an autodidact meets a dilettante…

So I feel it’s time for me to get back to the epidemiology and immunology stuff that I know so little about, especially as it pertains to SARS-Cov2. Watching Dr Seheult’s Medcram updates again after a long hiatus, and catching up with them from the end of April, I note that he’s arguing – and I presume this is a mainstream view, as he clearly keeps an eye on the latest research – that the virus mostly does its damage in attacking the body’s endothelium, and that this in turn causes oxidative stress. The endothelium is a thin layer of cells, or a layer of thin cells, that form the inner lining of the blood and lymph vessels (one day I’ll find out what lymph actually is and does).

Oxidative stress is associated with an imbalance in the level of oxidants such as super-oxide anion and hydrogen peroxide, reduced forms of oxygen (with extra electrons). I don’t really understand this, so I’ll start from scratch. But just preliminary to that, the effects of oxidative stress are manifold. Here’s a summary from news-medical.net:

Oxidative stress leads to many pathophysiological conditions in the body. Some of these include neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease, gene mutations and cancers, chronic fatigue syndrome, fragile X syndrome, heart and blood vessel disorders, atherosclerosis, heart failure, heart attack and inflammatory diseases.

It’s known that SARS-Cov2 enters via the lungs, and does damage there, but it’s now thought that most of the damage is done in the endothelium. To understand this, Dr Seheult is going to teach me some ‘basic’ stuff about metabolism, oxidation, energy production and such. So, we start with mitochondria, the energy-producing organelles inside our cells, which have their own DNA passed down the female line. Looking into a mitochondrion, we have the matrix inside, and around it, between the inner and outer membranes, is the inter-membrane space (IMS). Our food, broken down into its essential components, carbs, fats and proteins, is absorbed into the matrix, and somehow turned into ‘two-carbon units’ called acetyl coenzyme A. This is metabolism, apparently. These molecules go through a famous process called the Krebs cycle, of which I know nothing except that it’s about more metabolism… Although now I know that it produces electrons, tied up in two important molecules, NADH and FADH2. These electrons ‘love to be given up’, a way of saying they ‘want’ to be reduced. The molecule that gives up electrons is said to be oxidised, the receiving molecule is reduced. So think of a molecule being reduced as the opposite of losing, rather counter-intuitively. The oxidised molecule is the one that loses electrons. All this is about energy production within the matrix, and the aim is to end up with a molecule I’ve heard and forgotten much about, adenosine triphosphate (ATP). This molecule is the energy molecule, apparently, and the energy is produced by ‘knocking off’ one of the phosphates, according to Dr Seheult, leaving, apparently, adenosine diphosphate (ADP) plus ‘energy’ (clearly, this part needs a little more detail). So going from the diphosphate form to the triphosphate requires energy, going the other way releases energy – none of which really explains why ATP is the body’s energy source. Anyway…

Returning to the carbs, fats and proteins, they go through these mitochondrial processes to produce electrons which want to reduce stuff. So NADH goes to the membrane which separates the IMS from the matrix of the mitochondrion, where proteins can be found that are willing to accept electrons, i.e. to be reduced. The electrons are brought in ‘at the very top of the scale’ (?) and lose some of their reducing ability, so they go down to a lower state of reduction, and protons are pumped into the IMS. (I’m sure this is all true but making sense of it is another matter. It certainly makes me think of proton pump inhibitors, drugs that reduce gastric reflux, but that would be the subject of another set of posts). Then ‘it goes to another species’ by which I think Seheult means another protein, judging from the video, but what he means by ‘it’ I’ve no idea. The NADH? The wave/body of electrons? Anyway, things keep going down to a lower level, becoming more oxidised, and more and more protons are pumped out. So there comes to be a very high concentration of protons (H+) in the IMS, creating a very low PH (high acidity). Meanwhile, the electron transport chain has gone down so many levels that it can only reduce oxygen itself, which by accepting electrons turns finally into water. It’s apparently essential to have sufficient oxygen to keep this cycle going, and to keep the protons pumping, because the protons in the IMS want to move to a place of lower concentration, in the matrix. In doing this, they pass through a channel, which involves, somehow, a coupling of ADP to ATP. Without enough oxygen, this process is stymied, ATP can’t be supplied, leading to insufficient energy and cell death.

So, I think I understand this, as far as it goes. Now, if you over-eat, with lots of high-calorie fats and carbs entering the cells, you’ll likely end up with a surplus of electrons, tied up in NADH and FADH2, which can cause problems. This is where super-oxides come in.

Oxygen is the final electron acceptor in the electron transport chain, and when you add an electron to this final acceptor you get a super-oxide, an oxygen molecule with an additional electron, aka a radical. These are very reactive and dangerous. They can cause DNA damage and serious inflammation, and the body uses them to kill bacteria. If you add another electron, you get H₂O₂, hydrogen peroxide, and another one again produces a hydroxy radical, OH. Another electron gives water, so it’s these intermediate molecules that are called ‘dangerous species’. Cells such as neutrophils (a type of white blood cell) make these, via an enzyme called NADPH oxidase, as part of their defence against antigens, but an accumulation of these radicals is problematic and needs to be dealt with.

One enzyme the body uses to bring down these accumulating radicals is super-oxide dismutase (SOD), which takes two super-oxides and converts them into O₂ and H₂O₂. SOD comes in three types, related to where they reside – in the mitochondria, the cytosol and the extracellular matrix. These enzymes are powered by zinc, copper and, in the mitochondria, manganese. So what happens to the extra hydrogen peroxide created? An enzyme called glutathione peroxidase (GPx) reduces H₂O₂ to water by giving it two electrons. Where do these electrons come from? According to Seheult, and this is presumably ‘basic’ microbiology, the antioxidant glutathione has two forms, oxidised and reduced. The reduced form is 2GS-H, with a hydrogen bonded to the sulphur group. The oxidised form is G-S-S-G, a disulphide bond replacing the hydrogen. With the reduced form, GPx donates its extra two electrons to H₂O₂, reducing it to water. The glutathione system is recharged by reducing it back with NADPH, which has two electrons which are converted to NADP+ (?) Glutathione reductase is the key enzyme in that process. It might take me a few lifetimes to get my head around just this much.

Meanwhile there’s another system… Catalase, an iron-boosted enzyme, can convert two molecules of H₂O₂ into O₂ and H₂O. This occurs in organelles called peroxisomes. The major point to remember in all this is that super-oxides are harmful species that can cause oxidative stress, and the major solutions come in the form of SOD and GPx. In fact the general name for these harmful molecules – super-oxides, hydrogen peroxide, and hydroxy radicals – is reactive oxygen species (ROS).

So we have to relate all this to the effects of SARS-Cov2, which enters the body through the ACE-2 (angiotensin-converting enzyme-2) receptor. According to a 2008 research paper, ACE-2, the receptor for which is blocked by SARS-Cov2, ‘confers endothelial protection and attenuates atherosclerosis’. Quoting from the paper, we find a section called ‘ACE-2 modulates ANG II(angiotensin 2)-induced ROS production in endothelial cells’. The researchers’ essential finding was that ‘ACE-2 functions to improve endothelial homeostasis’, and it seems this function is being disrupted by SARS-Cov2. As Dr Seheult puts it, SARS-Cov2 inhibits the inhibitor, that is it inhibits ACE-2, which normally acts to regulate angiotensin 1,7 (not explained in this particular video), thus allowing NADPH oxidase to keep producing super-oxides, with the resultant oxidative stress. As Seheult concludes here, subjects with compromised systems caused by diabetes, cardiovascular disease or obesity, affecting the production or effectiveness of SOD and GPx, might be relying on ACE-2 and angiotensin 1,7 to maintain some semblance of health. Are these the subjects that are succumbing most to the virus? That’s to be explored in future videos, and future posts here.

Reference

Coronavirus Pandemic Update 63: Is COVID-19 a Disease of the Endothelium (Blood Vessels and Clots)? (video by Dr Roger Seheult – clearly a hero in this time)