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FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2

Author

Listed:
  • Teresa Brevini

    (Wellcome–MRC Cambridge Stem Cell Institute)

  • Mailis Maes

    (University of Cambridge)

  • Gwilym J. Webb

    (Cambridge University Hospitals NHS Foundation Trust)

  • Binu V. John

    (University of Miami and Miami VA Health System)

  • Claudia D. Fuchs

    (Medical University of Vienna)

  • Gustav Buescher

    (University Medical Centre Hamburg-Eppendorf)

  • Lu Wang

    (Newcastle University)

  • Chelsea Griffiths

    (Newcastle University)

  • Marnie L. Brown

    (Newcastle University)

  • William E. Scott

    (Newcastle University)

  • Pehuén Pereyra-Gerber

    (University of Cambridge)

  • William T. H. Gelson

    (Cambridge University Hospitals NHS Foundation Trust
    University of Cambridge)

  • Stephanie Brown

    (Wellcome–MRC Cambridge Stem Cell Institute)

  • Scott Dillon

    (Wellcome–MRC Cambridge Stem Cell Institute)

  • Daniele Muraro

    (Wellcome Sanger Institute)

  • Jo Sharp

    (University of Liverpool)

  • Megan Neary

    (University of Liverpool)

  • Helen Box

    (University of Liverpool)

  • Lee Tatham

    (University of Liverpool)

  • James Stewart

    (University of Liverpool)

  • Paul Curley

    (University of Liverpool)

  • Henry Pertinez

    (University of Liverpool)

  • Sally Forrest

    (University of Cambridge)

  • Petra Mlcochova

    (University of Cambridge
    University of Miami and Miami VA Health System)

  • Sagar S. Varankar

    (Wellcome–MRC Cambridge Stem Cell Institute)

  • Mahnaz Darvish-Damavandi

    (Wellcome–MRC Cambridge Stem Cell Institute
    University of Oxford)

  • Victoria L. Mulcahy

    (University of Cambridge)

  • Rhoda E. Kuc

    (University of Cambridge, Addenbrooke’s Hospital)

  • Thomas L. Williams

    (University of Cambridge, Addenbrooke’s Hospital)

  • James A. Heslop

    (Wellcome–MRC Cambridge Stem Cell Institute)

  • Davide Rossetti

    (Wellcome–MRC Cambridge Stem Cell Institute)

  • Olivia C. Tysoe

    (Wellcome–MRC Cambridge Stem Cell Institute
    University of Cambridge and NIHR Cambridge Biomedical Research Centre)

  • Vasileios Galanakis

    (Wellcome–MRC Cambridge Stem Cell Institute)

  • Marta Vila-Gonzalez

    (Wellcome–MRC Cambridge Stem Cell Institute)

  • Thomas W. M. Crozier

    (University of Cambridge)

  • Johannes Bargehr

    (Wellcome–MRC Cambridge Stem Cell Institute
    University of Cambridge
    University of Cambridge)

  • Sanjay Sinha

    (Wellcome–MRC Cambridge Stem Cell Institute
    University of Cambridge)

  • Sara S. Upponi

    (Cambridge University Hospitals NHS Foundation Trust)

  • Corrina Fear

    (University of Cambridge and NIHR Cambridge Biomedical Research Centre)

  • Lisa Swift

    (University of Cambridge and NIHR Cambridge Biomedical Research Centre)

  • Kourosh Saeb-Parsy

    (University of Cambridge and NIHR Cambridge Biomedical Research Centre
    Cambridge University Hospitals NHS Foundation Trust)

  • Susan E. Davies

    (Cambridge University Hospitals NHS Foundation Trust)

  • Axel Wester

    (Karolinska Institutet)

  • Hannes Hagström

    (Karolinska Institutet)

  • Espen Melum

    (Oslo University Hospital, Rikshospitalet
    Oslo University Hospital, Rikshospitalet
    University of Oslo
    Oslo University Hospital, Rikshospitalet)

  • Darran Clements

    (Wellcome–MRC Cambridge Stem Cell Institute)

  • Peter Humphreys

    (Wellcome–MRC Cambridge Stem Cell Institute)

  • Jo Herriott

    (University of Liverpool)

  • Edyta Kijak

    (University of Liverpool)

  • Helen Cox

    (University of Liverpool)

  • Chloe Bramwell

    (University of Liverpool)

  • Anthony Valentijn

    (University of Liverpool)

  • Christopher J. R. Illingworth

    (MRC–University of Glasgow Centre for Virus Research
    University of Cambridge)

  • Bassam Dahman

    (Virginia Commonwealth University)

  • Dustin R. Bastaich

    (Virginia Commonwealth University)

  • Raphaella D. Ferreira

    (University of Miami and Miami VA Health System)

  • Thomas Marjot

    (University of Oxford)

  • Eleanor Barnes

    (University of Oxford)

  • Andrew M. Moon

    (University of North Carolina)

  • Alfred S. Barritt

    (University of North Carolina)

  • Ravindra K. Gupta

    (University of Cambridge
    University of Cambridge)

  • Stephen Baker

    (University of Cambridge)

  • Anthony P. Davenport

    (University of Cambridge, Addenbrooke’s Hospital)

  • Gareth Corbett

    (Cambridge University Hospitals NHS Foundation Trust)

  • Vassilis G. Gorgoulis

    (National and Kapodistrian University of Athens
    University of Dundee
    Academy of Athens)

  • Simon J. A. Buczacki

    (Wellcome–MRC Cambridge Stem Cell Institute
    University of Oxford)

  • Joo-Hyeon Lee

    (Wellcome–MRC Cambridge Stem Cell Institute
    University of Cambridge)

  • Nicholas J. Matheson

    (University of Cambridge
    University of Cambridge
    University of North Carolina
    NHS Blood and Transplant)

  • Michael Trauner

    (Medical University of Vienna)

  • Andrew J. Fisher

    (Newcastle University)

  • Paul Gibbs

    (University of Cambridge and NIHR Cambridge Biomedical Research Centre
    Cambridge University Hospitals NHS Foundation Trust)

  • Andrew J. Butler

    (University of Cambridge and NIHR Cambridge Biomedical Research Centre
    Cambridge University Hospitals NHS Foundation Trust)

  • Christopher J. E. Watson

    (University of Cambridge and NIHR Cambridge Biomedical Research Centre
    Cambridge University Hospitals NHS Foundation Trust
    National Institute of Health Research (NIHR) Cambridge Biomedical Research Centre, and the NIHR Blood and Transplant Research Unit (BTRU) at the University of Cambridge in collaboration with Newcastle University and in partnership with NHS Blood and Transplant (NHSBT))

  • George F. Mells

    (Cambridge University Hospitals NHS Foundation Trust
    University of Cambridge)

  • Gordon Dougan

    (University of Cambridge)

  • Andrew Owen

    (University of Liverpool)

  • Ansgar W. Lohse

    (University Medical Centre Hamburg-Eppendorf)

  • Ludovic Vallier

    (Wellcome–MRC Cambridge Stem Cell Institute
    Wellcome Sanger Institute
    Charité—Universitätsmedizin Berlin
    Max Planck Institute for Molecular Genetics)

  • Fotios Sampaziotis

    (Wellcome–MRC Cambridge Stem Cell Institute
    Cambridge University Hospitals NHS Foundation Trust
    University of Cambridge)

Abstract

Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.

Suggested Citation

  • Teresa Brevini & Mailis Maes & Gwilym J. Webb & Binu V. John & Claudia D. Fuchs & Gustav Buescher & Lu Wang & Chelsea Griffiths & Marnie L. Brown & William E. Scott & Pehuén Pereyra-Gerber & William T, 2023. "FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2," Nature, Nature, vol. 615(7950), pages 134-142, March.
    • Handle: RePEc:nat:nature:v:615:y:2023:i:7950:d:10.1038_s41586-022-05594-0
    DOI: 10.1038/s41586-022-05594-0
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