FXR inhibition reduces ACE2 expression, SARS-CoV-2 infection and may improve COVID-19 outcome
Brevini, T.; Maes, M.; Webb, G. J.; Gelson, W. T. H.; Forrest, S.; Mlcochova, P.; Dillon, S.; Varankar, S.; Darvish-Damavandi, M.; Mulcahy, V. L.; Kuc, R. E.; Williams, T. L.; Galanakis, V.; Vila-Gonzalez, M.; Tysoe, O. C.; Muraro, D.; Crozier, T. W. M.; Bargehr, J.; Sinha, S.; Upponi, S. S.; Swift, L.; Saeb-Parsy, K.; Davies, S. E.; Marjot, T.; Barnes, E.; Lohse, A. W.; Moon, A. M.; Barritt, S. A.; Gupta, R. K.; Baker, S.; Davenport, A. P.; Corbett, G.; Buczacki, S. J. A.; Lee, J.-H.; Gibbs, P.; Butler, A. J.; Watson, C. J. E.; Mells, G. F.; Dougan, G.; vallier, L.; Sampaziotis, F.
Show abstract
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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