FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2
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 III, Pehuén Pereyra-Gerber, William T H Gelson, Stephanie Brown, Scott Dillon, Daniele Muraro, Jo Sharp, Megan Neary, Helen Box, Lee Tatham, James Stewart, Paul Curley, Henry Pertinez, Sally Forrest, Petra Mlcochova, Sagar S Varankar, Mahnaz Darvish-Damavandi, Victoria L Mulcahy, Rhoda E Kuc, Thomas L Williams, James A Heslop, Davide Rossetti, Olivia C Tysoe, Vasileios Galanakis, Marta Vila-Gonzalez, Thomas W M Crozier, Johannes Bargehr, Sanjay Sinha, Sara S Upponi, Corrina Fear, Lisa Swift, Kourosh Saeb-Parsy, Susan E Davies, Axel Wester, Hannes Hagström, Espen Melum, Darran Clements, Peter Humphreys, Jo Herriott, Edyta Kijak, Helen Cox, Chloe Bramwell, Anthony Valentijn, Christopher J R Illingworth, Bassam Dahman, Dustin R Bastaich, Raphaella D Ferreira, Thomas Marjot, Eleanor Barnes, Andrew M Moon, Alfred S Barritt, Ravindra K Gupta, Stephen Baker, Anthony P Davenport, Gareth Corbett, Vassilis G Gorgoulis, Simon J A Buczacki, Joo-Hyeon Lee, Nicholas J Matheson, Michael Trauner, Andrew J Fisher, Paul Gibbs, Andrew J Butler, Christopher J E Watson, George F Mells, Gordon Dougan, Andrew Owen, Ansgar W Lohse, Ludovic Vallier, Fotios Sampaziotis
Nature, doi:10.1038/s41586-022-05594-0
prophylaxis against COVID-19 2 . Therefore, there is a pressing need for novel prophylactic agents that reduce the risk of severe disease 3 , are less susceptible to viral resistance and are compatible with healthcare systems in low-and middle-income countries. Viral host receptors represent logical therapeutic targets, because they are essential for SARS-CoV-2 cellular entry and infection 1 . Among these, ACE2 is particularly appealing 1 . ACE2 is a transmembrane carboxypeptidase with a broad substrate specificity, including angiotensin II, that acts as the main receptor for SARS-CoV-2. It directly binds to the spike proteins of different coronaviruses, with a high affinity for SARS-CoV-2, rendering it indispensable for viral entry 11 . Accordingly, COVID-19 predominantly affects tissues that express ACE2, such as the lungs, the cardiovascular system, the digestive tract and the biliary tree 12, 13 . Modifying the expression of ACE2 could impede viral entry and protect against infection with SARS-CoV-2 and potentially other coronaviruses that use the same receptor. Furthermore, because ACE2 is a host-cell protein, its expression is not likely to be affected by mutations in the virus. Therefore, therapies that modulate ACE2 expression may be effective against multiple SARS-CoV-2 variants with a higher genetic barrier to resistance. However, the mechanisms that control ACE2 expression remain unclear. Here we use human cholangiocyte organoids as a proof-of-principle system to demonstrate that the bile acid receptor FXR controls the expression of ACE2. We show that this mechanism applies in several SARS-CoV-2-affected tissues, including gastrointestinal and respiratory epithelia. Subsequently, we demonstrate that suppressing FXR signalling, by using the approved drug UDCA or the over-the-counter phytosteroid z-guggulsterone (ZGG), reduces ACE2 expression and SARS-CoV-2 infection in vitro and in an airborne transmission model in golden Syrian hamsters. We repeat our experiments in human lungs and livers perfused ex situ and show that administering UDCA at physiologically relevant concentrations reduces ACE2 and viral infection in both organs ex vivo. We then demonstrate a reduction in the levels of ACE2 in the nasal epithelium of volunteers receiving clinically approved doses of UDCA. Finally, we interrogate an international registry cohort of patients with COVID-19 and chronic liver disease, identify a correlation between UDCA therapy and better clinical outcomes from COVID-19 and reproduce these results in a second independent cohort of liver-transplant recipients.
Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Reporting summary Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. Cambridge BRC Cell Phenotyping Hub for their help with flow cytometry and processing of samples; the building staff of the Jeffrey Cheah Biomedical Centre for maintaining the institute open and safe during the period of lockdown; K. Füssel for coordinating the volunteer study and sample collection at the University Medical Centre Hamburg-Eppendorf; J. Hails
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DOI record:
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"abstract": "<jats:title>Abstract</jats:title><jats:p>Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)<jats:sup>1</jats:sup>, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination<jats:sup>2,3</jats:sup>. 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 <jats:italic>ACE2</jats:italic> 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.</jats:p>",
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