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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
general
FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2
Nature, Volume 615, No. 7950, Year 2023
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Description
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. © 2022, The Author(s).
Authors & Co-Authors
Maes, Mailis
United Kingdom, Cambridge
University of Cambridge
Webb, Gwilym James
United Kingdom, Cambridge
Cambridge University Hospitals Nhs Foundation Trust
Fuchs, Claudia Daniela
Austria, Vienna
Medizinische Universität Wien
Dillon, Scott
United Kingdom, Cambridge
Wellcome - Mrc Cambridge Stem Cell Institute
Muraro, Daniele
United Kingdom, Hinxton
Wellcome Sanger Institute
Neary, Megan
United Kingdom, Liverpool
University of Liverpool
Tatham, Lee M.
United Kingdom, Liverpool
University of Liverpool
Stewart, James P.
United Kingdom, Liverpool
University of Liverpool
Pertinez, Henry E.
United Kingdom, Liverpool
University of Liverpool
Forrest, Sally
United Kingdom, Cambridge
University of Cambridge
Mlčochová, Petra
United Kingdom, Cambridge
University of Cambridge
United States, Coral Gables
University of Miami
Williams, Thomas Lloyd
United Kingdom, Cambridge
Addenbrooke's Hospital
Saeb-Parsy, Kourosh
United Kingdom, Cambridge
University of Cambridge
United Kingdom, Cambridge
Cambridge University Hospitals Nhs Foundation Trust
Davies, Susan E.
United Kingdom, Cambridge
Cambridge University Hospitals Nhs Foundation Trust
Hagström, Hannes
Sweden, Stockholm
Karolinska Institutet
Cox, Helen
United Kingdom, Liverpool
University of Liverpool
Illingworth, Christopher J.R.
United Kingdom, Glasgow
Mrc-university of Glasgow Centre for Virus Research
United Kingdom, Cambridge
University of Cambridge
Dahman, Bassam A.
United States, Richmond
Virginia Commonwealth University
Marjot, Thomas
United Kingdom, Oxford
Nuffield Department of Medicine
Barnes, Eleanor J.
United Kingdom, Oxford
Nuffield Department of Medicine
Moon, Andrew M.
United States, Chapel Hill
The University of North Carolina at Chapel Hill
Barritt, Alfred Sidney
United States, Chapel Hill
The University of North Carolina at Chapel Hill
Gupta, Ravindra K.
United Kingdom, Cambridge
University of Cambridge
Baker, Stephen G.
United Kingdom, Cambridge
University of Cambridge
Davenport, Anthony P.
United Kingdom, Cambridge
Addenbrooke's Hospital
Gorgoulis, Vassilis G.
Greece, Athens
National and Kapodistrian University of Athens
United Kingdom, Dundee
University of Dundee
Greece, Athens
Academy of Athens
Buczacki, Simon James Alexander
United Kingdom, Cambridge
Wellcome - Mrc Cambridge Stem Cell Institute
United Kingdom, Oxford
University of Oxford
Matheson, Nicholas J.
United Kingdom, Cambridge
University of Cambridge
United States, Chapel Hill
The University of North Carolina at Chapel Hill
United Kingdom, Bristol
Nhs Blood and Transplant
Trauner, Michael H.
Austria, Vienna
Medizinische Universität Wien
Fisher, Andrew J.
United Kingdom, Newcastle
Newcastle University
Watson, Christopher John Edward
United Kingdom, Cambridge
University of Cambridge
United Kingdom, Cambridge
Cambridge University Hospitals Nhs Foundation Trust
United Kingdom, Newcastle
Newcastle University
Mells, George F.G.
United Kingdom, Cambridge
Cambridge University Hospitals Nhs Foundation Trust
United Kingdom, Cambridge
University of Cambridge
Dougan, Gordon J.
United Kingdom, Cambridge
University of Cambridge
Owen, Andrew
United Kingdom, Liverpool
University of Liverpool
Lohse, Ansgar Wilhelm
Germany, Hamburg
Universitätsklinikum Hamburg-eppendorf
Vallier, Ludovic
United Kingdom, Cambridge
Wellcome - Mrc Cambridge Stem Cell Institute
United Kingdom, Hinxton
Wellcome Sanger Institute
Germany, Berlin
Charité – Universitätsmedizin Berlin
Germany, Berlin
Max Planck Institute for Molecular Genetics
Statistics
Citations: 121
Authors: 36
Affiliations: 24
Identifiers
Doi:
10.1038/s41586-022-05594-0
ISSN:
00280836
Research Areas
Covid
Study Design
Cohort Study