In:
PLOS Biology, Public Library of Science (PLoS), Vol. 19, No. 12 ( 2021-12-28), p. e3001490-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001490
DOI:
10.1371/journal.pbio.3001490.g001
DOI:
10.1371/journal.pbio.3001490.g002
DOI:
10.1371/journal.pbio.3001490.g003
DOI:
10.1371/journal.pbio.3001490.g004
DOI:
10.1371/journal.pbio.3001490.g005
DOI:
10.1371/journal.pbio.3001490.t001
DOI:
10.1371/journal.pbio.3001490.t002
DOI:
10.1371/journal.pbio.3001490.t003
DOI:
10.1371/journal.pbio.3001490.t004
DOI:
10.1371/journal.pbio.3001490.t005
DOI:
10.1371/journal.pbio.3001490.t006
DOI:
10.1371/journal.pbio.3001490.s001
DOI:
10.1371/journal.pbio.3001490.s002
DOI:
10.1371/journal.pbio.3001490.s003
DOI:
10.1371/journal.pbio.3001490.s004
DOI:
10.1371/journal.pbio.3001490.s005
DOI:
10.1371/journal.pbio.3001490.s006
DOI:
10.1371/journal.pbio.3001490.s007
DOI:
10.1371/journal.pbio.3001490.s008
DOI:
10.1371/journal.pbio.3001490.s009
DOI:
10.1371/journal.pbio.3001490.s010
DOI:
10.1371/journal.pbio.3001490.s011
DOI:
10.1371/journal.pbio.3001490.s012
DOI:
10.1371/journal.pbio.3001490.s013
DOI:
10.1371/journal.pbio.3001490.s014
DOI:
10.1371/journal.pbio.3001490.s015
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2126773-X