Journal Article

FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2

Wester, Axel, Darvish-Damavandi, Mahnaz, Tysoe, Olivia C., Brevini, Teresa, Illingworth, Christopher J. R., Webb, Gwilym J., Pereyra-Gerber, Pehuén, Crozier, Thomas W. M., Kijak, Edyta, Valentijn, Anthony, Heslop, James A., Sharp, Jo, Sinha, Sanjay, Trauner, Michael, Butler, Andrew J., Barritt, Alfred S., Dahman, Bassam, Muraro, Daniele, Moon, Andrew M., Owen, Andrew, Rossetti, Davide, Fear, Corrina, Corbett, Gareth, Gorgoulis, Vassilis G., Buescher, Gustav, Gelson, William T. H., Gupta, Ravindra K., Maes, Mailis, Scott, William E., Davies, Susan E., Box, Helen, Lee, Joo-Hyeon, Varankar, Sagar S., Marjot, Thomas, Bramwell, Chloe, Forrest, Sally, Clements, Darran, Vila-Gonzalez, Marta, Swift, Lisa, Melum, Espen, Barnes, Eleanor, Upponi, Sara S., Griffiths, Chelsea, Dillon, Scott, Humphreys, Peter, Mulcahy, Victoria L., Cox, Helen, Bastaich, Dustin R., Mells, George F., Galanakis, Vasileios, Fisher, Andrew J., Hagström, Hannes, Bargehr, Johannes, Stewart, James, Gibbs, Paul, Kuc, Rhoda E., Davenport, Anthony P., John, Binu V., Fuchs, Claudia D., Buczacki, Simon J. A., Pertinez, Henry, Williams, Thomas L., Bro

2023

Overview

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 vaccination 2 , 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. FXR regulates the levels of ACE2 in tissues of the respiratory and gastrointestinal systems that are affected by COVID-19, and inhibiting FXR with ursodeoxycholic acid downregulates ACE2 and reduces susceptibility to SARS-CoV-2 infection.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/106 / 13/109 / 13/31 / 13/51 / 13/89 / 14 / 14/19 / 14/28 / 14/63 / 38 / 38/15 / 38/91 / 42 / 42/109 / 45 / 59 / 631/326/590/2291 / 631/326/596/4130 / 64 / 64/60 / 692/308/2778 / 692/308/575 / 692/699/255/2514 / 82 / 96 / ACE2 / Acids / Angiotensin / Angiotensin-converting enzyme 2 / Angiotensin-Converting Enzyme 2 - genetics / Angiotensin-Converting Enzyme 2 - metabolism / Animal tissues / Animals / Bile / Clinical outcomes / Clinical trials / Coronaviruses / COVID-19 / COVID-19 - metabolism / COVID-19 - prevention & control / COVID-19 Drug Treatment / COVID-19 vaccines / Cricetinae / Disease prevention / Disease transmission / Epithelium / Hamsters / Humanities and Social Sciences / Humans / Infections / Liver - drug effects / Liver - metabolism / Liver Transplantation / Lung - drug effects / Lung - metabolism / Lungs / Mice / Monoclonal antibodies / multidisciplinary / Nasal Mucosa - drug effects / Nasal Mucosa - metabolism / Organoids / Organoids - drug effects / Organoids - metabolism / Peptidyl-dipeptidase A / Receptors / Receptors, Virus - genetics / Receptors, Virus - metabolism / Registries / Reproducibility of Results / Respiratory system / Retrospective Studies / SARS-CoV-2 - metabolism / Science / Science (multidisciplinary) / Severe acute respiratory syndrome coronavirus 2 / Signal transduction / Transcription, Genetic / Transplants / Transplants & implants / Ursodeoxycholic acid / Ursodeoxycholic Acid - pharmacology / Viral diseases / Viral infections