Nature: COVID-19 specific medicine or has it been found? For all variants, avoid immune escape!

Compared with microorganisms that can survive independently, such as bacteria and fungi, viruses are completely parasitic and can only survive and reproduce with the help of host cells. SARS CoV-2 is no exception. It needs to find host cells suitable for its own survival to complete its mission of "reproduction". Therefore, the corresponding prevention and control strategy is to block the occurrence of each key process, and it is crucial to block the virus from entering the host cell.

Vaccination is an effective means to block the virus from entering the cells. When the vaccine is inoculated into the human body, it will stimulate the immune system of the human body, thus producing 6 immune effector molecules (antibodies and cytokines) and immune effector cells, and finally removing the vaccine from the human body. When a vaccine like pathogen invades again, the immune system can quickly identify and generate a large number of specific antibodies and immune effector cells by recognizing the characteristics of the pathogen, making the human body free from the invasion of pathogens. The neutralizing antibody produced by the human body after inoculation of COVID-19 vaccine can combine with the virus, making it impossible for the virus to enter the cell. However, there are also shortcomings in vaccines, mainly as follows:

1. The effect of vaccine varies from person to person, because there are differences between people's immune systems.

2. Not all people can be vaccinated, such as people with allergies, patients with acute diseases, and people with immunodeficiency are not suitable for vaccination.

3. When there is a large variation of the virus, the role of the vaccine will be dwarfed. The repeated infection of people in many countries in the past three years is a living example, especially when Omicron appears, many breakthrough infections have occurred, and we can hardly guarantee that there will be no new immune escape variants in the future.

Is there a better way to block the virus from entering the host cell?

If the human body is compared to an ancient city, the vaccine is like training the soldiers in the city to be strong, and giving them pictures of the enemy so that they can recognize the enemy. Therefore, there is always a risk that the enemy will enter the city. If all the gates of the city are closed, the enemy will not be able to enter the city from the very beginning!

The angiotensin converting enzyme 2 (ACE2) receptor on human cells is such a door! Researchers from research institutions such as the University of Cambridge in the United Kingdom have found that ursodeoxycholic acid (UDCA), a drug used to treat cholestasis diseases in clinical practice, can shut down the ACE2 receptor, thus blocking the virus from entering human cells. Since the SARS CoV lineage from 2003 to 2019 uses ACE2 as the main invasion receptor, even though new small-scale mutations continue to appear in the subsequent SARS CoV-2, The drug also maintains its effect. The study was published in Nature magazine on December 5, 2022, entitled "FXR intrusion may protect from SARS-CoV-2 infection by reducing ACE2".

Ursodeoxycholic acid down regulates ACE2 level in cells through transcription factor FXR

Previous results showed that the expression of ACE2 in bile duct cells was very rich, which was also considered to be the reason why COVID-19 could cause liver dysfunction. Interestingly, the authors found that ursodeoxycholic acid could down regulate the expression of ACE2 on bile duct cells. Because ursodeoxycholic acid is a regulator of the transcription factor FXR, the authors hypothesized that ursodeoxycholic acid controls the expression of ACE2 through FXR. The results showed that the activated FXR could directly bind to the promoter of ACE2 and promote the expression of ACE2. Therefore, ursodeoxycholic acid inhibits the expression of ACE2 receptor on bile duct cells by inhibiting the transcription factor FXR.

Because FXR exists not only in the digestive system, but also in the whole body including the respiratory system, it may be a universal mechanism to regulate ACE2 through FXR. Using a multi organ model, the authors found that FXR was indeed involved in the regulation of ACE2 receptor expression in multiple organs, including the respiratory system.

Ursodeoxycholic acid can block COVID-19 from entering cells

Since ursodeoxycholic acid can regulate the level of ACE2 in cells, can it affect the process of COVID-19 entering cells? In order to explore this problem, the author carried out a series of experiments, step by step verifying the bright prospect of ursodeoxycholic acid as a specific drug of COVID-19:

1. Ursodeoxycholic acid can protect cells from COVID-19 infection in vitro.

2. Ursodeoxycholic acid can effectively prevent hamsters from being infected with COVID-19, and hamsters are the "gold standard" model for preclinical research of anti COVID-19 drugs.

3. The lung tissue donated by volunteers was used to maintain lung function through extracorporeal support such as ventilator. Ursodeoxycholic acid was injected into one of the lungs. The results showed that the lung injected with the drug would not be infected by COVID-19, while the other lung was infected with COVID-19.

4. Eight healthy volunteers were recruited to receive ursodeoxycholic acid treatment. The results showed that the level of ACE2 in nasal cells of the volunteers after treatment decreased.

5. Comparing those patients who received ursodeoxycholic acid treatment due to liver disease with those who did not, the results showed that patients who received the drug were less likely to develop severe disease or be hospitalized after infection.

Summary and outlook

In general, this study found that ursodeoxycholic acid (UDCA) can down regulate the expression of ACE2 by inhibiting FXR, thus closing the channel for COVID-19 to enter human cells. Because the drug acts on host cells rather than the virus itself, it can not only prevent current COVID-19 infection, but also prevent future new mutants of COVID-19 and other coronavirus infections using ACE2. At the same time, because ursodeoxycholic acid has been used clinically for many years, we know that it is safe and well tolerated, and that this tablet is cheap, can be produced rapidly in large quantities, and is easy to store or transport.

Fotios Sampaziotis, the corresponding author of the paper, said that vaccines play a protective role by strengthening the immune system to recognize and eliminate viruses. But the vaccine is not effective for everyone, such as some people with weak immune systems. Vaccines are not suitable for everyone. In addition, the virus is also constantly mutating, resulting in reduced protective effect of the vaccine. This research has found a way to close the door of COVID-19 entering human cells, which can prevent virus invasion from the beginning and protect the human body from infection.

Article link: https://www.nature.com/articles/s41586-022-05594-0