Inhibition Of This Receptor Reduces ACE2 Levels and SARS-CoV-2 Infection (Biology)

By using human cholangiocyte organoids as a proof-of-principle system, Dr. Teresa Brevini and colleagues demonstrated that the bile acid receptor farnesoid X receptor (FXR) controls ACE2 expression. They also demonstrated that FXR inhibition, with the approved drug ursodeoxycholic acid (UDCA) or the over-the-counter phytosteroid z-guggulsterone (ZGG), reduces ACE2 expression and SARS-CoV-2 infection in vitro and ex vivo.

As we all know that, Covid-19 vaccines are not efficient against established disease. So, there’s a need of another therapeutic approach. What, if we can be able to modulate viral host receptors like ACE2 in order to prevent SARS-CoV-2 entry in cells. However, the mechanisms controlling ACE2 expression remain elusive.

But, Teresa Brevini and colleagues now identified the farnesoid X receptor (FXR) as a direct regulator of ACE2 transcription in multiple Covid-19 affected-tissues, including those gastrointestinal and respiratory systems.

They demonstrated that FXR inhibition through UDCA or ZGG reduces ACE2 expression, and limits SARS-CoV-2 infection, in lung, cholangiocyte and gut organoids.

They also showed that, UDCA reduces SARS-CoV-2 infection in vitro and ex vivo and their clinical observations suggested that it could be associated with lower ACE2 and improved outcomes in COVID-19.

Fig 1: FXR regulates ACE2 in airway organoids and intestinal organoids: immunofluorescence (left, right) showing changes in ACE2 levels upon modulation of FXR activity in airway organoids © Teresa Brevini et al.

Additionally, it has been demonstrated that UDCA could reduce ACE2 levels and SARS-CoV-2 infection in machine perfused organs.

“This is one of the first studies testing the effect of a drug in a whole human organ perfused ex situ. This finding could prove important for organ transplantation, especially given concerns about peri-operative viral transmission.”

Furthermore, although more data are required to definitively establish this approach, their work sets the stage for future studies using machine-perfused organs for pharmacological studies.

“Our evidence of FXR approach in controlling ACE2 expression could be beneficial for reducing SARS-CoV-2 infection, thereby paving the road for future clinical trials.”

— concluded authors of the study

Reference: Teresa Brevini, Mailis Maes, Gwilym J Webb, William T H Gelson, Sally Forrest, Petra Mlcochova, Scott Dillon, Sagar Varankar, Mahnaz Darvish-Damavandi, Victoria L Mulcahy, Rhoda E Kuc, Thomas L Williams, Vasileios Galanakis, Marta Vila-Gonzalez, Olivia C Tysoe, Daniele Muraro, Thomas W M Crozier, Johannes Bargehr, Sanjay Sinha, Sara S Upponi, Lisa Swift, Kourosh Saeb-Parsy, Susan E Davies, Thomas Marjot, Eleanor Barnes, Ansgar W. Lohse, Andrew M Moon, Sidney A Barritt IV, Ravindra K Gupta, Stephen Baker, Anthony P Davenport, Gareth Corbett, Simon J A Buczacki, Joo-Hyeon Lee, Paul Gibbs, Andrew J Butler, Christopher J E Watson, George F Mells, Gordon Dougan, Ludovic vallier, Fotios Sampaziotis, “FXR inhibition reduces ACE2 expression, SARS-CoV-2 infection and may improve COVID-19 outcome”, bioRxiv 2021.06.06.446781; doi: https://doi.org/10.1101/2021.06.06.446781


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