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Bidirectional genome-wide CRISPR screens reveal host factors regulating SARS-CoV-2, MERS-CoV and seasonal coronaviruses

View ORCID ProfileAntoine Rebendenne, Priyanka Roy, View ORCID ProfileBoris Bonaventure, View ORCID ProfileAna Luiza Chaves Valadão, Lowiese Desmarets, View ORCID ProfileYves Rouillé, View ORCID ProfileMarine Tauziet, View ORCID ProfileMary Arnaud-Arnould, Donatella Giovannini, Yenarae Lee, Peter DeWeirdt, View ORCID ProfileMudra Hegde, View ORCID ProfileFrancisco Garcia de Gracia, View ORCID ProfileJoe McKellar, View ORCID ProfileMélanie Wencker, View ORCID ProfileJean Dubuisson, View ORCID ProfileSandrine Belouzard, View ORCID ProfileOlivier Moncorgé, View ORCID ProfileJohn G. Doench, View ORCID ProfileCaroline Goujon
doi: https://doi.org/10.1101/2021.05.19.444823
Antoine Rebendenne
1IRIM, CNRS, Montpellier University, France
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Priyanka Roy
2Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, USA
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Boris Bonaventure
1IRIM, CNRS, Montpellier University, France
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  • ORCID record for Boris Bonaventure
Ana Luiza Chaves Valadão
1IRIM, CNRS, Montpellier University, France
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  • ORCID record for Ana Luiza Chaves Valadão
Lowiese Desmarets
3Lille University, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, France
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Yves Rouillé
3Lille University, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, France
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Marine Tauziet
1IRIM, CNRS, Montpellier University, France
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  • ORCID record for Marine Tauziet
Mary Arnaud-Arnould
1IRIM, CNRS, Montpellier University, France
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Donatella Giovannini
4IGMM, CNRS, Montpellier University, France
5Metafora Biosystems, Paris, France
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Yenarae Lee
2Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, USA
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Peter DeWeirdt
2Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, USA
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Mudra Hegde
2Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, USA
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Francisco Garcia de Gracia
1IRIM, CNRS, Montpellier University, France
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Joe McKellar
1IRIM, CNRS, Montpellier University, France
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Mélanie Wencker
6CIRI, INSERM, CNRS, ENS-Lyon, Lyon University, France
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  • ORCID record for Mélanie Wencker
Jean Dubuisson
3Lille University, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, France
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Sandrine Belouzard
3Lille University, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, France
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Olivier Moncorgé
1IRIM, CNRS, Montpellier University, France
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John G. Doench
2Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, USA
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  • ORCID record for John G. Doench
  • For correspondence: caroline.goujon@irim.cnrs.fr
Caroline Goujon
1IRIM, CNRS, Montpellier University, France
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  • For correspondence: caroline.goujon@irim.cnrs.fr
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Abstract

Several genome-wide CRISPR knockout screens have been conducted to identify host factors regulating SARS-CoV-2 replication, but the models used have often relied on overexpression of ACE2 receptor. Additionally, such screens have yet to identify the protease TMPRSS2, known to be important for viral entry at the plasma membrane. Here, we conducted a meta-analysis of these screens and showed a high level of cell-type specificity of the identified hits, arguing for the necessity of additional models to uncover the full landscape of SARS-CoV-2 host factors. We performed genome-wide knockout and activation CRISPR screens in Calu-3 lung epithelial cells, as well as knockout screens in Caco-2 intestinal cells. In addition to identifying ACE2 and TMPRSS2 as top hits, our study reveals a series of so far unidentified and critical host-dependency factors, including the Adaptins AP1G1 and AP1B1 and the flippase ATP8B1. Moreover, new anti-SARS-CoV-2 proteins with potent activity, including several membrane-associated Mucins, IL6R, and CD44 were identified. We further observed that these genes mostly acted at the critical step of viral entry, with the notable exception of ATP8B1, the knockout of which prevented late stages of viral replication. Exploring the pro- and anti-viral breadth of these genes using highly pathogenic MERS-CoV, seasonal HCoV-NL63 and -229E and influenza A orthomyxovirus, we reveal that some genes such as AP1G1 and ATP8B1 are general coronavirus cofactors. In contrast, Mucins recapitulated their known role as a general antiviral defense mechanism. These results demonstrate the value of considering multiple cell models and perturbational modalities for understanding SARS-CoV-2 replication and provide a list of potential new targets for therapeutic interventions.

Competing Interest Statement

J.G.D. consults for Agios, Microsoft Research, Phenomic AI, BioNTech, and Pfizer. JGD consults for and has equity in Tango Therapeutics. J.G.D.s interests were reviewed and are managed by the Broad Institute in accordance with its conflict of interest policies. The other authors declare no competing interests.

Footnotes

  • Correction of a typo in a co-author surname.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 21, 2021.
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Bidirectional genome-wide CRISPR screens reveal host factors regulating SARS-CoV-2, MERS-CoV and seasonal coronaviruses
Antoine Rebendenne, Priyanka Roy, Boris Bonaventure, Ana Luiza Chaves Valadão, Lowiese Desmarets, Yves Rouillé, Marine Tauziet, Mary Arnaud-Arnould, Donatella Giovannini, Yenarae Lee, Peter DeWeirdt, Mudra Hegde, Francisco Garcia de Gracia, Joe McKellar, Mélanie Wencker, Jean Dubuisson, Sandrine Belouzard, Olivier Moncorgé, John G. Doench, Caroline Goujon
bioRxiv 2021.05.19.444823; doi: https://doi.org/10.1101/2021.05.19.444823
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Bidirectional genome-wide CRISPR screens reveal host factors regulating SARS-CoV-2, MERS-CoV and seasonal coronaviruses
Antoine Rebendenne, Priyanka Roy, Boris Bonaventure, Ana Luiza Chaves Valadão, Lowiese Desmarets, Yves Rouillé, Marine Tauziet, Mary Arnaud-Arnould, Donatella Giovannini, Yenarae Lee, Peter DeWeirdt, Mudra Hegde, Francisco Garcia de Gracia, Joe McKellar, Mélanie Wencker, Jean Dubuisson, Sandrine Belouzard, Olivier Moncorgé, John G. Doench, Caroline Goujon
bioRxiv 2021.05.19.444823; doi: https://doi.org/10.1101/2021.05.19.444823

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