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Evolution of enhanced innate immune evasion by SARS-CoV-2

Author

Listed:
  • Lucy G. Thorne

    (University College London)

  • Mehdi Bouhaddou

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Ann-Kathrin Reuschl

    (University College London)

  • Lorena Zuliani-Alvarez

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Ben Polacco

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Adrian Pelin

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Jyoti Batra

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Matthew V. X. Whelan

    (University College London)

  • Myra Hosmillo

    (Addenbrooke’s Hospital, University of Cambridge)

  • Andrea Fossati

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Roberta Ragazzini

    (The Francis Crick Institute)

  • Irwin Jungreis

    (MIT
    Broad Institute of MIT and Harvard)

  • Manisha Ummadi

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Ajda Rojc

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Jane Turner

    (University College London)

  • Marie L. Bischof

    (University College London)

  • Kirsten Obernier

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Hannes Braberg

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Margaret Soucheray

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Alicia Richards

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Kuei-Ho Chen

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Bhavya Harjai

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Danish Memon

    (European Bioinformatics Institute, Wellcome Genome Campus)

  • Joseph Hiatt

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Romel Rosales

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Briana L. McGovern

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Aminu Jahun

    (Addenbrooke’s Hospital, University of Cambridge)

  • Jacqueline M. Fabius

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Kris White

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Ian G. Goodfellow

    (Addenbrooke’s Hospital, University of Cambridge)

  • Yasu Takeuchi

    (University College London)

  • Paola Bonfanti

    (The Francis Crick Institute)

  • Kevan Shokat

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Natalia Jura

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    University of California San Francisco
    National Institute for Biological Standards and Control)

  • Klim Verba

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    University of California San Francisco)

  • Mahdad Noursadeghi

    (University College London)

  • Pedro Beltrao

    (University of California San Francisco
    European Bioinformatics Institute, Wellcome Genome Campus)

  • Manolis Kellis

    (MIT
    Broad Institute of MIT and Harvard)

  • Danielle L. Swaney

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

  • Adolfo García-Sastre

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Clare Jolly

    (University College London)

  • Greg J. Towers

    (University College London)

  • Nevan J. Krogan

    (University of California San Francisco
    Quantitative Biosciences Institute (QBI), University of California San Francisco
    J. David Gladstone Institutes
    University of California San Francisco)

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.

Suggested Citation

  • Lucy G. Thorne & Mehdi Bouhaddou & Ann-Kathrin Reuschl & Lorena Zuliani-Alvarez & Ben Polacco & Adrian Pelin & Jyoti Batra & Matthew V. X. Whelan & Myra Hosmillo & Andrea Fossati & Roberta Ragazzini &, 2022. "Evolution of enhanced innate immune evasion by SARS-CoV-2," Nature, Nature, vol. 602(7897), pages 487-495, February.
  • Handle: RePEc:nat:nature:v:602:y:2022:i:7897:d:10.1038_s41586-021-04352-y
    DOI: 10.1038/s41586-021-04352-y
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    Citations

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    Cited by:

    1. Nell Saunders & Blandine Monel & Nadège Cayet & Lorenzo Archetti & Hugo Moreno & Alexandre Jeanne & Agathe Marguier & Julian Buchrieser & Timothy Wai & Olivier Schwartz & Mathieu Fréchin, 2024. "Dynamic label-free analysis of SARS-CoV-2 infection reveals virus-induced subcellular remodeling," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Emily E. Bendall & Amy P. Callear & Amy Getz & Kendra Goforth & Drew Edwards & Arnold S. Monto & Emily T. Martin & Adam S. Lauring, 2023. "Rapid transmission and tight bottlenecks constrain the evolution of highly transmissible SARS-CoV-2 variants," Nature Communications, Nature, vol. 14(1), pages 1-7, December.
    3. Ana S. Gonzalez-Reiche & Hala Alshammary & Sarah Schaefer & Gopi Patel & Jose Polanco & Juan Manuel Carreño & Angela A. Amoako & Aria Rooker & Christian Cognigni & Daniel Floda & Adriana Guchte & Zain, 2023. "Sequential intrahost evolution and onward transmission of SARS-CoV-2 variants," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. Kelsey M. Haas & Michael J. McGregor & Mehdi Bouhaddou & Benjamin J. Polacco & Eun-Young Kim & Thong T. Nguyen & Billy W. Newton & Matthew Urbanowski & Heejin Kim & Michael A. P. Williams & Veronica V, 2023. "Proteomic and genetic analyses of influenza A viruses identify pan-viral host targets," Nature Communications, Nature, vol. 14(1), pages 1-27, December.
    5. Qihong Yan & Xijie Gao & Banghui Liu & Ruitian Hou & Ping He & Yong Ma & Yudi Zhang & Yanjun Zhang & Zimu Li & Qiuluan Chen & Jingjing Wang & Xiaohan Huang & Huan Liang & Huiran Zheng & Yichen Yao & X, 2024. "Antibodies utilizing VL6-57 light chains target a convergent cryptic epitope on SARS-CoV-2 spike protein and potentially drive the genesis of Omicron variants," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    6. Farina Karim & Catherine Riou & Mallory Bernstein & Zesuliwe Jule & Gila Lustig & Strauss Graan & Roanne S. Keeton & Janine-Lee Upton & Yashica Ganga & Khadija Khan & Kajal Reedoy & Matilda Mazibuko &, 2024. "Clearance of persistent SARS-CoV-2 associates with increased neutralizing antibodies in advanced HIV disease post-ART initiation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    7. Lisa-Marie Funk & Gereon Poschmann & Fabian Rabe von Pappenheim & Ashwin Chari & Kim M. Stegmann & Antje Dickmanns & Marie Wensien & Nora Eulig & Elham Paknia & Gabi Heyne & Elke Penka & Arwen R. Pear, 2024. "Multiple redox switches of the SARS-CoV-2 main protease in vitro provide opportunities for drug design," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    8. Denis Mongin & Nils Bürgisser & Gustavo Laurie & Guillaume Schimmel & Diem-Lan Vu & Stephane Cullati & Delphine Sophie Courvoisier, 2023. "Effect of SARS-CoV-2 prior infection and mRNA vaccination on contagiousness and susceptibility to infection," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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