Fibrinolysis influences SARS-CoV-2 infection in ciliated cells

  1. Yapeng Hou
  2. Yan Ding
  3. Hongguang Nie
  4. Hong-Long Ji

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Abstract

Rapid spread of COVID-19 has caused an unprecedented pandemic worldwide, and an inserted furin site in SARS-CoV-2 spike protein (S) may account for increased transmissibility. Plasmin, and other host proteases, may cleave the furin site of SARS-CoV-2 S protein and γ subunits of epithelial sodium channels (γ ENaC), resulting in an increment in virus infectivity and channel activity. As for the importance of ENaC in the regulation of airway surface and alveolar fluid homeostasis, whether SARS-CoV-2 will share and strengthen the cleavage network with ENaC proteins at the single-cell level is urgently worthy of consideration. To address this issue, we analyzed single-cell RNA sequence (scRNA-seq) datasets, and found the PLAU (encoding urokinase plasminogen activator), SCNN1G (γENaC), and ACE2 (SARS-CoV-2 receptor) were co-expressed in alveolar epithelial, basal, club, and ciliated epithelial cells. The relative expression level of PLAU, TMPRSS2, and ACE2 were significantly upregulated in severe COVID-19 patients and SARS-CoV-2 infected cell lines using Seurat and DESeq2 R packages. Moreover, the increments in PLAU, FURIN, TMPRSS2, and ACE2 were predominately observed in different epithelial cells and leukocytes. Accordingly, SARS-CoV-2 may share and strengthen the ENaC fibrinolytic proteases network in ACE2 positive airway and alveolar epithelial cells, which may expedite virus infusion into the susceptible cells and bring about ENaC associated edematous respiratory condition.

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  1. ScreenIT

    SciScore for 10.1101/2021.01.07.425801: (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

    Software and Algorithms
    SentencesResources
    Alignment of furin sites in viral and γENaC proteins: The sequences of γENaC proteins (rat, mouse, and humans) and human viruses were acquired from the UniProt (https://www.uniprot.org/).
    UniProt
    suggested: (UniProtKB, RRID:SCR_004426)
    https://www.uniprot.org/
    suggested: (Universal Protein Resource, RRID:SCR_002380)
    Alignment was performed using the JalView software (Version: 2.11.1.0).
    JalView
    suggested: (Jalview, RRID:SCR_006459)
    The expression of PLAU, SCNN1G, and ACE2 in the respiratory system were analyzed and graphed as heatmaps using R package pheatmap.
    pheatmap
    suggested: (pheatmap, RRID:SCR_016418)
    Acquisition, filtering, and processing of scRNA-seq data: The dataset downloaded from the Gene Expression Omnibus was filtered for integration.
    Gene Expression Omnibus
    suggested: (Gene Expression Omnibus (GEO, RRID:SCR_005012)
    Meanwhile, the graph-based clustering was performed on the PCA-reduced data for clustering analysis with Seurat v.3.
    Seurat
    suggested: (SEURAT, RRID:SCR_007322)
    Bulk-seq data (GSE147507) was analyzed for the differential genes in respiratory epithelial cell lines using the DESeq2 with Wald test and Benjamini-Hochberg post-hoc test (Blanco-Melo et al. 2020, Love, Huber, and Anders 2014).
    DESeq2
    suggested: (DESeq, RRID:SCR_000154)

    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.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.01.07.425801 on bioRxiv