The Type 2 Asthma Mediator IL-13 Inhibits Severe Acute Respiratory Syndrome Coronavirus 2 Infection of Bronchial Epithelium

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

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Abstract

Asthma is associated with chronic changes in the airway epithelium, a key target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Many epithelial changes, including goblet cell metaplasia, are driven by the type 2 cytokine IL-13, but the effects of IL-13 on SARS-CoV-2 infection are unknown. We found that IL-13 stimulation of differentiated human bronchial epithelial cells (HBECs) cultured at air–liquid interface reduced viral RNA recovered from SARS-CoV-2–infected cells and decreased double-stranded RNA, a marker of viral replication, to below the limit of detection in our assay. An intact mucus gel reduced SARS-CoV-2 infection of unstimulated cells, but neither a mucus gel nor SPDEF, which is required for goblet cell metaplasia, were required for the antiviral effects of IL-13. Bulk RNA sequencing revealed that IL-13 regulated 41 of 332 (12%) mRNAs encoding SARS-CoV-2–associated proteins that were detected in HBECs (>1.5-fold change; false discovery rate < 0.05). Although both IL-13 and IFN-α each inhibit SARS-CoV-2 infection, their transcriptional effects differed markedly. Single-cell RNA sequencing revealed cell type–specific differences in SARS-CoV-2–associated gene expression and IL-13 responses. Many IL-13–induced gene expression changes were seen in airway epithelium from individuals with type 2 asthma and chronic obstructive pulmonary disease. IL-13 effects on airway epithelial cells may protect individuals with type 2 asthma from COVID-19 and could lead to identification of novel strategies for reducing SARS-CoV-2 infection.

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  1. Version published to 10.1165/rcmb.2021-0364oc
  2. 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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  3. Version published to 10.1101/2021.02.25.432762 on bioRxiv