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FXR抑制可能通过降低ACE2来预防SARS-CoV-2感染 10.1038/s41586-022-05594-0 12-05, Article Abstract & Authors:展开 Abstract:收起
Prevention of SARS-CoV-2 infection through the modulation of viral host receptors, such as ACE21, could represent a new chemoprophylactic approach for COVID-19 complementing vaccination2,3. 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 then use the over-the-counter compound z-guggulsterone (ZGG) 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 demonstrate that UDCA-mediated ACE2 downregulation reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we illustrate that UDCA reduces ACE2 expression in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes following SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of liver transplant recipients. In conclusion, we identify a novel function of FXR in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the road for future clinical trials.
First Authors:
Teresa Brevini
Correspondence Authors:
Teresa Brevini,Ludovic Vallier,Fotios Sampaziotis
All Authors:
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,UK-PBC research consortium,Bassam Dahman,Dustin R Bastaich,Raphaella D Ferreira,Thomas Marjot,Eleanor Barnes,Andrew M Moon,Alfred S Barritt IV,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
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