Like other viruses in the coronavirus family, SARS-CoV-2 has a halo, a corona that surrounds it. In this crown there is a spike-shaped protein, the S protein, which binds to the receptors of our cells to infect them. This means that protein S is the key that the virus uses to enter our cells. That is why many laboratories that work on the COVID-19 vaccine have chosen this protein as a target, with the aim of preventing the virus from using its key. However, there is other research that suggests complementary strategies to fight the disease. Because what if the solution was in the lock?
At the beginning of the 21st century there was an epidemic of Acute Respiratory Syndrome (SARS) caused by another coronavirus, SARS-CoV, a cousin of the current SARS-CoV-2. Everything learned about that virus is being important to better understand COVID-19.
The main coincidence is that the keys of both viruses use the ACE2 protein as a lock. However, the SARS-CoV-2 key fits into the lock more easily, so to speak. And thus, he opens the “door” and enters the cell with greater success. Hence, the probability of infection and spread of COVID-19 is much higher than that of SARS. In fact, this is one of the reasons why SARS-CoV-2 has caused a pandemic: its ease of entering our cells.
ACE2 is the lock
Knowing the location of the lock (the ACE2) in our tissues is also helping us to understand the disease. The pulmonary alveoli resemble bunches of grapes, and have a total area of approximately 75 m². Throughout this surface we can find multiple entry locks for the virus into our body. Hence, it costs him so little to infect us.
Another tissue with a large surface area and presence of ACE2 is the intestinal mucosa, which would explain that a third of patients have digestive disorders. Furthermore, this protein is also abundant in the kidneys, blood vessels, nervous system, and other tissues.
The ubiquity of ACE2 in our body could be one of the reasons for the appearance of the varied symptoms that have been described in COVID-19 patients.
ACE2, RAS, and antihypertensives
The ACE2 protein is one of the key enzymes of the Renin Angiotensin System (RAS). Classically, RAS has been described as a hormonal system that regulates blood pressure. But today it is known that it also regulates cell growth, inflammation, coagulation and scarring (fibrosis) processes.
The following figure shows the two main axes of this system (that of ACE and that of ACE2), which under physiological conditions are in dynamic equilibrium. For example, the ACE axis increases blood pressure, while the ACE2 axis decreases it. And for this reason, many hypertensive patients take ACE inhibitors as medication on a daily basis.
Summary scheme of the Renin Angiotensin System (RAS). Angiotensin converting enzyme (ACE) is the best known element of RAS. Its catalytic action produces angiotensin II (AngII) from angiotensin I (AngI). AngII is a hormone that develops its action by binding to the AT1 receptor found on the plasma membrane of different cells in the body. Its best known physiological action is the increase in blood pressure because it induces vasoconstriction. Furthermore, this ACE / AngII / AT1 axis causes an increase in pro-inflammatory and fibrosis signals in the lungs and stimulates coagulation. Angiotensin converting enzyme 2 (ACE2) transforms AngII into angiotensin 1-7 (Ang1-7), which exerts its action through the Mas receptor. The action mediated by the ACE2 / Ang1-7 / Mas axis reduces blood pressure by vasodilation and induces anti-inflammatory, antifibrotic and antithrombotic signals. Under physiological conditions, these two axes are in dynamic equilibrium.
When the pandemic began, there was speculation about the increased susceptibility to infection in those patients taking ACE inhibitors in their treatment for hypertension. Today this hypothesis has been rejected, and it seems that in the most serious symptoms this type of treatment could even be beneficial.
COVID-19 and the RAS imbalance
It is possible that both severe lung inflammation and subsequent uncontrolled scarring of the damaged lung (pulmonary fibrosis) or the thrombotic processes that have been described in COVID-19 are associated with RAS imbalances. To the extent that, under physiological conditions, the ACE axis promotes signals that lead to inflammation, fibrosis and coagulation, the ACE2 axis has the opposite action.
The Renin Angiotensin System (RAS) in the progress of Covid-19. SARS-Cov-2 is capable of infecting tissues by binding its protein S (the key) to the ACE2 protein found in the cell membrane (the lock). As the disease progresses, new viruses bind to more ACE2 molecules in the membrane and re-enter cells. In this entry process, both the virus and ACE2 are internalized. As a consequence of the repetition of this cycle, the presence of ACE2 outside the cell decreases and the balance between the two axes of the RAS (ACE / AngII / AT1 and ACE2 / Ang1-7 / Mas) is broken, which could aggravate the illness.
As in the disease caused by SARS-CoV, it is believed that, in the case of COVID-19, when the virus enters the cell, so do the key (protein S) and its lock (ACE2). That would imply that, as the disease progresses, the presence of ACE2 on the surface of our cells would decrease as it enters the cell together with the virus. As a consequence, an imbalance in the RAS would occur, increasing the risk of severe lung inflammation, clot formation, and lung sequelae due to fibrosis.
If we fool the virus, ACE2 could be the key to the cure
With all this information, some leading research groups have proposed a deception strategy. Namely: injecting free ACE2 molecules into the blood so that the virus remains attached to them instead of to our cellular receptors. Thus, we could neutralize the infection and, in addition, we would avoid the imbalance in the RAS.
Treatment of Covid-19 with recombinant ACE2. Basic organoid research has shown that the human recombinant ACE2 protein is capable of neutralizing the virus and causing it to lose infectivity. The results of clinical trials will show whether this strategy is able to slow the progression of the disease.
This strategy has had positive results in organoid models (three-dimensional cell structures), and is already being tested in COVID-19 patients in a clinical trial. A positive result would represent a great advance in the fight against this disease and would open a new field in therapies against other viruses that threaten our health.
Begoña Sanz Echevarría, Associate Professor in the Department of Physiology and researcher of the “Aging On” group, University of the Basque Country / Euskal Herriko Unibertsitatea and Gorka Larrinaga Enbeita, Professor of Human Physiology, University of the Basque Country / Euskal Herriko Unibertsitatea
This article was originally published on The Conversation. Read the original.
