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Evolution of enhanced innate immune evasion by SARS-CoV-2.
Thorne, Lucy G; Bouhaddou, Mehdi; Reuschl, Ann-Kathrin; Zuliani-Alvarez, Lorena; Polacco, Ben; Pelin, Adrian; Batra, Jyoti; Whelan, Matthew V X; Hosmillo, Myra; Fossati, Andrea; Ragazzini, Roberta; Jungreis, Irwin; Ummadi, Manisha; Rojc, Ajda; Turner, Jane; Bischof, Marie L; Obernier, Kirsten; Braberg, Hannes; Soucheray, Margaret; Richards, Alicia; Chen, Kuei-Ho; Harjai, Bhavya; Memon, Danish; Hiatt, Joseph; Rosales, Romel; McGovern, Briana L; Jahun, Aminu; Fabius, Jacqueline M; White, Kris; Goodfellow, Ian G; Takeuchi, Yasu; Bonfanti, Paola; Shokat, Kevan; Jura, Natalia; Verba, Klim; Noursadeghi, Mahdad; Beltrao, Pedro; Kellis, Manolis; Swaney, Danielle L; García-Sastre, Adolfo; Jolly, Clare; Towers, Greg J; Krogan, Nevan J.
  • Thorne LG; Division of Infection and Immunity, University College London, London, UK.
  • Bouhaddou M; QBI Coronavirus Research Group (QCRG), University of California San Francisco, San Francisco, CA, USA.
  • Reuschl AK; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
  • Zuliani-Alvarez L; J. David Gladstone Institutes, San Francisco, CA, USA.
  • Polacco B; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
  • Pelin A; Division of Infection and Immunity, University College London, London, UK.
  • Batra J; QBI Coronavirus Research Group (QCRG), University of California San Francisco, San Francisco, CA, USA.
  • Whelan MVX; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
  • Hosmillo M; J. David Gladstone Institutes, San Francisco, CA, USA.
  • Fossati A; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
  • Ragazzini R; QBI Coronavirus Research Group (QCRG), University of California San Francisco, San Francisco, CA, USA.
  • Jungreis I; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
  • Ummadi M; J. David Gladstone Institutes, San Francisco, CA, USA.
  • Rojc A; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
  • Turner J; QBI Coronavirus Research Group (QCRG), University of California San Francisco, San Francisco, CA, USA.
  • Bischof ML; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
  • Obernier K; J. David Gladstone Institutes, San Francisco, CA, USA.
  • Braberg H; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
  • Soucheray M; QBI Coronavirus Research Group (QCRG), University of California San Francisco, San Francisco, CA, USA.
  • Richards A; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
  • Chen KH; J. David Gladstone Institutes, San Francisco, CA, USA.
  • Harjai B; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
  • Memon D; Division of Infection and Immunity, University College London, London, UK.
  • Hiatt J; Division of Virology, Department of Pathology, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
  • Rosales R; QBI Coronavirus Research Group (QCRG), University of California San Francisco, San Francisco, CA, USA.
  • McGovern BL; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
  • Jahun A; J. David Gladstone Institutes, San Francisco, CA, USA.
  • Fabius JM; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
  • White K; Epithelial Stem Cell Biology and Regenerative Medicine Laboratory, The Francis Crick Institute, London, UK.
  • Goodfellow IG; MIT Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA, USA.
  • Takeuchi Y; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Bonfanti P; QBI Coronavirus Research Group (QCRG), University of California San Francisco, San Francisco, CA, USA.
  • Shokat K; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
  • Jura N; J. David Gladstone Institutes, San Francisco, CA, USA.
  • Verba K; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
  • Noursadeghi M; QBI Coronavirus Research Group (QCRG), University of California San Francisco, San Francisco, CA, USA.
  • Beltrao P; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
  • Kellis M; J. David Gladstone Institutes, San Francisco, CA, USA.
  • Swaney DL; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
  • García-Sastre A; Division of Infection and Immunity, University College London, London, UK.
  • Jolly C; Division of Infection and Immunity, University College London, London, UK.
  • Towers GJ; QBI Coronavirus Research Group (QCRG), University of California San Francisco, San Francisco, CA, USA.
  • Krogan NJ; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
Nature ; 602(7897): 487-495, 2022 02.
Article in English | MEDLINE | ID: covidwho-1585830
ABSTRACT
The emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission1,2. Although much effort has focused on the characterization of changes in the spike protein in variants of concern, mutations outside of spike are likely to contribute to adaptation. Here, using unbiased abundance proteomics, phosphoproteomics, RNA sequencing and viral replication assays, we show that isolates of the Alpha (B.1.1.7) variant3 suppress innate immune responses in airway epithelial cells more effectively than first-wave isolates. We found that the Alpha variant has markedly increased subgenomic RNA and protein levels of the nucleocapsid protein (N), Orf9b and Orf6-all known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein that is required for activation of the RNA-sensing adaptor MAVS. Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful transmission of the Alpha variant, and may increase in vivo replication and duration of infection4. The importance of mutations outside the spike coding region in the adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the N and Orf9b regulatory regions of the Delta and Omicron variants.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Evolution, Molecular / Immune Evasion / SARS-CoV-2 / COVID-19 / Immunity, Innate Type of study: Observational study / Prognostic study Topics: Variants Limits: Humans Language: English Journal: Nature Year: 2022 Document Type: Article Affiliation country: S41586-021-04352-y

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Evolution, Molecular / Immune Evasion / SARS-CoV-2 / COVID-19 / Immunity, Innate Type of study: Observational study / Prognostic study Topics: Variants Limits: Humans Language: English Journal: Nature Year: 2022 Document Type: Article Affiliation country: S41586-021-04352-y