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SARS-CoV-2 infects a cell as follows: SARS-CoV-2 Spike undergoes a conformational change where the S1 trimers flip up and extend, locking onto ACE2 bound to the surface of a cell. TMPRSS2, or transmembrane protease serine 2, comes along and cuts off the heads of the Spike, exposing the S2 stalk-shaped subunit inside. The remainder of the Spike undergoes a conformational change that causes it to unfold like an extension ladder, embedding itself in the cell membrane. Then, it folds back upon itself, pulling the viral membrane and the cell membrane together. The two membranes fuse, with the virus’s proteins migrating out onto the surface of the cell. The SARS-CoV-2 nucleocapsid enters the cell, disgorging its genetic material and beginning the viral replication process, hijacking the cell’s own structures to produce more virus.

SARS-CoV-2 Spike proteins embedded in a cell can actually cause human cells to fuse together, forming syncytia/MGCs (multinuclear giant cells). They also have other pathogenic, harmful effects. SARS-CoV- 2’s viroporins, such as its Envelope protein, act as calcium ion channels, introducing calcium into infected cells. The virus suppresses the natural interferon response, resulting in delayed inflammation. SARS-CoV-2 N protein can also directly activate the NLRP3 inflammasome. Also, it suppresses the Nrf2 antioxidant pathway. The suppression of ACE2 by binding with Spike causes a buildup of bradykinin that would otherwise be broken down by ACE2.

This constant calcium influx into the cells results in (or is accompanied by) noticeable hypocalcemia, or low blood calcium, especially in people with Vitamin D deficiencies and pre-existing endothelial dysfunction. Bradykinin upregulates cAMP, cGMP, COX, and Phospholipase C activity. This results in prostaglandin release and vastly increased intracellular calcium signaling, which promotes highly aggressive ROS release and ATP depletion. NADPH oxidase releases superoxide into the extracellular space. Superoxide radicals react with nitric oxide to form peroxynitrite. Peroxynitrite reacts with the tetrahydrobiopterin cofactor needed by endothelial nitric oxide synthase, destroying it and “uncoupling” the enzymes, causing nitric oxide synthase to synthesize more superoxide instead. This proceeds in a positive feedback loop until nitric oxide bioavailability in the circulatory system is depleted.

Dissolved nitric oxide gas produced constantly by eNOS serves many important functions, but it is also antiviral against SARS-like coronaviruses, preventing the palmitoylation of the viral Spike protein and making it harder for it to bind to host receptors. The loss of NO allows the virus to begin replicating with impunity in the body. Those with endothelial dysfunction (i.e. hypertension, diabetes, obesity, old age, African-American race) have redox equilibrium issues to begin with, giving the virus an advantage.

Due to the extreme cytokine release triggered by these processes, the body summons a great deal of neutrophils and monocyte-derived alveolar macrophages to the lungs. Cells of the innate immune system are the first-line defenders against pathogens. They work by engulfing invaders and trying to attack them with enzymes that produce powerful oxidants, like SOD and MPO. Superoxide dismutase takes superoxide and makes hydrogen peroxide, and myeloperoxidase takes hydrogen peroxide and chlorine ions and makes hypochlorous acid, which is many, many times more reactive than sodium hypochlorite bleach.

Neutrophils have a nasty trick. They can also eject these enzymes into the extracellular space, where they will continuously spit out peroxide and bleach into the bloodstream. This is called neutrophil extracellular trap formation, or, when it becomes pathogenic and counterproductive, NETosis. In severe and critical COVID-19, there is actually rather severe NETosis.

2.68K viewsHarold Wren, 14:40