FXR inhibition reduces ACE2 expression, SARS-CoV-2 infection and may improve COVID-19 outcome

  1. Teresa Brevini
  2. Mailis Maes
  3. Gwilym J. Webb
  4. William T. H. Gelson
  5. Sally Forrest
  6. Petra Mlcochova
  7. Scott Dillon
  8. Sagar Varankar
  9. Mahnaz Darvish-Damavandi
  10. Victoria L. Mulcahy
  11. Rhoda E. Kuc
  12. Thomas L. Williams
  13. Vasileios Galanakis
  14. Marta Vila-Gonzalez
  15. Olivia C. Tysoe
  16. Daniele Muraro
  17. Thomas W. M. Crozier
  18. Johannes Bargehr
  19. Sanjay Sinha
  20. Sara S. Upponi
  21. Lisa Swift
  22. Kourosh Saeb-Parsy
  23. Susan E. Davies
  24. Thomas Marjot
  25. Eleanor Barnes
  26. Ansgar W. Lohse
  27. Andrew M. Moon
  28. A. Sidney Barritt
  29. Ravindra K. Gupta
  30. Stephen Baker
  31. Anthony P. Davenport
  32. Gareth Corbett
  33. Simon J. A. Buczacki
  34. Joo-Hyeon Lee
  35. Paul Gibbs
  36. Andrew J. Butler
  37. Christopher J. E. Watson
  38. George F. Mells
  39. Gordon Dougan
  40. Ludovic Vallier
  41. Fotios Sampaziotis

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Abstract

Prevention of SARS-CoV-2 entry in cells through the modulation of viral host receptors, such as ACE2, could represent a new therapeutic approach complementing vaccination. However, the mechanisms controlling ACE2 expression remain elusive. Here, we identify the farnesoid X receptor (FXR) as a direct regulator of ACE2 transcription in multiple COVID19-affected tissues, including the gastrointestinal and respiratory systems. We demonstrate that FXR antagonists, including the over-the-counter compound z-guggulsterone (ZGG) and the off-patent drug ursodeoxycholic acid (UDCA), downregulate ACE2 levels, and reduce susceptibility to SARS-CoV-2 infection in lung, cholangiocyte and gut organoids. We then show that therapeutic levels of UDCA downregulate ACE2 in human organs perfused ex situ and reduce SARS-CoV-2 infection ex vivo . Finally, we perform a retrospective study using registry data and identify a correlation between UDCA treatment and positive clinical outcomes following SARS-CoV-2 infection, including hospitalisation, ICU admission and death. In conclusion, we identify a novel function of FXR in controlling ACE2 expression and provide evidence that this approach could be beneficial for reducing SARS-CoV-2 infection, thereby paving the road for future clinical trials.

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  1. ScreenIT

    SciScore for 10.1101/2021.06.06.446781: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: Ethical approval: All human samples were obtained from patients, deceased transplant organ donors or liver explants with informed consent for use in research, and ethical approval (Research Ethics Committee - REC 09/H0305/68; 14/NW/1146; 15/EE/0152; 15/WA/0131; 18/EE/0269; and Papworth Hospital Research Tissue Bank project number T02233).
    IRB: Ethical approval: All human samples were obtained from patients, deceased transplant organ donors or liver explants with informed consent for use in research, and ethical approval (Research Ethics Committee - REC 09/H0305/68; 14/NW/1146; 15/EE/0152; 15/WA/0131; 18/EE/0269; and Papworth Hospital Research Tissue Bank project number T02233).
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    BlindingBlood sample collection and processing: Blood samples were collected from patients as part of the UK-PBC Nested Cohort study after obtaining informed consent, anonymised and analysed by a blinded researcher.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    In brief, following pre-clearing, the lysate was incubated overnight with the FXR antibody (Santa Cruz sc-25309 X) (Supplementary Table S1) or non-immune IgG.
    FXR
    suggested: (Santa Cruz Biotechnology Cat# sc-25309, RRID:AB_628039)
    Experimental Models: Cell Lines
    SentencesResources
    Vero E6 cells (ATCC™ CRL – 1586) were grown on tissue culture plates or T25 flasks in 10% FBS DMEM supplemented with L-glutamine and Penicillin-streptomycin as previously described52.
    Vero E6
    suggested: None
    Software and Algorithms
    SentencesResources
    10X raw data (fastq files) have been deposited in the repository ArrayExpress with the accession number E-MTAB-8495.
    ArrayExpress
    suggested: (ArrayExpress, RRID:SCR_002964)
    Imagej 2.0.0 software (Wayne Rasband
    Imagej
    suggested: (ImageJ, RRID:SCR_003070)
    All flow cytometric analyses were performed on a BD LSR-II flow cytometer from BD Biosciences and analysed using FlowJo v.10.4.2.
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    For viral infection primary organoids were passaged and incubated with SARS-CoV-2 in suspension at a multiplicity of infection (MOI) of 1 for 2 hours.
    SARS-CoV-2
    suggested: (BioLegend Cat# 944703, RRID:AB_2890874)

    Results from OddPub: Thank you for sharing your 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: Please consider improving the rainbow (“jet”) colormap(s) used on page 50. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    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.

  2. Version published to 10.1101/2021.06.06.446781v1 on bioRxiv