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Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant

View ORCID ProfileLucy G Thorne, View ORCID ProfileMehdi Bouhaddou, View ORCID ProfileAnn-Kathrin Reuschl, View ORCID ProfileLorena Zuliani-Alvarez, View ORCID ProfileBen Polacco, View ORCID ProfileAdrian Pelin, View ORCID ProfileJyoti Batra, View ORCID ProfileMatthew V.X. Whelan, View ORCID ProfileManisha Ummadi, View ORCID ProfileAjda Rojc, View ORCID ProfileJane Turner, View ORCID ProfileKirsten Obernier, View ORCID ProfileHannes Braberg, View ORCID ProfileMargaret Soucheray, View ORCID ProfileAlicia Richards, View ORCID ProfileKuei-Ho Chen, Bhavya Harjai, View ORCID ProfileDanish Memon, View ORCID ProfileMyra Hosmillo, View ORCID ProfileJoseph Hiatt, View ORCID ProfileAminu Jahun, View ORCID ProfileIan G. Goodfellow, Jacqueline M. Fabius, View ORCID ProfileKevan Shokat, View ORCID ProfileNatalia Jura, View ORCID ProfileKlim Verba, View ORCID ProfileMahdad Noursadeghi, View ORCID ProfilePedro Beltrao, View ORCID ProfileDanielle L. Swaney, View ORCID ProfileAdolfo Garcia-Sastre, View ORCID ProfileClare Jolly, View ORCID ProfileGreg J. Towers, View ORCID ProfileNevan J. Krogan
doi: https://doi.org/10.1101/2021.06.06.446826
Lucy G Thorne
1Division of Infection and Immunity, University College London, London, WC1E 6BT, United Kingdom
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Mehdi Bouhaddou
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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Ann-Kathrin Reuschl
1Division of Infection and Immunity, University College London, London, WC1E 6BT, United Kingdom
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  • ORCID record for Ann-Kathrin Reuschl
Lorena Zuliani-Alvarez
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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  • ORCID record for Lorena Zuliani-Alvarez
Ben Polacco
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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Adrian Pelin
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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  • ORCID record for Adrian Pelin
Jyoti Batra
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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Matthew V.X. Whelan
1Division of Infection and Immunity, University College London, London, WC1E 6BT, United Kingdom
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  • ORCID record for Matthew V.X. Whelan
Manisha Ummadi
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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  • ORCID record for Manisha Ummadi
Ajda Rojc
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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  • ORCID record for Ajda Rojc
Jane Turner
1Division of Infection and Immunity, University College London, London, WC1E 6BT, United Kingdom
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  • ORCID record for Jane Turner
Kirsten Obernier
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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  • ORCID record for Kirsten Obernier
Hannes Braberg
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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  • ORCID record for Hannes Braberg
Margaret Soucheray
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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  • ORCID record for Margaret Soucheray
Alicia Richards
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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  • ORCID record for Alicia Richards
Kuei-Ho Chen
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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Bhavya Harjai
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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Danish Memon
7European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
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Myra Hosmillo
8Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK
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Joseph Hiatt
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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Aminu Jahun
8Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK
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Ian G. Goodfellow
8Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK
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Jacqueline M. Fabius
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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Kevan Shokat
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
6Howard Hughes Medical Institute, San Francisco, CA 94158, USA
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Natalia Jura
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
9Cardiovascular Research Institute, University of California - San Francisco, San Francisco, CA 94158, U.S.A
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Klim Verba
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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Mahdad Noursadeghi
1Division of Infection and Immunity, University College London, London, WC1E 6BT, United Kingdom
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Pedro Beltrao
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
7European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
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Danielle L. Swaney
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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Adolfo Garcia-Sastre
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
10Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
11Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
12The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
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Clare Jolly
1Division of Infection and Immunity, University College London, London, WC1E 6BT, United Kingdom
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  • ORCID record for Clare Jolly
  • For correspondence: nevan.krogan@ucsf.edu g.towers@ucl.ac.uk c.jolly@ucl.ac.uk
Greg J. Towers
1Division of Infection and Immunity, University College London, London, WC1E 6BT, United Kingdom
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  • ORCID record for Greg J. Towers
  • For correspondence: nevan.krogan@ucsf.edu g.towers@ucl.ac.uk c.jolly@ucl.ac.uk
Nevan J. Krogan
2Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA
3Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, 94158, USA
4J. David Gladstone Institutes, San Francisco, CA 94158, USA
5Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
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  • ORCID record for Nevan J. Krogan
  • For correspondence: nevan.krogan@ucsf.edu g.towers@ucl.ac.uk c.jolly@ucl.ac.uk
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Abstract

Emergence of SARS-CoV-2 variants, including the globally successful B.1.1.7 lineage, suggests viral adaptations to host selective pressures resulting in more efficient transmission. Although much effort has focused on Spike adaptation for viral entry and adaptive immune escape, B.1.1.7 mutations outside Spike likely contribute to enhance transmission. Here we used unbiased abundance proteomics, phosphoproteomics, mRNA sequencing and viral replication assays to show that B.1.1.7 isolates more effectively suppress host innate immune responses in airway epithelial cells. We found that B.1.1.7 isolates have dramatically increased subgenomic RNA and protein levels of Orf9b and Orf6, both known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein required for RNA sensing adaptor MAVS activation, and Orf9b binding and activity was regulated via phosphorylation. We conclude that B.1.1.7 has evolved beyond the Spike coding region to more effectively antagonise host innate immune responses through upregulation of specific subgenomic RNA synthesis and increased protein expression of key innate immune antagonists. We propose that more effective innate immune antagonism increases the likelihood of successful B.1.1.7 transmission, and may increase in vivo replication and duration of infection.

Competing Interest Statement

The Krogan Laboratory has received research support from Vir Biotechnology and F. Hoffmann-La Roche. Nevan Krogan has consulting agreements with the Icahn School of Medicine at Mount Sinai, New York, Maze Therapeutics and Interline Therapeutics, is a shareholder of Tenaya Therapeutics and has received stocks from Maze Therapeutics and Interline Therapeutics. The A.G.-S. laboratory has received research support from Pfizer, Senhwa Biosciences, Kenall Manufacturing, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix and Merck. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Pagoda, Accurius, Esperovax, Farmak and Pfizer. A.G.-S. is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections, owned by the Icahn School of Medicine at Mount Sinai, New York.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant
Lucy G Thorne, Mehdi Bouhaddou, Ann-Kathrin Reuschl, Lorena Zuliani-Alvarez, Ben Polacco, Adrian Pelin, Jyoti Batra, Matthew V.X. Whelan, Manisha Ummadi, Ajda Rojc, Jane Turner, Kirsten Obernier, Hannes Braberg, Margaret Soucheray, Alicia Richards, Kuei-Ho Chen, Bhavya Harjai, Danish Memon, Myra Hosmillo, Joseph Hiatt, Aminu Jahun, Ian G. Goodfellow, Jacqueline M. Fabius, Kevan Shokat, Natalia Jura, Klim Verba, Mahdad Noursadeghi, Pedro Beltrao, Danielle L. Swaney, Adolfo Garcia-Sastre, Clare Jolly, Greg J. Towers, Nevan J. Krogan
bioRxiv 2021.06.06.446826; doi: https://doi.org/10.1101/2021.06.06.446826
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Evolution of enhanced innate immune evasion by the SARS-CoV-2 B.1.1.7 UK variant
Lucy G Thorne, Mehdi Bouhaddou, Ann-Kathrin Reuschl, Lorena Zuliani-Alvarez, Ben Polacco, Adrian Pelin, Jyoti Batra, Matthew V.X. Whelan, Manisha Ummadi, Ajda Rojc, Jane Turner, Kirsten Obernier, Hannes Braberg, Margaret Soucheray, Alicia Richards, Kuei-Ho Chen, Bhavya Harjai, Danish Memon, Myra Hosmillo, Joseph Hiatt, Aminu Jahun, Ian G. Goodfellow, Jacqueline M. Fabius, Kevan Shokat, Natalia Jura, Klim Verba, Mahdad Noursadeghi, Pedro Beltrao, Danielle L. Swaney, Adolfo Garcia-Sastre, Clare Jolly, Greg J. Towers, Nevan J. Krogan
bioRxiv 2021.06.06.446826; doi: https://doi.org/10.1101/2021.06.06.446826

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