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Updated on April 24, 2020

It takes at least two things to cause a viral infection in the body: a virus and a receptor in the body that this virus can attach to. In the case of COVID-19, the receptor is angiotensin-converting enzyme 2 (ACE2) receptor and the virus is SARS-CoV-2.

The link between ACE2 receptors and SARS-CoV-2 was probably one of the first things that scientists discovered while studying the 2019 novel coronavirus infection. Almost every research paper has some mention of these receptors and how they help the COVID-19 infection gain entry into the body.

Normally, of course, ACE2 receptors help to maintain crucial bodily functions like our blood pressure. Read on to know the connection between ACE2 receptors and SARS-CoV-2, and why COVID-19 causes shortness of breath and other respiratory symptoms.

Read more: COVID-19 timeline

  1. What are ACE2 receptors?
  2. ACE2 and COVID-19: why SARS-CoV-2 produces respiratory symptoms
  3. ACE-2 variants and the risk of COVID-19
  4. RAAS inhibitors for COVID-19
  5. Doctors for Why coronavirus SARS-CoV-2 affects the lungs
  6. Can COVID-19 cause permanent lung damage?

The ACE2 receptors are actually a part of a hormonal system in our body that is responsible for controlling blood pressure and fluid and electrolyte balance. The system is called RAS - renin-angiotensin system.

This system has three hormones - renin, angiotensin and aldosterone - which act as enzymes in three different reactions in your body. 

A hormone is a chemical compound that is directly released into the bloodstream by specialised glands called endocrine glands. Hormones relay messages from one part of the body to another and help regulate various processes in the body. An example of a hormone is insulin, which is released by the pancreas and promotes the uptake of sugars by the liver.

Enzymes, on the other hand, are compounds that catalyze (speed up) all the biological reactions in the body. Pepsin is an enzyme that is released into the stomach; it helps break down proteins in food.

The RAS system includes organs such as the lungs, kidneys, liver, brain and the circulatory system.

The function of the RAS system: In response to low blood pressure, specialised cells in our kidneys release the hormone renin into the bloodstream. This renin breaks down a protein called angiotensinogen (which is released by the liver and is constantly present in the blood) into angiotensin 1.

Now, angiotensin 1 is an inactive protein that needs to be converted into angiotensin 2 to be active. This conversion is done by the angiotensin-converting enzyme (ACE). This enzyme is present in ample amounts in the blood vessels of our lungs and kidneys.

ACE then binds to the ACE receptors present on the surface of the blood vessels of lungs and kidneys and constricts the blood vessels. This leads to an increase in blood pressure - or balance thereof if you already had low blood pressure. Angiotensin 2 also leads to the release of a hormone called aldosterone from the kidneys, which improves kidney function and the sodium-potassium (electrolyte) balance in the body. 

This is why most patients with high blood pressure and chronic kidney disease are given ACE receptor blockers or ACE inhibitors. 

Cell surface receptors are specialized molecules (usually proteins) that are present on the surface or through the surface (like a tunnel) of all body cells. These receptors help something from the outside (an enzyme or hormone, for example) to gain entry into the cell and perform its function.

Angiotensin-converting enzyme 2

ACE2 is very similar in structure to ACE. However, it does the opposite of what ACE does. That is, it brings down blood pressure.

ACE2 converts the active angiotensin 2 into angiotensin (1-7), which dilates blood vessels. ACE2 helps reduce the risk of fibrosis in the body (scarring or hardening of body tissues) and reduces the risk of heart disease.

Receptors for ACE2 are found in the lungs, liver, oral and nasal mucosa, stomach, intestines, kidney and brain.

Viruses are basically a complex of proteins, carbohydrates, lipids and genetic material (DNA or RNA). They are unable to replicate on their own and are considered to be non-living when outside a host - more accurately, they are on the cusp of a living and non-living thing.

Simply put, viruses are parasites that need a host to live and grow. And to get into the host’s body, these parasites use various mechanisms - most of which include specialising themselves to trick the host cells and gain entry into the host. Once the virus enters a cell, it takes over the cellular machinery and starts replicating itself, producing more copies of itself that release the first cell and infects all the surrounding cells. 

In the case of COVID-19, the causative virus SARS-CoV-2 binds to the ACE2 receptors. 

Since the ACE2 receptors are present in the lungs, this virus causes respiratory disease and spreads through droplet infection. So if you touch a contaminated surface, the virus sticks to your palms, and when you touch your face, specifically your mouth, eyes, ears or nose, it can easily gain entry into your respiratory tract. 

We do know that that the ears and nose are connected through the eustachian tube - a tube present in the middle ear that goes to the back of the nose and helps maintain pressure in the ear. 

Though the exact link between eyes and respiratory system is not clear, experts say that tear ducts may have some link with the nose and hence lungs.

ACE2 receptors are also found in the intestines and hence it is considered to be a possible entry route for the COVID-19 virus.

Read more: Tips for caring for someone with COVID-19 at home

Recently, a study done on about 290,000 samples (representing more than 400 population groups) suggested that the presence of certain variants of ACE-2 can increase or decrease the susceptibility of a person to COVID-19.

Some variants bind strongly with the SARS-COV-2 virus, making the person more susceptible to COVID-19. While some variants of ACE-2 don’t bind as strongly with the COVID-19 causing virus, making the person at lesser risk of the disease. 

The study further indicated that these variants are rare in humans right now mainly because there was no selection pressure before (they were not needed urgently), However, considering the history of the SARS-COV epidemics (and hence an increased need for specific variants of ACE-2), these variants may play an important role in changing the susceptibility of humans to coronaviruses in the future. 

The said study is still in the pre-print phase and has not yet been peer-reviewed.

ACE inhibitors (ACEs) or ACE receptor blockers (ARBs) are normally used to treat COVID-19 patients with comorbidities. However, currently, there is conflicting evidence on the safety of these drugs as prophylaxis for COVID-19 or to treat COVID-19 patients. 

Preclinical studies show that administration of ACEIs/ARBs can raise the levels of ACE2 in body, which can worsen the patient’s condition.

Researchers also postulate that if SARS-COV-2 binds to ACE2 receptors, it would disbalance the ACE1/ACE2 system and lead to increased inflammation and blood pressure. 

Read more: Inflammation and COVID-19

Contrarily, the other end of the argument suggests that the increased ACE2 can compete with SARS-COV-2 for binding with ACE2 receptors and reduce the severity of the disease. This would also balance the ACE1/ACE2 system.

There is no concrete evidence to explain how ACE inhibitors or ACE receptor blockers work in human body, especially lungs.

In a study, administration of ACE2 inhibitors had no effect on patients with high blood pressure. Another study showed that that ACE2 inhibitor did not cause an increase in the production of angiotensin-(1–7) in coronary artery disease patients.

However, scientists say that healthcare practitioners should not stop giving these drugs to treat COVID-19 (where necessary) since withdrawing them may worsen the patient’s condition.

Dr. Arun R

Dr. Arun R

Infectious Disease
5 Years of Experience

Dr. Neha Gupta

Dr. Neha Gupta

Infectious Disease
16 Years of Experience

Dr. Lalit Shishara

Dr. Lalit Shishara

Infectious Disease
8 Years of Experience

Dr. Alok Mishra

Dr. Alok Mishra

Infectious Disease
5 Years of Experience

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References

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  2. Fountain JH, Lappin SL. Physiology, Renin Angiotensin System. [Updated 2019 May 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan
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  4. Chamsi-Pasha Mohammed A.R., Shao Zhili, Tang W. H. Wilson. Angiotensin-Converting Enzyme 2 as a Therapeutic Target for Heart Failure. Curr Heart Fail Rep. 2014 Mar; 11(1): 58–63. PMID: 24293035.
  5. Patel Vaibhav B., Zhong Jiu-Chang, Grant Maria B., Oudit Gavin Y. Role of the ACE2/Angiotensin 1–7 Axis of the Renin–Angiotensin System in Heart Failure. Circulation research; 118(8). 1313-1326.
  6. Microbiology Society [Internet]. UK; Are viruses alive?
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  8. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631–637. PMID: 15141377.
  9. Vaduganathan Muthiah, et al. Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19. nejm. 2020.
  10. American College of Cardiology [Internet]. Washington DC. US; COVID-19 Infection and Renin Angiotensin System Blockers
  11. Krumholz Harlan M. reviewing Vaduganathan M et al. N Engl J Med 2020 Mar 30. Discontinuing RAAS Inhibitors in COVID-19 Patients? There's No Evidence. Journal watch: New England Journal of Medicine [Internet].
  12. Eric W. Stawiski, et al. Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility. 2020 April.
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