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Kratzel, A.* ; Kelly, J.N.* ; V'kovski, P.* ; Portmann, J.* ; Brüggemann, Y.* ; Todt, D.* ; Ebert, N.* ; Shrestha, N.* ; Plattet, P.* ; Staab-Weijnitz, C.A. ; von Brunn, A. * ; Steinmann, E.* ; Dijkman, R.* ; Zimmer, G.* ; Pfaender, S.* ; Thiel, V.*

A genome-wide CRISPR screen identifies interactors of the autophagy pathway as conserved coronavirus targets.

PLoS Biol. 19:e3001490 (2021)
Publ. Version/Full Text Research data DOI
Open Access Gold
Creative Commons Lizenzvertrag
Over the past 20 years, 3 highly pathogenic human coronaviruses (HCoVs) have emerged-Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and, most recently, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)-demonstrating that coronaviruses (CoVs) pose a serious threat to human health and highlighting the importance of developing effective therapies against them. Similar to other viruses, CoVs are dependent on host factors for their survival and replication. We hypothesized that evolutionarily distinct CoVs may exploit similar host factors and pathways to support their replication cycles. Herein, we conducted 2 independent genome-wide CRISPR/Cas-9 knockout (KO) screens to identify MERS-CoV and HCoV-229E host dependency factors (HDFs) required for HCoV replication in the human Huh7 cell line. Top scoring genes were further validated and assessed in the context of MERS-CoV and HCoV-229E infection as well as SARS-CoV and SARS-CoV-2 infection. Strikingly, we found that several autophagy-related genes, including TMEM41B, MINAR1, and the immunophilin FKBP8, were common host factors required for pan-CoV replication. Importantly, inhibition of the immunophilin protein family with the compounds cyclosporine A, and the nonimmunosuppressive derivative alisporivir, resulted in dose-dependent inhibition of CoV replication in primary human nasal epithelial cell cultures, which recapitulate the natural site of virus replication. Overall, we identified host factors that are crucial for CoV replication and demonstrated that these factors constitute potential targets for therapeutic intervention by clinically approved drugs.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Respiratory Syndrome Coronavirus; Cyclosporine-a; Functional Receptor; Cyclophilin-a; Replication; Virus; Calcineurin; Complex; Gene; Ace2
ISSN (print) / ISBN 1544-9173
e-ISSN 1545-7885
Journal PLoS Biology
Quellenangaben Volume: 19, Issue: 12, Pages: , Article Number: e3001490 Supplement: ,
Publisher Public Library of Science (PLoS)
Publishing Place 1160 Battery Street, Ste 100, San Francisco, Ca 94111 Usa
Reviewing status Peer reviewed
Grants Federal Ministry of Education and Research (RAPID grant)
Horizon 2020 Marie Sklodowska-Curie "COV RESTRICT"
Swiss National Science Foundation