Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men

  1. Zaniar Ghazizadeh
  2. Homa Majd
  3. Mikayla Richter
  4. Ryan Samuel
  5. Seyedeh Maryam Zekavat
  6. Hosseinali Asgharian
  7. Sina Farahvashi
  8. Ali Kalantari
  9. Jonathan Ramirez
  10. Hongyu Zhao
  11. Pradeep Natarajan
  12. Hani Goodarzi
  13. Faranak Fattahi

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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to a global health crisis, and yet our understanding of the disease pathophysiology and potential treatment options remains limited. SARS-CoV-2 infection occurs through binding and internalization of the viral spike protein to angiotensin converting enzyme 2 (ACE2) on the host cell membrane. Lethal complications are caused by damage and failure of vital organs that express high levels of ACE2, including the lungs, the heart and the kidneys. Here, we established a high-throughput drug screening strategy to identify therapeutic candidates that reduce ACE2 levels in human embryonic stem cell (hESC) derived cardiac cells. Drug target analysis of validated hit compounds, including 5 alpha reductase inhibitors, revealed androgen signaling as a key modulator of ACE2 levels. Treatment with the 5 alpha reductase inhibitor dutasteride reduced ACE2 levels and internalization of recombinant spike receptor binding domain (Spike-RBD) in hESC-derived cardiac cells and human alveolar epithelial cells. Finally, clinical data on coronavirus disease 2019 (COVID-19) patients demonstrated that abnormal androgen states are significantly associated with severe disease complications and cardiac injury as measured by blood troponin T levels. These findings provide important insights on the mechanism of increased disease susceptibility in male COVID-19 patients and identify androgen receptor inhibition as a potential therapeutic strategy.

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  1. ScreenIT

    SciScore for 10.1101/2020.05.12.091082: (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

    Antibodies
    SentencesResources
    24 hours after treatment, cells were fixed stained with ACE2 antibody.
    ACE2
    suggested: None
    The cells were subsequently fixed, permeabilized and stained with antibodies against ACE2 and human Fc receptor.
    antibodies against ACE2
    suggested: None
    Non-specific antigen binding was blocked by treating the cells with PBS+0.5% BSA prior to adding the primary antibodies (ACE2 or TMPRSS2, Proteintech cat#21115-1-AP and Novus Biologicals cat# NBP1-20984, respectively).
    TMPRSS2
    suggested: (Novus Cat# NBP1-20984, RRID:AB_1643199)
    Secondary antibodies and fluorophore conjugated anti human Fc antibody were incubated for 30 minutes at room temperature.
    anti human Fc
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Transcriptional changes associated with AR down-regulation: We used an existing AR ChIP-seq dataset generated in LNCaP cells to identify direct transcriptional targets of AR.
    LNCaP
    suggested: CLS Cat# 300265/p761_LNCaP, RRID:CVCL_0395)
    Software and Algorithms
    SentencesResources
    Protein-protein interaction network construction: Protein-protein interaction network analysis was performed using the Search Tool for the Retrieval of Interacting Genes (STRING) database.
    STRING
    suggested: (STRING, RRID:SCR_005223)
    Adobe Illustrator 24.1 was used for visualization.
    Adobe Illustrator
    suggested: (Adobe Illustrator, RRID:SCR_010279)
    We downloaded processed peaks from the Gene Expression Omnibus (GSM3148987) and lifted the peaks from hg19 over to hg38.
    Gene Expression Omnibus
    suggested: (Gene Expression Omnibus (GEO, RRID:SCR_005012)
    We downloaded raw fastq files and aligned them to the transcriptome (gencode.v28) using Salmon (v0.14.1 using --validateMappings and −l ISR flags).
    Salmon
    suggested: (Salmon, RRID:SCR_017036)
    We then used DESeq2 (1.22.2) to compare gene expression changes in response to AR knockdown.
    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 10.1101/2020.05.12.091082 on bioRxiv