Author: Brevini, Teresa; Maes, Mailis; Webb, Gwilym J.; Gelson, William T. H.; Forrest, Sally; Mlcochova, Petra; Dillon, Scott; Varankar, Sagar; Darvish-Damavandi, Mahnaz; Mulcahy, Victoria L.; Kuc, Rhoda E.; Williams, Thomas L.; Galanakis, Vasileios; Vila-Gonzalez, Marta; Tysoe, Olivia C.; Muraro, Daniele; Crozier, Thomas W. M.; Bargehr, Johannes; Sinha, Sanjay; Upponi, Sara S.; Swift, Lisa; Saeb-Parsy, Kourosh; Davies, Susan E.; Marjot, Thomas; Barnes, Eleanor; Lohse, Ansgar W.; Moon, Andrew M.; Sidney Barritt, A.; Gupta, Ravindra K.; Baker, Stephen; Davenport, Anthony P.; Corbett, Gareth; Buczacki, Simon J. A.; Lee, Joo-Hyeon; Gibbs, Paul; Butler, Andrew J.; Watson, Christopher J. E.; Mells, George F.; Dougan, Gordon; Vallier, Ludovic; Sampaziotis, Fotios
Title: FXR inhibition reduces ACE2 expression, SARS-CoV-2 infection and may improve COVID-19 outcome Cord-id: v3tzqykq Document date: 2021_6_7
ID: v3tzqykq
Snippet: 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 compo
Document: 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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