Metabolic diseases alter ACE2 expression and increase COVID-19 severity

As the COVID-19 pandemic continues to cause illness and take lives across the world, it is clear that the virus affects different population segments disparately. A new study published on the preprint server medRxiv* in June 2020 reports that one mechanism for this variable severity is the differential expression of the ACE2 receptor in various metabolic conditions, thereby facilitating viral entry into the host cells.

Viral Entry

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19 is known to bind to the human ACE2 molecule on the host cell surface, and this attachment is crucial for viral-host cell membrane fusion and viral entry. While the earlier SARS-CoV also binds ACE2, the current virus has 10-20 times more affinity. Again, when the viral S protein binds ACE2, protease-mediated cleavage of the protein occurs before viral entry.

Novel Coronavirus SARS-CoV-2 This scanning electron microscope image shows SARS-CoV-2 (yellow)—also known as 2019-nCoV, the virus that causes COVID-19—isolated from a patient in the U.S., emerging from the surface of cells (blue/pink) cultured in the lab. Image captured and colorized at NIAID
Novel Coronavirus SARS-CoV-2 This scanning electron microscope image shows SARS-CoV-2 (yellow)—also known as 2019-nCoV, the virus that causes COVID-19—isolated from a patient in the U.S., emerging from the surface of cells (blue/pink) cultured in the lab. Image captured and colorized at NIAID's Rocky Mountain Laboratories (RML) in Hamilton, Montana. Credit: NIAID

While COVID-19 is thought to produce asymptomatic or mild infection in the majority of cases, it can also cause severe respiratory failure and death in a high percentage of elderly and sick patients, especially males. Some of the conditions that increase the risk include coronary heart disease, hypertension, kidney disease, type 2 diabetes, and obesity. As a result, many developed countries are experiencing higher mortality rates than other countries that are underdeveloped and lack healthcare facilities.

What Causes Variable Susceptibility?

The factors leading to the different levels of susceptibility of these patient groups include variations in the level of the ACE2 receptor and its soluble form. The mechanism by which the membrane-bound and soluble forms are kept in equilibrium is still unclear.

Finding ACE2 Levels in Metabolic Illnesses

The current study aims at examining the hypothesis that viral productivity may depend on the individual patient’s level of circulating ACE2.

ACE2 is a membrane-bound enzyme on the cell surface of the host cell and is secreted into the circulation after it releases its ectodomain. The levels of ACE2 vary widely because of genetic factors, different levels of expression of different genes, and natural feedback loops from the renin-angiotensin system (RAS).

The researchers looked at ACE2 concentrations in the serum of patients with metabolic conditions like those mentioned above, in a population of about 5,400 patients of 65 years old and above. All participants were drawn from the Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS) study.

The group was screened for any of these conditions using defined criteria set individually for each disease. Smoking was also classified as a risk factor. The ACE2 levels were measured in all patients.

Metabolic Disease Increases ACE2 Expression

The researchers found that males had lower serum ACE2 levels than females, but ACE2 levels were higher in obese and overweight individuals, compared to those who were lean, that is, whose BMI was below 25. With increasing obesity, the serum ACE2 levels rose.

Both prediabetics and diabetics (type 2 diabetes) had higher ACE2 levels than if the sugar levels were normal. Smoking was also linked to higher ACE2 expression. On the other hand, individuals with coronary heart disease (CHD), chronic obstructive pulmonary disease (COPD), or the estimated glomerular filtration rate (eGFR) were not found to have increased ACE2 concentrations.

Using the Framingham risk score (FRS) that predicts the 10-year risk of cerebrovascular disease (CVD), they also examined its linkage to ACE2 levels and found a positive association.

The study shows that COVID-19 severity is heavily dependent on these coexisting medical conditions as well as poor lifestyle habits and the male sex. Estrogen may increase ACE2 expression in females, but this is not seen in a recent paper, which demonstrates that male patients with heart failure had higher ACE2 levels.

Limitations and Implications of the Study

It is challenging to trace ACE2 in the blood to the tissue of origin since it comes from a wide and diverse set of host tissues. Moreover, ACE2 in the blood is affected by genetic factors, degree of expression, and the effects of disease, drugs, and feedback loops within the RAS.

However, the study does show that “serum levels of ACE2 are altered in some frequent comorbidities and other related phenotypes associated with severity of outcome in COVID-19.”

Of course, independent studies must validate these conclusions and also determine whether the outcomes in these COVID-19 patients with higher ACE2 levels are worse than with others. Also, using only serum levels may not accurately reflect the effect of such illnesses on ACE2 levels in the lungs. However, lung injury may be the central event determining severe or critical disease.

Another issue is that circulating levels of ACE2 may well fall far short of actual levels on the cell surface in solid tissue. And finally, all participants were whites, which makes it difficult to transfer and generalize the victory, because other people groups also get the virus.

The researchers conclude: “ACE2 levels are upregulated in some patient groups with comorbidities linked to COVID-19 and as such may have an emerging role as a circulating biomarker for severity of outcome in COVID-19.”

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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