The common denominator of COVID-19 and vascular diseases — could glycans and human glycocalyx be the answer?
There is increasing evidence that men and older people (>65 years) have a higher COVID-19 mortality than the rest of the population (Yang et al., 2020). There is also a tendency of higher mortality in people with comorbidities such as hypertension (30.0%) and diabetes mellitus (12.1%) (Zhang et al., 2020) as well as coronary heart diseases (5.8%), and cerebrovascular disease (2.3%) (Guan et al., 2020).
The scientific community doesn’t seem to agree on the reasons why this mortality increase is present in people with said diseases.
To explain why, let’s dig into the mechanisms of SARS-CoV-2 and medications often used in said diseases treatment.
A person with hypertension, diabetic nephropathy caused by diabetes mellitus or heart problems often receives angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type-I receptor blockers (ARBs) (Abuissa et al. 2005).
These drugs could increase the amount of angiotensin-converting enzyme 2 (ACE2) receptors in, for example, cells of the lung tissue.
The SARS-CoV-2 works by attaching itself on the ACE2 receptor. Therefore, this receptor serves as a viral entry point into the cell. The ACE2 receptor is expressed by epithelial cells of the lung, intestine, kidney, and blood vessels. Having this in mind, one might conclude that the increase of the ACE2 receptor is the primary reason for a detected increase in mortality among the people who suffer from hypertension, diabetic nephropathy or heart disease (Fang et al, 2020).
However, Gurwitz (2020) comments that the more ACE2 receptors a person has, the more likely it is for the attacked cell to go into apoptosis and thus inhibit the spread of the virus. Some scientists (Phadke and Saunik, Feb 2020) even go so far as suggesting that ARBs could be used in the treatment of COVID-19.
There are two scenarios when it comes to viruses entering the cells:
1. A virus enters the cell and takes over the cell’s machinery in order to produce copies of itself — in this case, the cell is just a tool used in the spreading of the virus.
2. A virus enters the cell, cell recognises that something strange is happening and destroys itself — in this case, the cell slows down the further spread of the virus.
As you can see, a clear solution was not given. Why is that? Could there be something else in play here?
There is ‘something’ that connects the pathophysiology of these diseases — the destruction of the endothelial glycocalyx. All of the mentioned diseases are in some way connected to the vascular system and are termed ‘vascular diseases’.
In my previous post, I gave a brief introduction to endothelial glycocalyx (eGC). Beside the endothelium, this thick proteoglycan layer is present in various body tissues. Maybe the most important information related to SARS-CoV-2 is that the epithelial cells of the lungs are covered with glycocalyx as well. The vast majority of evidence is present, connecting the glycocalyx destruction and hypertension, diabetes, sepsis, diabetic nephropathy, and others.
One of many glycocalyx functions is the protection of the cell membranes. In short, the glycocalyx acts as a gatekeeper, deciding ‘who’ can enter the cell and ‘who’ cannot.
Based on this evidence, a person with diabetes, hypertension or other mentioned condition, in most cases, has an impaired glycocalyx function. That means that their cells are more susceptible to the outside (or inside) attackers — because they lack the full protection capacity.
Could this be the answer?
Allow me to elaborate further.
When explaining the mechanism of SARS-CoV-2 entry, illustrations like the following one are usually presented.
This is a model of virus entry. Here you see that the spike proteins on the surface of the SARS-CoV-2 bind to ACE-2 receptors on the surface of the target cell. This illustration, while fairly straightforward, is flawed. Everyone using this model should be aware of the more complicated situation at play.
The SARS-CoV-2 virus is not that simple and the ACE2 receptor is not alone and exposed.
In reality, the spike proteins are coated with glycans — the same class of molecules that make up the human glycocalyx!
Here, you can see the 3-d representation of SARS-CoV-2 together with its glycans and here is the complete glycosylation profile of the virus.
The latter is a link to a company that does a brilliant job in providing important information on glycans in the body. I hope they will get even more recognition in the future.
As for the cell membrane part of the illustration, the more realistic illustration is something like this:
A model modified from Mitchell et al. (2014). This model is used to explain the tumour cell adhesion, but I imagine the mechanism for SARS-CoV-19 attachment would look similar.
The ACE2 receptor is surrounded by a variety of glycocalyx constituents — proteoglycans, glycosaminoglycans, hyaluronan and others.
Another important piece of information
Other than cell membrane protection, the glycocalyx mediates the production of nitric oxide (Bartosch, et al., 2017), a very helpful molecule that causes vasodilation and is crucial in maintaining vascular health. Currently, there are trials on the way which hypothesize that treating COVID-19 patients with nitric oxide could improve their rehabilitation time and decrease related lung injury (Announcing trials here, and here).
Commentary
It is because of the complexity of the realistic physiology and pathophysiology that scientists cannot reach a consensus on the question: why do people with said comorbidities have a higher death rate? Furthermore, most of the doctors and other health professionals I have talked to are not yet aware of the full scope of the glycocalyx importance.
This article is trying to connect the dots based on the subjective point of view and it was written to inspire someone in a relevant position to start including glycocalyx and glycans in the COVID-19 related research. In addition, the endothelial glycocalyx could be a novel target ‘organ’ for early detection and treatment of diabetes-related comorbidities, such as the diabetic nephropathy, as well as other vascular diseases. But of course, more research and more public interest is needed.
I want to hear from you:
Have you ever heard about the human glycocalyx?
Did you know that the spike proteins of SARS-CoV-2 are highly glycosylated?
