An endogenously activated antiviral state restricts SARS-CoV-2 infection in differentiated primary airway epithelial cells

  1. Lindsay Broadbent
  2. Connor G. G. Bamford
  3. Guillermo Lopez Campos
  4. Sheerien Manzoor
  5. David Courtney
  6. Ahlam Ali
  7. Olivier Touzelet
  8. Conall McCaughey
  9. Ken Mills
  10. Ultan F. Power

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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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  1. Version published to 10.1371/journal.pone.0266412
  2. ScreenIT

    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

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    The virus was passaged 4 times on Vero cells, including isolation.
    Vero
    suggested: CLS Cat# 605372/p622_VERO, RRID:CVCL_0059)
    RSV titres in biological samples were determined using HEp-2 cells, as previously described39.
    HEp-2
    suggested: None
    Software and Algorithms
    SentencesResources
    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!
    FastQC
    suggested: (FastQC, RRID:SCR_014583)
    Trim Galore
    suggested: (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.
    STAR
    suggested: (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.
    pheatmap
    suggested: (pheatmap, RRID:SCR_016418)
    WikiPathways
    suggested: (WikiPathways, RRID:SCR_002134)
    In addition to SNP calling we also annotated the variants identified using SnpEff software and the GRCh38.99 database46.
    SnpEff
    suggested: (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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  3. Version published to 10.1101/2021.08.17.456707v1 on bioRxiv