An endogenously activated antiviral state restricts SARS-CoV-2 infection in differentiated primary airway epithelial cells
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Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the coronavirus disease-19 (COVID-19) pandemic, was identified in late 2019 and caused >5 million deaths by February 2022. To date, targeted antiviral interventions against COVID-19 are limited. The spectrum of SARS-CoV-2 infection ranges from asymptomatic to fatal disease. However, the reasons for varying outcomes to SARS-CoV-2 infection are yet to be elucidated. Here we show that an endogenously activated interferon lambda (IFNλ1) pathway leads to resistance against SARS-CoV-2 infection. Using a well-differentiated primary nasal epithelial cell (WD-PNEC) culture model derived from multiple adult donors, we discovered that susceptibility to SARS-CoV-2 infection, but not respiratory syncytial virus (RSV) infection, varied. One of four donors was resistant to SARS-CoV-2 infection. High baseline IFNλ1 expression levels and associated interferon stimulated genes correlated with resistance to SARS-CoV-2 infection. Inhibition of the JAK/STAT pathway in WD-PNECs with high endogenous IFNλ1 secretion resulted in higher SARS-CoV-2 titres. Conversely, prophylactic IFNλ treatment of WD-PNECs susceptible to infection resulted in reduced viral titres. An endogenously activated IFNλ response, possibly due to genetic differences, may be one explanation for the differences in susceptibility to SARS-CoV-2 infection in humans. Importantly, our work supports the continued exploration of IFNλ as a potential pharmaceutical against SARS-CoV-2 infection.
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SciScore for 10.1101/2021.08.17.456707: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources The virus was passaged 4 times on Vero cells, including isolation. Verosuggested: CLS Cat# 605372/p622_VERO, RRID:CVCL_0059)RSV titres in biological samples were determined using HEp-2 cells, as previously described39. HEp-2suggested: NoneSoftware and Algorithms Sentences Resources Raw sequence reads were quality checked with FastQC and pre-processed for the sequence cleaning and adapter removal using cutadapt 2.1 and Trim Galore! FastQCsuggested: (FastQC, RRID:SCR_01458…SciScore for 10.1101/2021.08.17.456707: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources The virus was passaged 4 times on Vero cells, including isolation. Verosuggested: CLS Cat# 605372/p622_VERO, RRID:CVCL_0059)RSV titres in biological samples were determined using HEp-2 cells, as previously described39. HEp-2suggested: NoneSoftware and Algorithms Sentences Resources Raw sequence reads were quality checked with FastQC and pre-processed for the sequence cleaning and adapter removal using cutadapt 2.1 and Trim Galore! FastQCsuggested: (FastQC, RRID:SCR_014583)Trim Galoresuggested: (Trim Galore, RRID:SCR_011847)These pre-processed fastq files were then aligned to the human genome GRCh38v33 using STAR aligner version 2.7.3a42 using default parameters and subsequently genes were quantified using htseq version 0.11.343. STARsuggested: (STAR, RRID:SCR_004463)These logCPM values were subsequently used to generate a heatmap using pheatmap package for comparison and visualisation purposes using a selection of interferon related genes extracted from a selection of pathways annotated in WikiPathways and Reactome Pathway Database (WP2113; R-HSA-913531; WP1904; R-HSA-168928; WP4880; WP1835; R-HSA-909733; WP75), ACE2 and TMPRSS2. pheatmapsuggested: (pheatmap, RRID:SCR_016418)WikiPathwayssuggested: (WikiPathways, RRID:SCR_002134)In addition to SNP calling we also annotated the variants identified using SnpEff software and the GRCh38.99 database46. SnpEffsuggested: (SnpEff, RRID:SCR_005191)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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
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.
Results from scite Reference Check: We found no unreliable references.
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