SARS-CoV-2 receptor is co-expressed with elements of the kinin–kallikrein, renin–angiotensin and coagulation systems in alveolar cells

  1. Davi Sidarta-Oliveira
  2. Carlos Poblete Jara
  3. Adriano J. Ferruzzi
  4. Munir S. Skaf
  5. William H. Velander
  6. Eliana P. Araujo
  7. Licio A. Velloso

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Abstract

SARS-CoV-2, the pathogenic agent of COVID-19, employs angiotensin converting enzyme-2 (ACE2) as its cell entry receptor. Clinical data reveal that in severe COVID-19, SARS-CoV-2 infects the lung, leading to a frequently lethal triad of respiratory insufficiency, acute cardiovascular failure, and coagulopathy. Physiologically, ACE2 plays a role in the regulation of three systems that could potentially be involved in the pathogenesis of severe COVID-19: the kinin–kallikrein system, resulting in acute lung inflammatory edema; the renin–angiotensin system, promoting cardiovascular instability; and the coagulation system, leading to thromboembolism. Here we assembled a healthy human lung cell atlas meta-analysis with ~ 130,000 public single-cell transcriptomes and show that key elements of the bradykinin, angiotensin and coagulation systems are co-expressed with ACE2 in alveolar cells and associated with their differentiation dynamics, which could explain how changes in ACE2 promoted by SARS-CoV-2 cell entry result in the development of the three most severe clinical components of COVID-19.

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  1. Version published to 10.1038/s41598-020-76488-2
  2. Version published to 10.1101/2020.06.02.20120634v2 on medRxiv
  3. ScreenIT

    SciScore for 10.1101/2020.06.02.20120634: (What is this?)

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

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Networks: Protein functional interaction networks were performed with STRING v11 (47), a software toolkit which performs datamining on a large number of databases and on individually published high-throughput datasets.
    STRING
    suggested: (STRING, RRID:SCR_005223)
    Single-cell RNA sequencing data acquisition, filtering, and processing: Control samples (healthy donors) digital expression matrices were downloaded from Gene Expression Omnibus for data published elsewhere (26) (GSE122960) and for Human Cell Landscape (HCL) data (27) (GSE132355).
    Gene Expression Omnibus
    suggested: (Gene Expression Omnibus (GEO, RRID:SCR_005012)
    In addition, preprint data from Travaglini and coworkers (https://doi.org/10.1101/742320) was obtained from synapse (Human Lung Cell Atlas – https://www.synapse.org/#!Synapse:syn21041850/wiki/600865).
    https://www.synapse.org/#
    suggested: (Multiple Myeloma survival predictor, RRID:SCR_017651)
    Each individual sample was processed in Seurat v3.1.5 (48) using the default Seurat workflow.
    Seurat
    suggested: (SEURAT, RRID:SCR_007322)
    Identification of marker genes: Cluster marker genes were found with Seurat’s function FindAllMarkers, which finds differentially expressed genes between a cluster and all remaining cells with a Wilxocon rank sum test.
    Cluster
    suggested: (Cluster, RRID:SCR_013505)

    Results from OddPub: Thank you for sharing your code and data.

    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.

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  4. Version published to 10.1101/2020.06.02.20120634v1 on medRxiv