The Entry Point for COVID-19: The ACE-2 Receptor

To replicate, a virus must locate a host cell. Such cells are typically accessed by binding to specific receptors. In the case of SARS-CoV-2, the receptor utilized is the Angiotensin-Converting Enzyme (ACE) 2 receptor.

A hypothesis presented in the video below by www.medcram.com illustrates the following:

As indicated in the figure, a hormone known as angiotensinogen is transformed into angiotensin 1 (AT-1). In the lungs, ACE converts AT-1 into angiotensin 2 (AT-2), which is a potent vasoconstrictor, meaning it can narrow blood vessels and elevate blood pressure.

AT-2 functions in three primary ways. Firstly, it promotes the secretion of aldosterone, which reduces potassium levels while increasing sodium levels, leading to a rise in blood pressure.

Secondly, when AT-2 is present in low concentrations, the Angiotensin Receptor (ATR) 1 occupies the catalytic site of the ACE-2 receptor. ACE-2 then converts AT-2 into AT-1,7, which causes vasodilation (widening of blood vessels) and reduces inflammation.

Conversely, at high concentrations of AT-2, the ATR1 receptor does not attach to the ACE-2 receptor, allowing the S-proteins of the coronavirus to bind to the catalytic site. This binding leads to vasoconstriction, heightened blood pressure, and increased vascular permeability, affecting the flow of molecules and cells in and out of blood vessels.

Experiments involving ACE-2 knockouts in mice revealed that those lacking the ACE-2 receptor:

• Showed resistance to COVID-19
• Experienced worse outcomes in viral pneumonia
• Had reduced cardiac contractility
• Exhibited elevated levels of AT-2, indicating that ACE-2 may degrade AT-2 at lower concentrations [1].

For further details on this hypothesis, check out the video below:

The Mechanisms Behind SARS-CoV-2 Fatalities

Now that we have a foundational understanding of the ACE-2 receptor's role, we can examine how the coronavirus impacts the body.

As noted in an article from April 9, 2020, there is an ongoing debate among medical professionals regarding whether it is the body's severe immune response that leads to fatalities in COVID-19 patients or if other factors are at play. Clinical data has suggested that the immune response is critical in COVID-19-related deaths, prompting interest in treatments like steroids to suppress the immune system. However, there is currently no solid evidence to support that this approach will be effective; it may even exacerbate the severity of the illness.

How Does the Coronavirus Cause Death?

1. Lungs Once the virus infects a person, it begins to replicate while the immune system attempts to combat it. If the immune response fails, the virus progresses to the lungs, where it targets the alveoli—air sacs essential for oxygen transfer. These sacs contain cells with ACE-2 receptors, making them vulnerable to viral infection. As the virus replicates, it triggers an immune response that leads to increased chemokines and inflammation. This battle results in fluid accumulation in the air sacs, hindering oxygen absorption and causing pneumonia symptoms such as coughing and fever. Some patients may recover, while others may not.

Not only the lungs but several other organs may also sustain severe damage due to the virus or the body's immune response (see figure 2).

2. Cardiovascular System After infecting the lungs, the virus can enter the bloodstream, where it attacks the heart and blood vessels. Although the exact mechanisms remain unclear, studies indicate that COVID-19 adversely impacts the vascular system. For instance, a study involving 416 patients in Wuhan found that approximately 20% experienced heart damage, while another study revealed that about 38% of 184 patients exhibited abnormal blood clotting.

This targeting of the vascular system could explain why individuals with pre-existing conditions such as diabetes, obesity, and hypertension face more severe outcomes.

The article proposes three theories regarding the vascular system's susceptibility:

1. The endothelium of blood vessels contains numerous ACE-2 receptors.
2. The lung damage may lower oxygen levels, resulting in vascular harm.
3. A cytokine storm (an extreme immune response) may damage the heart and other organs.

3. Kidneys Kidney damage is frequently observed in COVID-19 patients (refer to figure 2). Studies conducted in China have indicated instances of kidney failure, with one study revealing that 27% of 85 patients experienced this condition. Another study found that 59% of 200 patients had protein in their urine and 44% had blood present.

The reasons behind kidney failure are still being investigated. It may result from direct viral attack, a cytokine storm, or collateral damage from ventilator use, which increases the risk of kidney injury. Antiviral medications being explored for COVID-19 could also contribute to kidney issues. Notably, the kidneys are seldom the only organs affected, complicating the immune system's battle against the virus in both the kidneys and lungs.

4. Brain Research shows that around 5-10% of hospitalized COVID-19 patients require neurological assistance, with some exhibiting signs of encephalitis (brain inflammation). The presence of ACE-2 receptors on neurons in the brain stem and cortex may explain this vulnerability, although the precise mechanism of viral entry into the brain remains uncertain.

Alternatively, it may not be the virus directly affecting the brain, but rather the consequences of a cytokine storm leading to swelling or blood clotting resulting in strokes.

5. Gut An example provided in the article is a woman in Michigan who exhibited gastrointestinal symptoms such as diarrhea, vomiting, and abdominal pain. While this is just one case, it adds to the evidence suggesting that the gut can also be impacted by the virus. The lower digestive tract is lined with cells containing ACE-2 receptors, making it a potential site of infection.

If COVID-19 patients experience gut-related issues, it raises concerns about the contagiousness of their fecal matter. It remains unclear whether their feces contain intact and infectious virus particles or merely RNA and proteins [3].

This article illustrates the various ways in which the virus can affect different organs in the body. The precise mechanisms and the proportion of patients impacted require further investigation. What seems evident, however, is that cells with ACE-2 receptors are particularly vulnerable to the virus, and organs abundant in ACE-2 appear to be at greater risk for damage.

References

1. https://www.youtube.com/watch?v=1vZDVbqRhyM
2. https://www.nature.com/articles/d41586-020-01056-7
3. https://www.sciencemag.org/news/2020/04/how-does-coronavirus-kill-clinicians-trace-ferocious-rampage-through-body-brain-toes#
4. https://www.thrombosisresearch.com/article/S0049-3848(20)30120-1/fulltext
5. https://jamanetwork.com/journals/jamacardiology/fullarticle/2763524