immune evasion, interferon, replicon, severe acute respiratory syndrome coronavirus 2",
author = "Hongjie Xia and Zengguo Cao and Xuping Xie and Xianwen Zhang and Chen, {John Yun Chung} and Hualei Wang and Menachery, {Vineet D.} and Ricardo Rajsbaum and Shi, {Pei Yong}",
note = "Funding Information: We thank lab members and UTMB colleagues for helpful discussions during the course of this project. P.-Y.S. was supported by NIH grants AI142759, AI134907, AI145617, and UL1TR001439 and awards from the Sealy & Smith Foundation, Kleberg Foundation, John S. Dunn Foundation, Amon G. Carter Foundation, Gillson Longenbaugh Foundation, and Summerfield Robert Foundation. R.R. was supported by NIH grants R01AI134907, R21AI132479-01, and R21AI126012-01A1. V.D.M. was supported by NIH grants U19AI100625, R00AG049092, R24AI120942, and STARs Award from the University of Texas System. H.X. Z.C. X.X. X.Z. H.W. and P.-Y.S. designed experiments, analyzed data, and interpreted results. H.X. Z.C. X.X. X.Z. and J.Y.-C.C. performed experiments. V.D.M. and R.R. provided critical reagents and advice on experimental approaches. H.X. Z.C. and P.-Y.S. wrote the paper. All authors read and edited the paper. The authors declare no competing interests. Funding Information: We thank lab members and UTMB colleagues for helpful discussions during the course of this project. P.-Y.S. was supported by NIH grants AI142759 , AI134907 , AI145617 , and UL1TR001439 and awards from the Sealy & Smith Foundation , Kleberg Foundation , John S. Dunn Foundation , Amon G. Carter Foundation , Gillson Longenbaugh Foundation , and Summerfield Robert Foundation . R.R. was supported by NIH grants R01AI134907 , R21AI132479-01 , and R21AI126012-01A1 . V.D.M. was supported by NIH grants U19AI100625 , R00AG049092 , R24AI120942 , and STARs Award from the University of Texas System . Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = oct,
day = "6",
doi = "10.1016/j.celrep.2020.108234",
language = "English (US)",
volume = "33",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",
}