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

Kratzel, Annika; Kelly, Jenna N; V'kovski, Philip; Portmann, Jasmine; Brüggemann, Yannick; Todt, Daniel; Ebert, Nadine; Shrestha, Neeta; Plattet, Philippe; Staab-Weijnitz, Claudia A; von Brunn, Albrecht; Steinmann, Eike; Dijkman, Ronald; Zimmer, Gert; Pfaender, Stephanie; Thiel, Volker (2021). A genome-wide CRISPR screen identifies interactors of the autophagy pathway as conserved coronavirus targets. PLoS biology, 19(12), e3001490. Public Library of Science 10.1371/journal.pbio.3001490

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases > Research
04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Experimental Clinical Research
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Virology and Immunology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Kratzel, Annika; Kelly, Jenna Nicole; V'kovski, Philip; Portmann, Jasmine; Ebert, Nadine; Shrestha, Neeta; Plattet, Philippe; Dijkman, Ronald; Zimmer, Gert and Thiel, Volker Earl

Subjects:

600 Technology > 630 Agriculture
500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1544-9173

Publisher:

Public Library of Science

Language:

English

Submitter:

Ronald Dijkman

Date Deposited:

24 Jan 2022 13:55

Last Modified:

05 Dec 2022 16:03

Publisher DOI:

10.1371/journal.pbio.3001490

PubMed ID:

34962926

BORIS DOI:

10.48350/164323

URI:

https://boris.unibe.ch/id/eprint/164323

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