The biochemistry of how COVID-19 attacks the body: a synopsis of the medical studies

 - by New Deal democrat

I’ve been doing some reading over the past several weeks, trying to understand how the COVID-19 virus attacks the human body. Below are quotes I found most noteworthy or interesting from these articles.

In essence, they indicate that biochemically the novel coronavirus, COVID-19, mainly binds to the ACE-2 receptor of cell surfaces to gain entrance. These are most prevalent in nasal and mucus cells, alveoli (oxygen-exchanging cells in the longs), and some cells lining the small intestine, which explains why the disease may start as abdominal discomfort in many patients. There are some conditions, especially high blood pressure and diabetes - or, possibly, medications for those conditions - which cause these ACE-2 receptors to be more expressed. 

Conversely, nicotine may cause a decline in the expression of ACE-2 receptors, acting to protect against the disease. But if smokers do get the disease and are admitted to the hospital, the cessation of nicotine ingestion may lead to a rebound in those receptors, worsening the condition.

The virus also appears to bind to an iron ion in hemoglobin in red blood cells, causing blood clots and also preventing those cells from carrying oxygen to the rest of the body. This may explain the horribly low blood oxygen levels seen in many patients; and also why some otherwise asymptomatic patients suffer heart attacks or strokes.

Even more alarming, like HIV the coronavirus appears to attack the immune system itself, binding to a different receptor, called CD147, on the T-cell leukocytes that are sent to attack it, disabling them and causing the immune system to be suppressed. It seems to be when the immune system is overwhelmed in this way (in about 10 days on average) that the disease suddenly takes a deadly turn.

[One obvious note of caution: since the following research was necessarily conducted on the fly, in the teeth of a raging pandemic, it would not be a surprise if ultimately of much of it were  found, if not wrong, at least significantly in error.]

Here are the synopses: 

Science Daily: The virus gains interest to cells by means of the ACE-2 receptor on the cell surface, that typically is involved in blood glucose regulation:

“These investigators used the knowledge they gleaned from multiple SARS-CoV strains -- isolated from different hosts in different years -- and angiotensin-converting enzyme-2 (ACE2) receptors from different animal species to model predictions for the novel Wuhan coronavirus. [NOTE: ACE2 serves normally as a regulator for heart function.]

"Our structural analyses confidently predict that the Wuhan coronavirus uses ACE2 as its host receptor," the investigators wrote. That and several other structural details of the new virus are consistent with the ability of the Wuhan coronavirus to infect humans and with some capability to transmit among humans.”

BioQuick News: How SARS-CoV-2 (COVID-19) Gets into Respiratory Tissue -- And How It May Exploit One of Our Anti-Viral Defenses; Interferon Boosts ACE2, Which Is Cell Surface Receptor That COVID-19 Binds To:

“ Recent research had found that SARS-CoV-2--like the closely related SARS-CoV that caused the SARS pandemic--uses a receptor called ACE2 (angiotensin-converting enzyme 2) to gain entry into human cells, aided by an enzyme called TMPRSS2 (transmembrane serine protease 2). That led Dr. Ordovas-Montanes and Dr. Shalek and colleagues to ask a simple question: which cells in respiratory and intestinal tissue express both ACE2 and TMPRSS2? 

“ .... They found that only a tiny percentage of human respiratory and intestinal cells, often well below 10 percent, make both ACE2 and TMPRSS2. Those cells fall in three types: goblet cells in the nose that secrete mucus; lung cells known as type II pneumocytes that help maintain the alveoli (the sacs where oxygen is taken in); and one type of so-called enterocytes that line the small intestine and are involved in nutrient absorption. 

Nature: Infection prodeeds through as many as three phases: (1) an asymptomatic phase; if the body does not fight off the virus quickly enough, it proceeds to (2) a mildly symptomatic phase. If after about 10 days or so the body has still not fought off the virus, it proceeds to the devastating phase, including the oxygen transfer cells in the lungs, and also involving the blood cells themselves: 

“SARS-CoV-2 infection can be roughly divided into three stages: stage I, an asymptomatic incubation period with or without detectable virus; stage II, non-severe symptomatic period with the presence of virus; stage III, severe respiratory symptomatic stage with high viral load.

 “when a protective immune response is impaired, virus will propagate and massive destruction of the affected tissues will occur, especially in organs that have high ACE2 expression, such as intestine and kidney. The damaged cells induce innate inflammation in the lungs that is largely mediated by pro-inflammatory macrophages and granulocytes. Lung inflammation is the main cause of life-threatening respiratory disorders at the severe stage.

“The cytokine release syndrome (CRS) seems to affect patients with severe conditions. Since lymphocytopenia* is often seen in severe COVID-19 patients, the CRS caused by SARS-CoV-2 virus has to be mediated by leukocytes other than T cells, as in patients receiving CAR-T therapy; a high WBC-count is common, suggesting it, in association with lymphocytopenia, as a differential diagnostic criterion for COVID-19.”

[*low T-cell count. More about COVID-19 and T-cells and the immune system below.]

Science Magazine: also addresses the stages by which the disease progresses:  

“ As the virus multiplies, an infected person may shed copious amounts of it, especially during the first week or so. Symptoms may be absent at this point. Or the virus’ new victim may develop a fever, dry cough, sore throat, loss of smell and taste, or head and body aches. “If the immune system doesn’t beat back SARS-CoV-2 during this initial phase, the virus then marches down the windpipe to attack the lungs, where it can turn deadly. The thinner, distant branches of the lung’s respiratory tree end in tiny air sacs called alveoli, each lined by a single layer of cells that are also rich in ACE2 receptors.

“ Normally, oxygen crosses the alveoli into the capillaries, tiny blood vessels that lie beside the air sacs; the oxygen is then carried to the rest of the body. But as the immune system wars with the invader, the battle itself disrupts this healthy oxygen transfer. Front-line white blood cells release inflammatory molecules called chemokines, which in turn summon more immune cells that target and kill virus-infected cells, leaving a stew of fluid and dead cells—pus—behind. This is the underlying pathology of pneumonia, with its corresponding symptoms: coughing; fever; and rapid, shallow respiration (see graphic). Some COVID-19 patients recover, sometimes with no more support than oxygen breathed in through nasal prongs.

“ .... The disruption seems to extend to the blood itself. Among 184 COVID-19 patients in a Dutch ICU, 38% had blood that clotted abnormally, and almost one-third already had clots, according to a 10 April paper in Thrombosis Research. Blood clots can break apart and land in the lungs, blocking vital arteries—a condition known as pulmonary embolism, which has reportedly killed COVID-19 patients. Clots from arteries can also lodge in the brain, causing stroke. Many patients have “dramatically” high levels of D-dimer, a byproduct of blood clots, says Behnood Bikdeli, a cardiovascular medicine fellow at Columbia University Medical Center.” 


ChemRxiv (pre-print server for chemistry studies): The virus seems  to bind to the hemoglobin in red blood cells, preventing oxygen transfer to other cells in the body, and promoting clotting of the red blood cells themselves:

“The results showed the ORF8 and surface glycoprotein could bind to the porphyrin, r espectively. At the same time, orf1ab, ORF10, and ORF3a proteins could coordinate attack the heme on the 1-beta chain of hemoglobin to dissociate the iron to form the porphyrin. The attack will cause less and less hemoglobin that can carry oxygen and carbon dioxide. The lung cells have extremely intense poisoning and inflammatory due to the inability to exchange carbon dioxide and oxygen frequently, which eventually results in ground-glass-like lung images. The mechanism also interfered with the normal heme anabolic pathway of the human body, is expected to result in human disease.”


Thailand Medical News: More on the virus’s effect on red blood cells. It binds to the iron ion in the red blood cells. This is how it prevents oxygen transfer:

“The research discovered that some of these proteins are to hijack the red blod cells and remove the Iron ions from the heme groups (HBB) and replace themselves with it. This makes the hemoglobin unable to transport oxygen.
 
“As a result the lungs are stressed out and inflamed while the rest of the organs are also being affected. The so called ARDS and subsequent organ failure could be attributed to this.” 

“The cells that the virus binds to using the ACE-2 receptor or three types: mucus producing cells; the alveoli in the lungs that hold oxygen; and nutrient absorbing cells in the intestines.

[This probably explains why a large number of coronavirus infections  begin with intestinal distress. The above two articles also explain why so many severe infections include strikingly low blood oxygen levels, and also why so much blood clotting is found in patients, including otherwise symptomatic patients who may suffer heart attacks or strokes.] 

BioQuick News: How SARS-CoV-2 (COVID-19) Gets into Respiratory Tissue -- And How It May Exploit One of Our Anti-Viral Defenses; Interferon Boosts ACE2, Which Is Cell Surface Receptor That COVID-19 Binds To:

“ The biggest pre-existing condition that is associated of a bad outcome to the infection is high blood pressure. Another significant predisposing condition is diabetes. Because some drugs used to treat each condition stimulate the increase of ACE-2 receptors, concern has been raised by users about the safety of those medications. At least 14 medical societies have weighed in, cautioning patients that they should continue with their medications:”  

ArXiv (publication services for various physical sciences and mathematical disciplines) on whether treatments for high blood pressure and diabetes, rather than the conditions themselves, lead to the bad outcomes:  

“ The discovery of the role of ACE2 as the membrane receptor of SARS-CoVs and SARS-CoV2, raises controversial opinions concerning the effect of medical treatments in facilitating virus infection in human body. Because of the comorbidity of COVID19 with several diseases, like hypertension and diabetes, conventional pharmacological treatments are also under consideration. Hypotheses have been therefore put forward, especially from social media, to suggest potential adverse effects of angiotensin converting enzyme inhibitors (ACE-i) or Angiotensin Receptor Blockers (ARBs or Sartans), in COVID-2019, because of their action on the RAS pathway. This also provoked justified alarmed recommendations from different Scientific Societies that underlined the lack of evidence against ACE-i or ARB medication.” 

Touch Endocrinology: Here is another article, questioning if they is the treatment of high blood pressure and diabetes that raises the incidence of severe infections, rather than the disease itself:

“ The most frequent comorbidities to COVID 19 are hypertension and diabetes. Both diseases are often treated with angiotensin-converting enzymes (ACE) inhibitors. Coronavirus binds to target cells through angiotensin-converting enzyme 2 (ACE2), which expressed in the epithelial cells in the lungs, blood vessels and in the intestine. In patients treated with ACE and angiotensin II receptor blockers, expression of ACE2 is increased. Therefore, it has been suggested that ACE2 expression may be increased in these two groups of patients with hypertension and diabetes, which could facilitate infection with COVID-19 and increase the risk of severe disease and fatality.”

Nephrology Journal club: Here is another note advising patients not to change their medication: : 

“Patients who are taking ACE inhibitors or ARBs are not advised to change their therapy unless advised to do so by their physician.[citing 14 specialized medical associations]

Diabetes Research and Clinical Practice: Here is an article about the blood pressure medications that stimulate the expression of ACE-2 receptors in cells: 

 “ SARS-CoV-2 utilizes ACE2 as a receptor for entry into the host pneumocytes. Herein comes the confounding role of ACE inhibitors (ACEi) and angiotensin-receptor blockers (ARBs), drugs that are so widely used in DM. The expression of ACE2 is markedly increased in patients with DM (and hypertension) on ACEi or ARBs as an adaptive response to counteract the elevated levels of Ang-II and Ang-I. Thus, use of ACE2-stimulating drugs would facilitate the entry of SARS-CoV-2 into pneumocytes and consequently might result in more severe and fatal disease. Amongst others, pioglitazone and liraglutide have also been shown to be associated with ACE2 upregulation in animal studies. Unfortunately, none of the studies have taken into account the baseline treatment. Furthermore, a recently concluded study showed that severe and critically ill patients with COVID-19 had a higher prevalence of hypokalemia that resulted from renal potassium wasting. This can be explained by downregulation of ACE2 following viral intrusion resulting in decreased degradation of angiotensin-II, increased aldosterone secretion and subsequent increased urinary potassium loss. Infact early normalization of serum potassium has been proposed to be a predictor of good prognosis in COVID-19” 

Diabetes Controal:   On the other hand, the most-prescribed medication for diabetes, metformin, is not subjec to this issue, and has been identified as potentially having chemical benefits in treating the infection:

“ On the list [of drugs which appeared chemically to be of use against coronavirus]  were certain antibiotics, metformin, the go-to drug for type 2 diabetes ....” 

Qeios Open Science platform: Nicotine may alter the expression of the ACE-2 receptor, offering protection against severe disease; but cessation of smoking in a hospital setting may lead to an opposite effect:

“ There are however, sufficient scientific data to suggest that smoking protection is likely to be mediated by nicotine. SARS-CoV2 is known to use the angiotensin converting enzyme 2 (ACE2) receptor for cell entry, and there is evidence that nicotine modulates ACE2 expression which could in turn modulate the nicotinic acetyl choline receptor (manuscript submitted). We  hypothesize that SARS-CoV2 might alter the control of the nicotine receptor by acetylcholine. This hypothesis may also explain why previous studies have found an association between smoking and Covid-19 severity. As hospitals generally impose smoking cessation and nicotine withdrawal at the time of hospitalization, tobacco (nicotine) cessation could lead to the release of nicotine receptors, that are increased in smokers, and to a “rebound effect” responsible for the worsening of disease observed in hospitalized smokers.” 

Thailand Medical News: The novel coronavirus goes further, attacking the immune system itself, in a manner similar to HIV. It binds with T-cells and disables them:

“ Researchers from the New York Blood Centre and also from Fudan University in Shanghai have discovered that the SARS-CoV-2 coronavirus which causes the COVID-19 disease that often results severe acute respiratory syndrome also attacks the immune system’s T lymphocytes. The worrying findings highlight the destructive power of the novel coronavirus, which can destroy the immune system, leaving the patient vulnerable and unable to fight off the infection.
 
“ The researchers’ surprise discovery has shed light on the potency of the novel coronavirus is killing powerful immune cells, which are supposed to kill the virus instead.

“ However, surprisingly, the researchers found that when the SARS-Cov-2 coronavirus and the T cell came into contact with each other, the T cell became prey to the coronavirus, wherein a structure in the spike of the coronavirus triggered the attachment of a viral envelope to the cell membrane of the T cells. After, the genes of the virus entered the T cell and overwhelmed it and took it hostage, the SARS-Cov-2 coronavirus deactivated its ability to protect the human host body.

“ Also, the team found that unlike HIV that replicates faulty T cells, the coronavirus does not replicate, showing that the T cells and the virus may end up dying together.”

Medical News: But the mechanism for attacking the T-cells does not seem to involve ACE-2 receptors, of which the T-cells only have a few:

“ T cells contain only a few ACE2 receptor proteins.” 

Nature: The receptor on T-cells that the novel coronavirus is a different one, called CD147:

  

“ ... T-cell lines were significantly more sensitive to SARS-CoV-2 infection when compared with SARS-CoV. In other words, these results tell us that T lymphocytes may be more permissive to SARS-CoV-2 infection .... Therefore, it is plausible that the S protein of SARS-CoV-2 might mediate potent infectivity, even on cells expressing low hACE2, which would, in turn, explain why the transmission rate of SARS-CoV-2 is so high. It is also possible that other receptors mediate the entry of SARS-CoV-2 into T cells, such as CD147, present on the surface of T lymohocytes, which was recently reported to be a novel invasive route for SARS-CoV-2. 

Science Magazine: using genetics to identify individual susceptibility to the virus, to identify people who most need protection, and also those who might be at little risk:

 “COVID-19, caused by the new pandemic coronavirus, is strangely—and tragically—selective. Only some infected people get sick, and although most of the critically ill are elderly or have complicating problems such as heart disease, some killed by the disease are previously healthy and even relatively young. Researchers are now gearing up to scour the patients’ genomes for DNA variations that explain this mystery. The findings could be used to identify those most at risk of serious illness and those who might be protected, and they might also guide the search for new treatments.

“ Ganna heads up a major effort to pool COVID-19 patients’ genetic data from around the world. The idea “came quite spontaneously”  about 2 weeks ago when “everyone was sitting at their computers watching  this crisis,” says Ganna, who is also affiliated with the Broad Institute, a U.S. genomic powerhouse.treatments.

“He and FIMM Director Mark Daly quickly created a website for their project, the COVID-19 Host Genetics Initiative, and reached out to colleagues who run large biobank studies that follow thousands of volunteers for years to look for links between their DNA and health. At least a dozen biobanks, mostly in Europe and the United States, have expressed interest in contributing COVID-19 data from participants who agreed to this. 

“In addition to genetic variants of the ACE2 receptor, scientists want to see whether differences in the human leukocyte antigen genes, which influence the immune system’s response to viruses and bacteria, affect disease severity. And some investigators want to follow up a finding, which a Chinese team reported in a preprint: that people with type O blood may be protected from the virus. “We’re trying to figure out if those findings are robust,” says Stanford University human geneticist Manuel Rivas, who is contributing to Ganna’s initiative.”