Low-Dose Fluvoxamine Modulates Endocytic Trafficking of SARS-CoV-2 Spike Protein: A Potential Mechanism for Anti-COVID-19 Protection by Antidepressants

  1. Oleg O. Glebov

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Abstract

Commonly prescribed antidepressants may be associated with protection against severe COVID-19. The mechanism of their action in this context, however, remains unknown. Here, I investigated the effect of an antidepressant drug fluvoxamine on membrane trafficking of the SARS-CoV-2 spike protein and its cell host receptor ACE2 in HEK293T cells. A sub-therapeutic concentration (80 nM) of fluvoxamine rapidly upregulated fluid-phase endocytosis, resulting in enhanced accumulation of the spike-ACE2 complex in enlarged early endosomes. Diversion of endosomal trafficking provides a simple cell biological mechanism consistent with the protective effect of antidepressants against COVID-19, highlighting their therapeutic and prophylactic potential.

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  1. Version published to 10.3389/fphar.2021.787261
  2. ScreenIT

    SciScore for 10.1101/2021.06.15.448391: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Recombinant SARS-CoV-2 spike protein and the anti-spike mouse polyclonal antibody were kindly provided by Dr. Paul F.
    anti-spike
    suggested: None
    The following rabbit antibodies were used: anti-EEA1, anti-ACE2 (GeneTex),
    anti-EEA1
    suggested: (GeneTex Cat# GTX50769, RRID:AB_11163294)
    The following antibody dilutions (v/v) were used: 1/1000 (anti-spike), 1/1000 (anti-6xHis), 1/500 (anti-ACE2), 1/400 (anti-EEA1), 1/400 (anti-LAMP1).
    anti-LAMP1
    suggested: None
    For spike protein uptake measurements, cells were fixed, immunostained with the anti-6xHis antibody for 30 min to label the surface pool, permeabilized, immunostained with an anti-spike antibody for 30 min to label the total spike pool.
    anti-6xHis
    suggested: None
    Following fixation and permeabilization, coverslips were labelled with the anti-ACE2 antibody to visualise the total pool of ACE2.
    anti-ACE2
    suggested: None
    Finally, coverslips were incubated with the anti-rabbit-Alexa Fluor 488 and anti-mouse Alexa Fluor 594 secondary antibodies for 30 min.
    anti-rabbit-Alexa
    suggested: None
    anti-mouse
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Cell culture and uptake assays: HEK293T cells were cultured in DMEM supplemented with 10% bovine serum.
    HEK293T
    suggested: None
    Software and Algorithms
    SentencesResources
    Quantification of the images was carried out in ImageJ.
    ImageJ
    suggested: (ImageJ, RRID:SCR_003070)
    Statistical analysis was carried out using the Prism 6.0c software package (GraphPad Software).
    Prism
    suggested: (PRISM, RRID:SCR_005375)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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.

    Results from scite Reference Check: We found no unreliable references.

    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.

  3. Version published to 10.1101/2021.06.15.448391v1 on bioRxiv