Direct activation of endothelial cells by SARS-CoV-2 nucleocapsid protein is blocked by Simvastatin

  1. Yisong Qian
  2. Tianhua Lei
  3. Parth S. Patel
  4. Chi H Lee
  5. Paula Monaghan-Nichols
  6. Hong-Bo Xin
  7. Jianming Qiu
  8. Mingui Fu

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Abstract

Emerging evidence suggests that endothelial activation plays a central role in the pathogenesis of acute respiratory distress syndrome (ARDS) and multi-organ failure in patients with COVID-19. However, the molecular mechanisms underlying endothelial activation in COVID-19 patients remain unclear. In this study, the SARS-CoV-2 viral proteins that potently activate human endothelial cells were screened to elucidate the molecular mechanisms involved with endothelial activation. It was found that nucleocapsid protein (NP) of SARS-CoV-2 significantly activated human endothelial cells through TLR2/NF-κB and MAPK signaling pathways. Moreover, by screening a natural microbial compound library containing 154 natural compounds, simvastatin was identified as a potent inhibitor of NP-induced endothelial activation. Remarkablely, though the protein sequences of N proteins from coronaviruses are highly conserved, only NP from SARS-CoV-2 induced endothelial activation. The NPs from other coronaviruses such as SARS-CoV, MERS-CoV, HUB1-CoV and influenza virus H1N1 did not affect endothelial activation. These findings are well consistent with the results from clinical investigations showing broad endotheliitis and organ injury in severe COVID-19 patients. In conclusion, the study provides insights on SARS-CoV-2-induced vasculopathy and coagulopathy, and suggests that simvastatin, an FDA-approved lipid-lowering drug, may benefit to prevent the pathogenesis and improve the outcome of COVID-19 patients.

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  1. ScreenIT

    SciScore for 10.1101/2021.02.14.431174: (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.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    ICAM-1 (60299-1-Ig) and GAPDH (60004-1-Ig) antibodies were from Proteintech (Rosemont, IL).
    60299-1-Ig
    suggested: (Proteintech Cat# 60299-1-Ig, RRID:AB_2881414)
    GAPDH
    suggested: None
    60004-1-Ig
    suggested: (Proteintech Cat# 60004-1-Ig, RRID:AB_2107436)
    VCAM-1 (sc-8304) and β-actin (sc-47778) antibodies were obtained from Santa Cruz Biotechnology, Inc (Dallas, TX).
    sc-8304
    suggested: (Santa Cruz Biotechnology Cat# sc-8304, RRID:AB_2214058)
    β-actin
    suggested: (Santa Cruz Biotechnology Cat# sc-47778 HRP, RRID:AB_2714189)
    sc-47778
    suggested: None
    SARS-CoV/SARS-CoV-2 Nucleocapsid Antibody (40143-MM05) and SARS-CoV-2 Nucleocapsid antibody (40588-T62) were from Sino biological (Beijing, China).
    SARS-CoV-2
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    The images of adherent THP-1 cells were taken under Cytation 3 Cell Imaging Multi-mode Reader.
    THP-1
    suggested: CLS Cat# 300356/p804_THP-1, RRID:CVCL_0006)

    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 found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    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 10.1101/2021.02.14.431174 on bioRxiv