This is a summary of: Brevini, T. et al. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2. Nature https://doi.org/10.1038/s41586-022-05594-0 (2022).
Vaccines changed the course of the COVID-19 pandemic by training people’s immune systems to recognize and clear the SARS-CoV-2 virus. However, they are not always effective in individuals with weak immune systems, or against some viral variants1. Moreover, despite international efforts, not everyone has access to vaccination, owing to its cost and disparities in vaccine availability. A huge challenge in managing COVID-19 in this post-vaccine era is preventing SARS-CoV-2 infection in high-risk unvaccinated groups2. Using drugs that are widely accessible could provide a solution.
To help individuals with weak immunity, such drugs against SARS-CoV-2 should not require a well-functioning immune system. And to prevent the virus from being able to escape treatment by mutating, they should not act on the virus. To meet these requirements, we targeted a receptor protein called angiotensin-converting enzyme 2 (ACE2) that is found on the membrane of human cells and constitutes the main ‘doorway’ that SARS-CoV-2 uses to enter and infect cells3. To study ACE2’s function and how it affects viral infection, we used human cells to create organoids — 3D tissue structures grown in vitro to resemble and model different organs — in the laboratory4.
Through the organoid experiments, we discovered that blocking a bile-acid-sensing protein called farnesoid X receptor (FXR) — which is found in large amounts in the liver, but is also present in other parts of the body — reduces the amount of ACE2 on the surface of cells. We treated our organoids with a drug called ursodeoxycholic acid (UDCA), which blocks FXR5 and is used to treat some liver diseases. UDCA reduced ACE2 levels and SARS-CoV-2 infection of cells in organoid models of the human lung, gut and liver.
To confirm these findings in living animals, we treated hamsters with UDCA and showed that the drug prevented SARS-CoV-2 infection. To test whether these findings could be translated to humans, we tested UDCA in a pair of donated human lungs that were not suitable for transplantation. The lungs were ventilated and perfused with a blood-like fluid to keep them functioning, and then treated with either UDCA dissolved in a saline solution or just the saline solution, before infection with SARS-CoV-2 (Fig. 1a). UDCA treatment reduced SARS-CoV-2 infection of samples from the lungs (Fig. 1b). In eight healthy volunteers who received UDCA, ACE2 levels in nasal cells — the main entry points for the virus into the body — were reduced, in theory increasing people’s resistance to infection.
Given that UDCA is widely used in the clinic, we interrogated existing data to compare COVID-19 outcomes of people who were taking UDCA for liver conditions with those of people who were not. Individuals taking UDCA were less likely to have severe COVID-19 than were those who did not receive the drug.
UDCA is widely used, accessible, cost effective, off-patent and easy to manufacture and store — overcoming cost and distribution barriers. It does not target the immune system or the virus itself and could therefore be both effective in people with weak immune systems and protect against viral resistance. It could also be effective in future coronavirus pandemics, because ACE2 is a doorway for many such viruses.
This is one of the first studies to provide a proof of concept for drug testing in donated human organs. This approach could reduce the need for animal experiments and increase the predictive power of preclinical drug testing.
Our results suggest that UDCA could have an important role in the management of COVID-19. However, this study is not a clinical trial, and our findings must be validated and confirmed in large groups of individuals who are studied over time. Importantly, where possible, we propose that UDCA should be used together with vaccination, rather than replacing it. The obvious next step is to conduct large, randomized and controlled trials to assess its effectiveness in the clinic. — Fotios Sampaziotis and Teresa Brevini are at the Wellcome–MRC Cambridge Stem Cell Institute, Cambridge, UK.
Behind the paper
Our research started early in the COVID-19 pandemic, with the serendipitous finding that blocking FXR in bile-duct cells reduces ACE2 expression. When ACE2 was identified as the SARS-CoV-2 receptor3, everything ‘clicked’. We reasoned that, if UDCA reduced the expression of the entry point for the virus into cells, it could prevent SARS-CoV-2 infection. Proving this during the pandemic was challenging, with disruptions at every step, from reagent shortages and institute lockdowns to losing access to animal facilities, human tissue and volunteers for clinical studies. Nevertheless, as we shared our findings, colleagues far and wide came to our help. On-site scientists for the company Abcam hand-delivered antibodies; the Blood and Transplant branch of the United Kingdom’s National Health Service fast-tracked one of the first pairs of human lungs that was available for research during the pandemic; and our physician colleagues volunteered to receive UDCA. This has been our most collaborative and most enjoyable work so far. — F.S.