Mutations in SARS-CoV-2 variants of concern link to increased spike cleavage and virus transmission

Alba Escalera; Ana S Gonzalez-Reiche; Sadaf Aslam; Ignacio Mena; Manon Laporte; Rebecca L Pearl; Andrea Fossati; Raveen Rathnasinghe; Hala Alshammary; Adriana van de Guchte; Keith Farrugia; Yiren Qin; Mehdi Bouhaddou; Thomas Kehrer; Lorena Zuliani-Alvarez; David A Meekins; Velmurugan Balaraman; Chester McDowell; Jürgen A Richt; Goran Bajic; Emilia Mia Sordillo; Marion Dejosez; Thomas P Zwaka; Nevan J Krogan; Viviana Simon; Randy A Albrecht; Harm van Bakel; Adolfo García-Sastre; Teresa Aydillo

doi:10.1016/j.chom.2022.01.006

Mutations in SARS-CoV-2 variants of concern link to increased spike cleavage and virus transmission

Cell Host Microbe. 2022 Mar 9;30(3):373-387.e7. doi: 10.1016/j.chom.2022.01.006. Epub 2022 Jan 21.

Authors

Alba Escalera¹, Ana S Gonzalez-Reiche², Sadaf Aslam³, Ignacio Mena³, Manon Laporte³, Rebecca L Pearl³, Andrea Fossati⁴, Raveen Rathnasinghe¹, Hala Alshammary⁵, Adriana van de Guchte², Keith Farrugia², Yiren Qin⁶, Mehdi Bouhaddou⁴, Thomas Kehrer¹, Lorena Zuliani-Alvarez⁴, David A Meekins⁷, Velmurugan Balaraman⁷, Chester McDowell⁷, Jürgen A Richt⁷, Goran Bajic⁵, Emilia Mia Sordillo⁸, Marion Dejosez⁶, Thomas P Zwaka⁶, Nevan J Krogan⁹, Viviana Simon¹⁰, Randy A Albrecht³, Harm van Bakel¹¹, Adolfo García-Sastre¹², Teresa Aydillo¹³

Affiliations

¹ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
² Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
³ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁴ Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; QBI Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158-2140, USA.
⁵ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁶ Huffington Center for Cell-based Research in Parkinson's Disease, Black Family Stem Cell Institute, Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10502, USA.
⁷ Department of Diagnostic Medicine/Pathobiology and Center of Excellence for Emerging and Zoonotic Animal Diseases, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA.
⁸ Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁹ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94158, USA; QBI Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158-2140, USA.
¹⁰ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹¹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: adolfo.garcia-sastre@mssm.edu.
¹³ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: teresa.aydillo-gomez@mssm.edu.

Abstract

SARS-CoV-2 lineages have diverged into highly prevalent variants termed "variants of concern" (VOCs). Here, we characterized emerging SARS-CoV-2 spike polymorphisms in vitro and in vivo to understand their impact on transmissibility and virus pathogenicity and fitness. We demonstrate that the substitution S:655Y, represented in the gamma and omicron VOCs, enhances viral replication and spike protein cleavage. The S:655Y substitution was transmitted more efficiently than its ancestor S:655H in the hamster infection model and was able to outcompete S:655H in the hamster model and in a human primary airway system. Finally, we analyzed a set of emerging SARS-CoV-2 variants to investigate how different sets of mutations may impact spike processing. All VOCs tested exhibited increased spike cleavage and fusogenic capacity. Taken together, our study demonstrates that the spike mutations present in VOCs that become epidemiologically prevalent in humans are linked to an increase in spike processing and virus transmission.

Keywords: H655Y mutation; SARS-CoV-2; fusion; gamma; omicron; spike cleavage; syncytia formation; variants of concern.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

COVID-19*
Humans
Mutation
SARS-CoV-2* / genetics
Spike Glycoprotein, Coronavirus / genetics

Mutations in SARS-CoV-2 variants of concern link to increased spike cleavage and virus transmission

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