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Nat Genet
. 2022 Jul 25.
doi: 10.1038/s41588-022-01110-2. Online ahead of print.
Bidirectional genome-wide CRISPR screens reveal host factors regulating SARS-CoV-2, MERS-CoV and seasonal HCoVs
Antoine Rebendenne 1 , Priyanka Roy 2 , Boris Bonaventure # 1 , Ana Luiza Chaves Valadão # 1 , Lowiese Desmarets 3 , Mary Arnaud-Arnould 1 , Yves Rouillé 3 , Marine Tauziet 1 , Donatella Giovannini 4 5 , Jawida Touhami 4 6 , Yenarae Lee 2 , Peter DeWeirdt 2 , Mudra Hegde 2 , Serge Urbach 7 , Khadija El Koulali 8 , Francisco Garcia de Gracia 1 , Joe McKellar 1 , Jean Dubuisson 3 , Mélanie Wencker 9 , Sandrine Belouzard 3 , Olivier Moncorgé 1 , John G Doench 10 , Caroline Goujon 11
Affiliations
- PMID: 35879413
- DOI: 10.1038/s41588-022-01110-2
Abstract
CRISPR knockout (KO) screens have identified host factors regulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. Here, we conducted a meta-analysis of these screens, which showed a high level of cell-type specificity of the identified hits, highlighting the necessity of additional models to uncover the full landscape of host factors. Thus, we performed genome-wide KO and activation screens in Calu-3 lung cells and KO screens in Caco-2 colorectal cells, followed by secondary screens in four human cell lines. This revealed host-dependency factors, including AP1G1 adaptin and ATP8B1 flippase, as well as inhibitors, including mucins. Interestingly, some of the identified genes also modulate Middle East respiratory syndrome coronavirus (MERS-CoV) and seasonal human coronavirus (HCoV) (HCoV-NL63 and HCoV-229E) replication. Moreover, most genes had an impact on viral entry, with AP1G1 likely regulating TMPRSS2 activity at the plasma membrane. These results demonstrate the value of multiple cell models and perturbational modalities for understanding SARS-CoV-2 replication and provide a list of potential targets for therapeutic interventions.