The type 2 asthma mediator IL-13 inhibits SARS-CoV-2 infection of bronchial epithelium

  1. Luke R. Bonser
  2. Walter L. Eckalbar
  3. Lauren Rodriguez
  4. Jiangshan Shen
  5. Kyung Duk Koh
  6. Lorna T. Zlock
  7. Stephanie Christenson
  8. Prescott G. Woodruff
  9. Walter E. Finkbeiner
  10. David J. Erle

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Abstract

Rationale

Asthma is associated with chronic changes in the airway epithelium, a key target of SARS-CoV-2. Many epithelial changes are driven by the type 2 cytokine IL-13, but the effects of IL-13 on SARS-CoV-2 infection are unknown.

Objectives

We sought to discover how IL-13 and other cytokines affect expression of genes encoding SARS-CoV-2-associated host proteins in human bronchial epithelial cells (HBECs) and determine whether IL-13 stimulation alters susceptibility to SARS-CoV-2 infection.

Methods

We used bulk and single cell RNA-seq to identify cytokine-induced changes in SARS-CoV-2-associated gene expression in HBECs. We related these to gene expression changes in airway epithelium from individuals with mild-moderate asthma and chronic obstructive pulmonary disease (COPD). We analyzed effects of IL-13 on SARS-CoV-2 infection of HBECs.

Measurements and Main Results

Transcripts encoding 332 of 342 (97%) SARS-CoV-2-associated proteins were detected in HBECs (≥1 RPM in 50% samples). 41 (12%) of these mRNAs were regulated by IL-13 (>1.5-fold change, FDR < 0.05). Many IL-13-regulated SARS-CoV-2-associated genes were also altered in type 2 high asthma and COPD. IL-13 pretreatment reduced viral RNA recovered from SARS-CoV-2 infected cells and decreased dsRNA, a marker of viral replication, to below the limit of detection in our assay. Mucus also inhibited viral infection.

Conclusions

IL-13 markedly reduces susceptibility of HBECs to SARS-CoV-2 infection through mechanisms that likely differ from those activated by type I interferons. Our findings may help explain reports of relatively low prevalence of asthma in patients diagnosed with COVID-19 and could lead to new strategies for reducing SARS-CoV-2 infection.

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  1. ScreenIT

    SciScore for 10.1101/2021.02.25.432762: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot 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:
    Our study has some important limitations. While we focused on a set of SARS-CoV-2-associated genes that have been defined in previous studies, other IL-13-regulated genes are also likely to be important for anti-viral effects. Some IL-13-regulated genes we identified in cell culture were not associated with a type 2 signature in cells from individuals with asthma or COPD, reflecting the influence of other factors, including other asthma mediators, or differences in IL-13 responses in cell culture versus in vivo. As individual genes that contribute to inhibition of viral infection in HBECs are identified, it will be important to specifically examine the expression of those genes in asthma and COPD. Our HBEC infection studies used only one strain of SARS-CoV-2 and cells from only two donors, and further experiments with additional strains and more donors (including donors with asthma), will be required to better understand the interactions between virus, epithelial cells, and IL-13. Finally, our infection model focuses solely on the role of epithelial cells, but the effects of IL-13 on other cell types found in the lung are also deserving of further study. In conclusion, we found that the central asthma mediator IL-13 has a strong inhibitory effect on SARS-CoV-2 infection of HBECs. The mechanisms that account for this effect are unknown, but widespread effects of IL-13 on expression of SARS-CoV-2 associated genes that are distinct from those induced by interferons suggest that ...

    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.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2021.02.25.432762 on bioRxiv