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New Theories / What is the underlying mechanism of the pathophysiology of COVID-19?
« on: 07/06/2021 05:10:11 »
I've been studying COVID-19 extensively for the past year or so, going over the primary literature, and I started connecting the dots on a number of things.
SARS-CoV-2's effect on the human body is actually a bit more insidious than people give it credit for. Basically, when a COVID-19 infection leads to a lethal outcome, it does so by setting off a cascade of events that lead to lipid peroxidation and sepsis.
SARS-CoV-2's Spike down-regulates ACE2 and triggers a bradykinin storm. Its E proteins act as viroporins and introduce calcium into cells. Its other proteins down-regulate Nrf2 and its main protease may even cleave glutathione peroxidase. It also suppresses the expression of selenoproteins, and it suppresses the interferon response.
These events lead to the release of large quantities of inflammatory cytokines, chemokines, renal potassium wasting, the initial suppression of the innate immune response followed by overreaction, the down-regulation of cellular antioxidant enzymatic protections, and a massive release of superoxide ROS from vascular NADPH oxidase.
The superoxide causes NOS uncoupling, by reacting with vascular nitric oxide to form peroxynitrite. This peroxynitrite goes on to cause nitrosative stress, and it also reacts with and destroys the tetrahydrobiopterin cofactor needed by endothelial nitric oxide synthase to produce nitric oxide. When this happens, the NOS enzyme is uncoupled, causing it to release superoxide instead of nitric oxide. This superoxide reacts with nitric oxide to form more peroxynitrite, and so on and so on. The result is a feedback loop called "NO/ONOO- Disease". Eventually, all the nitric oxide bioavailability is lost due to being eliminated by reaction with superoxide. With no nitric oxide left to scavenge it, superoxide predominates. The virus starts replicating out of control because nitric oxide is antiviral against coronaviruses of this type (it prevents the palmitoylation of the Spike protein).
Neutrophilia and sepsis set in. Chemokines start summoning huge numbers of neutrophils to the site of infection. These neutrophils release destructive enzymes by way of degranulation and NETosis. Superoxide dismutase dismutes superoxide to hydrogen peroxide. Myeloperoxidase produces hypochlorous acid. The hypochlorous acid starts destroying heme and releasing free iron into the bloodstream. Free, unliganded iron, hydrogen peroxide, and superoxide are all in one place. The recipe for disaster is complete. The Haber-Weiss and Fenton reactions begin producing hydroxyl radicals.
Fe3+ + O2•– → Fe2+ + O2
Fe2+ + H2O2 → Fe3+ + OH– + OH•
This oxidative stress occurring in this disease is potent enough to strip the iron out of iron-sulfur groups in aconitases and their homologs, like Iron Regulatory Proteins (IRPs), feeding into the Fenton reaction even more and possibly dysregulating aspects of the Krebs cycle and iron metabolism.
There is no enzyme that protects against hydroxyl radicals, so they start oxidizing lipids within nanoseconds of their formation. They form oxidized phospholipids, oxidized cardiolipin, oxidized LDL cholesterol, malondialdehyde, 4-hydroxynonenal, et cetera. The body starts producing antibodies against the oxidized lipids, which are perceived as "non-self" molecules. This is where you get the lupus anticoagulant (antiphospholipid antibodies). The oxidized lipids also feed into PRRs as damage-associated molecular patterns, summoning even more neutrophils to spill even more ROS-forming enzymes, and so on and so on, promoting ferroptosis, a kind of iron-mediated cell death that occurs due to lipid peroxidation. This cycle repeats ad infinitum until the sufferer dies of organ failure. The underlying cause is the down-regulation of Nrf2 expression and the failure of the body's antioxidant enzymes to break down the various forms of ROS before they start injuring cells. The virus's own proteins interfere with these enzymes and their protective functions.
It's an open question whether or not the hypoxia and coagulopathy of COVID-19 can accelerate this process even further by triggering ischemia-reperfusion injury, causing xanthine oxidase to generate even more ROS.
This hypothesis seems to have great explanatory power over many features of the disease. It explains the hypoxemia, the rapid deterioration, the strange vascular issues, edema, and clotting syndromes. It explains the loss of vascular nitric oxide. It explains why people with pre-existing hypovitaminosis D and/or endothelial dysfunction get so terribly sick. It explains why Vitamin D, N-acetylcysteine, and various other antioxidants are protective; they break the chain of ROS formation before it becomes lethal. It explains why drugs like famotidine lessen the severity of the illness; not because they're histamine blockers, but because H2 blockers like famotidine, ranitidine, and cimetidine are powerful scavengers of hydroxyl radicals and prevent them from oxidizing lipids.
COVID-19 is something akin to an "autoimmune virus". It triggers a severe immune reaction with properties and molecular pathways similar to Lupus and Rheumatoid Arthritis, attacking the lining of the blood vessels. It can also trigger multiple organ failure due to hypoxia, sepsis, and vascular edema. The key thing to keep in mind is that SARS-CoV-2 is not really a virus of the airway, but a vascular endotheliitis, attacking and infecting vascular endothelial cells, promoting endothelial cell sloughing and activation, edema, leakage of fluid into the air spaces in the lungs, coagulopathy, and so on.
A reasonable strategy for treating this disease is defanging neutrophils, the way one would do it for treating osteoarthritis and so forth: by targeting and inhibiting NADPH oxidase and preventing the formation of the "kindling radicals", one also prevents the loss of nitric oxide and the downstream formation of hydroxyl radicals, and so on. For instance, using substances like apocynin, APX-115, etc. However, this would depend on whether the lion's share of superoxide is coming from neutrophils or endothelial cells. Different NADPH oxidase inhibitors are effective only at inhibiting certain isoforms of NOX, and none of them have really seen much clinical testing or usage in the past. The idea of NADPH oxidase inhibition therapy has been entertained in cell cultures in the lab, but in living organisms, there is little data as to the effects, beneficial or not. There have been trials here and there, but they have failed to attain widespread use.
I have made a COVID-19 interaction map that outlines some features of this fascinating pathology:
SARS-CoV-2's effect on the human body is actually a bit more insidious than people give it credit for. Basically, when a COVID-19 infection leads to a lethal outcome, it does so by setting off a cascade of events that lead to lipid peroxidation and sepsis.
SARS-CoV-2's Spike down-regulates ACE2 and triggers a bradykinin storm. Its E proteins act as viroporins and introduce calcium into cells. Its other proteins down-regulate Nrf2 and its main protease may even cleave glutathione peroxidase. It also suppresses the expression of selenoproteins, and it suppresses the interferon response.
These events lead to the release of large quantities of inflammatory cytokines, chemokines, renal potassium wasting, the initial suppression of the innate immune response followed by overreaction, the down-regulation of cellular antioxidant enzymatic protections, and a massive release of superoxide ROS from vascular NADPH oxidase.
The superoxide causes NOS uncoupling, by reacting with vascular nitric oxide to form peroxynitrite. This peroxynitrite goes on to cause nitrosative stress, and it also reacts with and destroys the tetrahydrobiopterin cofactor needed by endothelial nitric oxide synthase to produce nitric oxide. When this happens, the NOS enzyme is uncoupled, causing it to release superoxide instead of nitric oxide. This superoxide reacts with nitric oxide to form more peroxynitrite, and so on and so on. The result is a feedback loop called "NO/ONOO- Disease". Eventually, all the nitric oxide bioavailability is lost due to being eliminated by reaction with superoxide. With no nitric oxide left to scavenge it, superoxide predominates. The virus starts replicating out of control because nitric oxide is antiviral against coronaviruses of this type (it prevents the palmitoylation of the Spike protein).
Neutrophilia and sepsis set in. Chemokines start summoning huge numbers of neutrophils to the site of infection. These neutrophils release destructive enzymes by way of degranulation and NETosis. Superoxide dismutase dismutes superoxide to hydrogen peroxide. Myeloperoxidase produces hypochlorous acid. The hypochlorous acid starts destroying heme and releasing free iron into the bloodstream. Free, unliganded iron, hydrogen peroxide, and superoxide are all in one place. The recipe for disaster is complete. The Haber-Weiss and Fenton reactions begin producing hydroxyl radicals.
Fe3+ + O2•– → Fe2+ + O2
Fe2+ + H2O2 → Fe3+ + OH– + OH•
This oxidative stress occurring in this disease is potent enough to strip the iron out of iron-sulfur groups in aconitases and their homologs, like Iron Regulatory Proteins (IRPs), feeding into the Fenton reaction even more and possibly dysregulating aspects of the Krebs cycle and iron metabolism.
There is no enzyme that protects against hydroxyl radicals, so they start oxidizing lipids within nanoseconds of their formation. They form oxidized phospholipids, oxidized cardiolipin, oxidized LDL cholesterol, malondialdehyde, 4-hydroxynonenal, et cetera. The body starts producing antibodies against the oxidized lipids, which are perceived as "non-self" molecules. This is where you get the lupus anticoagulant (antiphospholipid antibodies). The oxidized lipids also feed into PRRs as damage-associated molecular patterns, summoning even more neutrophils to spill even more ROS-forming enzymes, and so on and so on, promoting ferroptosis, a kind of iron-mediated cell death that occurs due to lipid peroxidation. This cycle repeats ad infinitum until the sufferer dies of organ failure. The underlying cause is the down-regulation of Nrf2 expression and the failure of the body's antioxidant enzymes to break down the various forms of ROS before they start injuring cells. The virus's own proteins interfere with these enzymes and their protective functions.
It's an open question whether or not the hypoxia and coagulopathy of COVID-19 can accelerate this process even further by triggering ischemia-reperfusion injury, causing xanthine oxidase to generate even more ROS.
This hypothesis seems to have great explanatory power over many features of the disease. It explains the hypoxemia, the rapid deterioration, the strange vascular issues, edema, and clotting syndromes. It explains the loss of vascular nitric oxide. It explains why people with pre-existing hypovitaminosis D and/or endothelial dysfunction get so terribly sick. It explains why Vitamin D, N-acetylcysteine, and various other antioxidants are protective; they break the chain of ROS formation before it becomes lethal. It explains why drugs like famotidine lessen the severity of the illness; not because they're histamine blockers, but because H2 blockers like famotidine, ranitidine, and cimetidine are powerful scavengers of hydroxyl radicals and prevent them from oxidizing lipids.
COVID-19 is something akin to an "autoimmune virus". It triggers a severe immune reaction with properties and molecular pathways similar to Lupus and Rheumatoid Arthritis, attacking the lining of the blood vessels. It can also trigger multiple organ failure due to hypoxia, sepsis, and vascular edema. The key thing to keep in mind is that SARS-CoV-2 is not really a virus of the airway, but a vascular endotheliitis, attacking and infecting vascular endothelial cells, promoting endothelial cell sloughing and activation, edema, leakage of fluid into the air spaces in the lungs, coagulopathy, and so on.
A reasonable strategy for treating this disease is defanging neutrophils, the way one would do it for treating osteoarthritis and so forth: by targeting and inhibiting NADPH oxidase and preventing the formation of the "kindling radicals", one also prevents the loss of nitric oxide and the downstream formation of hydroxyl radicals, and so on. For instance, using substances like apocynin, APX-115, etc. However, this would depend on whether the lion's share of superoxide is coming from neutrophils or endothelial cells. Different NADPH oxidase inhibitors are effective only at inhibiting certain isoforms of NOX, and none of them have really seen much clinical testing or usage in the past. The idea of NADPH oxidase inhibition therapy has been entertained in cell cultures in the lab, but in living organisms, there is little data as to the effects, beneficial or not. There have been trials here and there, but they have failed to attain widespread use.
I have made a COVID-19 interaction map that outlines some features of this fascinating pathology: