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ACE 2 expression and SARS-COV-2 infection: various research studies and reviews of COVID-19 and ACE2 show the infection’s multisystemic nature

2020-07-16

Coronavirus studies by Engin Akyurt via pixabay.com

SARS-COV-2 enters human cells by attaching to a cell surface protein called the ACE2 receptor.  The ACE2 receptor is found on the cell surfaces of epithelial (surface) cells in the lung, vascular endothelium (lining), and intestinal epithelial cells.  It is also on vascular smooth muscle cells and the endothelium of the urinary tract (kidneys, bladder, and tubing).  There is some ACE2 in the brain, but not as much as on the surface epithelium and vascular smooth muscle.

When it was first discovered in 2000, ACE2 was found at high levels in the kidneys(on the endothelial (lining) cells), heart (now known to be in heart muscle cells as well as blood vessels within the heart), and testis.  Later, somewhat lower levels were found in the lung, vascular endothelium, vascular smooth muscle, and intestinal epithelium.

ACE2 functions in blood pressure control by relaxing smooth muscle lining the blood vessels.  It does this by breaking down angiotensin II, which is a vasoconstrictor.  Angiotensin II also has pro-inflammatory and pro-fibrotic effects.  It is hydrolyzed (one amino acid is removed from its end) to angiotensin(1-7).  This has the opposite effect to angiotensin II and “mediates vasodilatation, anti‐proliferation, and apoptosis…”

Normally, the body has a finely-tuned balance between higher and lower blood pressure.  The kidneys balance retention of sodium and water with and excretion of sodium and water– this regulates total body blood volume and affects blood pressure.  The inflammatory system balances between attacking foreign cells and proteins and accepting domestic cells and proteins.  The body’s repair systems balance between killing off severely damaged cells (apoptosis), replacing them with scars (fibrosis), versus repairing mildly damaged cells and encouraging production of new cells.  One of the balance-setting hormone systems is the renin-angiotensin complex.

There is some preliminary evidence that, when the virus invades an ACE2-bearing cell, it damages the ACE2 and leads to loss of function, causing a loss of the balance between angiotensin II and angiotensin(1-7).  This seems to result in acute lung injury and respiratory distress syndrome.  Invasion of the circulatory system may lead to increased blood pressure and an inflammatory cascade.

The most critical tissues directly invaded by SARS-COV-2 are lung epithelial cells, vascular endothelial (lining) cells, and intestinal epithelial cells.  The virus gains entry to the body through the epithelium of the nose and through the lungs, but the nose is not severely affected.  Instead, virus invasion of the deep lungs results in dry cough and shortness of breath.   Most of the specific symptoms of infection relate to the lungs.  Even in mild or asymptomatic cases, damage can be seen on lung computerized tomography (CT) and in pulmonary function tests.

The virus is responsible for diarrhea (sometimes watery) but not consistently– many patients do not experience intestinal symptoms.   However, the virus readily invades the intestinal epithelium and virus RNA is consistently isolated from the stool.  We do not know whether the virus can be transmitted by the fecal-oral route– all attention has been to the airways: droplet and aerosol infection.

Most cases also present with anosmia (loss of sense of smell) and/or ageusia or dysgeusia (loss or perversion of sense of taste) but this symptom is frequently overlooked.  It is unclear whether this symptom is caused by damage to surface neurons in the nose and mouth, to epithelial cells, or even to deeper nerve cells in the brain.

/Update with data from article below:

Information From “New Understanding of the Damage of SARS-COV-2 Infection Outside the Respiratory System”

SARS-COV-2 invades the central nervous system through the olfactory nerves, and might also invade through nerves from the lungs.  A patient with encephalitis was found to have the virus in his cerebrospinal fluid (CSF), and the authors of that case report worried that the virus might persist in the central nervous system even after apparent recovery.  The presence of virus in CSF suggests that headache might be related to central nervous system infection; additional, more serious symptoms could be expected if encephalitis becomes established.

The “New Understanding” article discusses the possibility that gastrointestinal (GI) infection by consumption of an infected animal may have been the route of transmission for the initial jump from animals to humans.  In cases where the GI tract is the infection route, we would expect diarrhea and other non-respiratory symptoms to predominate.

/End update

Fever, muscle aches and fatigue are prominent nonspecific symptoms that may be caused by the release of hormones that react to all viral infections rather than to specific invasion by the virus of tissues.  The virus does not appear to invade immune cells in the blood or immune tissues like lymph nodes or bone marrow.

When the virus infection spreads beyond the lung epithelium, it attacks the vascular endothelium of the blood vessels and the smooth muscles of the capillaries.  Here begin the more serious consequences of infection.  Once the virus has invaded the blood vessels, we see the effects of the virus throughout the body, with small blood clots everywhere, reduced kidney function, high fever, delirium, reduced cardiac function, and so on.  Oddly, virus RNA is usually not isolated from the blood; it is unclear what happens to the virus once it gets into the endothelium.

In autopsies, increased numbers of megakaryocytes (the cells that are parents to platelets) were found in the lungs and heart.  Small and large blood clots rich in platelets (the cells that participate in blood clotting) were found throughout the body.  Blood clots were found in the venous side of the heart as well as within the heart muscle.  Prominent “acute tubular necrosis” (death of the kidney’s tubules) was found in most autopsies with tiny blood clots within the kidneys.

In all autopsied lungs,  there was “diffuse alveolar damage” (breakdowns in the terminal sacs where oxygen is exchanged from the air to the blood) and the lungs were filled with fluid and pus.  There were also signs of growth of new lung cells that were attempting to repair the acute lung damage.

The autopsy findings show that the lungs were the first site of infection, but damage to the kidneys and heart was prominent, and blood clots formed throughout the body.

This sketch shows the multisystemic nature of COVID-19 and how it relates to the ACE2 receptor and its normal function in the body.

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