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

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 BajicEmilia Mia Sordillo, Marion Dejosez, Thomas P. Zwaka, Nevan J. Krogan, Viviana Simon, Randy A. Albrecht, Harm van Bakel, Adolfo García-Sastre, Teresa Aydillo

Research output: Contribution to journal › Article › peer-review

124 Scopus citations

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.

Original language	English
Pages (from-to)	373-387.e7
Journal	Cell Host and Microbe
Volume	30
Issue number	3
DOIs	https://doi.org/10.1016/j.chom.2022.01.006
State	Published - 9 Mar 2022

Keywords

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

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10.1016/j.chom.2022.01.006

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Escalera, A., Gonzalez-Reiche, A. S., Aslam, S., Mena, I., Laporte, M., Pearl, R. L., Fossati, A., Rathnasinghe, R., Alshammary, H., van de Guchte, A., Farrugia, K., Qin, Y., Bouhaddou, M., Kehrer, T., Zuliani-Alvarez, L., Meekins, D. A., Balaraman, V., McDowell, C., Richt, J. A., ... Aydillo, T. (2022). Mutations in SARS-CoV-2 variants of concern link to increased spike cleavage and virus transmission. Cell Host and Microbe, 30(3), 373-387.e7. https://doi.org/10.1016/j.chom.2022.01.006

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

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",

author = "Alba Escalera and Gonzalez-Reiche, {Ana S.} and Sadaf Aslam and Ignacio Mena and Manon Laporte and Pearl, {Rebecca L.} and Andrea Fossati and Raveen Rathnasinghe and Hala Alshammary and {van de Guchte}, Adriana and Keith Farrugia and Yiren Qin and Mehdi Bouhaddou and Thomas Kehrer and Lorena Zuliani-Alvarez and Meekins, {David A.} and Velmurugan Balaraman and Chester McDowell and Richt, {J{\"u}rgen A.} and Goran Bajic and Sordillo, {Emilia Mia} and Marion Dejosez and Zwaka, {Thomas P.} and Krogan, {Nevan J.} and Viviana Simon and Albrecht, {Randy A.} and {van Bakel}, Harm and Adolfo Garc{\'i}a-Sastre and Teresa Aydillo",

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Escalera, A, Gonzalez-Reiche, AS, Aslam, S, Mena, I, Laporte, M, Pearl, RL, Fossati, A, Rathnasinghe, R, Alshammary, H, van de Guchte, A, Farrugia, K, Qin, Y, Bouhaddou, M, Kehrer, T, Zuliani-Alvarez, L, Meekins, DA, Balaraman, V, McDowell, C, Richt, JA, Bajic, G , Sordillo, EM, Dejosez, M, Zwaka, TP, Krogan, NJ, Simon, V , Albrecht, RA , van Bakel, H , García-Sastre, A & Aydillo, T 2022, 'Mutations in SARS-CoV-2 variants of concern link to increased spike cleavage and virus transmission', Cell Host and Microbe, vol. 30, no. 3, pp. 373-387.e7. https://doi.org/10.1016/j.chom.2022.01.006

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AU - Escalera, Alba

AU - Gonzalez-Reiche, Ana S.

AU - Aslam, Sadaf

AU - Mena, Ignacio

AU - Laporte, Manon

AU - Pearl, Rebecca L.

AU - Fossati, Andrea

AU - Rathnasinghe, Raveen

AU - Alshammary, Hala

AU - van de Guchte, Adriana

AU - Farrugia, Keith

AU - Qin, Yiren

AU - Bouhaddou, Mehdi

AU - Kehrer, Thomas

AU - Zuliani-Alvarez, Lorena

AU - Meekins, David A.

AU - Balaraman, Velmurugan

AU - McDowell, Chester

AU - Richt, Jürgen A.

AU - Bajic, Goran

AU - Sordillo, Emilia Mia

AU - Dejosez, Marion

AU - Zwaka, Thomas P.

AU - Krogan, Nevan J.

AU - Simon, Viviana

AU - Albrecht, Randy A.

AU - van Bakel, Harm

AU - García-Sastre, Adolfo

AU - Aydillo, Teresa

PY - 2022/3/9

Y1 - 2022/3/9

N2 - 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.

AB - 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.

KW - H655Y mutation

KW - SARS-CoV-2

KW - fusion

KW - gamma

KW - omicron

KW - spike cleavage

KW - syncytia formation

KW - variants of concern

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DO - 10.1016/j.chom.2022.01.006

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C2 - 35150638

AN - SCOPUS:85124452901

SN - 1931-3128

VL - 30

SP - 373-387.e7

JO - Cell Host and Microbe

JF - Cell Host and Microbe

IS - 3

ER -

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

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Keywords

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