A genome-wide CRISPR screen identifies interactors of the autophagy pathway as conserved coronavirus targets
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (ScreenIT)
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.
Article activity feed
-
-
SciScore for 10.1101/2021.02.24.432634: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:To address these limitations, we also tested these drugs on primary human nasal epithelial cell cultures and found that both Alisporivir and Cyclosporin A potently inhibit SARS-CoV-2 replication at concentrations known to be …
SciScore for 10.1101/2021.02.24.432634: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:To address these limitations, we also tested these drugs on primary human nasal epithelial cell cultures and found that both Alisporivir and Cyclosporin A potently inhibit SARS-CoV-2 replication at concentrations known to be achievable and efficacious in patients. Together these findings depict a promising path towards the repurposing of Cyclosporin A and Alisporivir as COVID-19 treatment options. Infection with highly pathogenic CoVs is frequently accompanied by inflammatory immunopathogenesis, including the virus-induced destruction of lung tissue and subsequent triggering of a host immune response. Importantly, in certain cases a dysregulated immune response is associated with severe lung pathology and systemic pathogenesis34. The latter highlights the need for dual-acting antiviral drugs that also target inflammation and/or cell death. Of interest, Alisporivir also blocks mitochondrial cyclophilin-D, a key regulator of mitochondrial permeability transition pore (mPTP) opening, which is a mechanism involved in triggering cell death. Hence, besides its antiviral properties, it is possible that Alisporivir also reduces CoV-induced lung tissue damage65. Trials using either Cyclosporin in patients with moderate COVID-19 (ClinicalTrials.gov Identifier: NCT04412785 and NCT04540926) or Alisporivir (ClinicalTrials.gov Identifier: NCT04608214) for the treatment of hospitalized COVID19 patients have been registered. The identification of MINAR1, TMEM41 and FKBP8 as conserved HCoVs H...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04412785 Recruiting Cyclosporine in Patients With Moderate COVID-19 NCT04540926 Not yet recruiting Cyclosporine A Plus Low-steroid Treatment in COVID-19 Pneumo… NCT04608214 Not yet recruiting Evaluation of Alisporivir for the Treatment of Hospitalised … Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
-
