“The Coronavirus” is officially called SARS-CoV-2, and the disease is Covid-19.

“The ability of the virus to evade the host immune response have been major reasons for high morbidity and mortality.” [17]

SARS-CoV-2 is a spherical virus. The sphere itself is a lipid bilayer which makes up the viral membrane. This membrane is made of the same material as the wall of cells in the human body. And that is no coincidence. When the virus infects a cell, it causes that cell to manufacture the lipid bilayer for all of the new virus particles. This means that the immune system cannot recognize the viral membrane as foreign because it is not foreign; it is the same as cell walls of ordinary cells in the human body.

Now the viral membrane does have different proteins embedded in that lipid bilayer, which the immune system ought to be able to recognize as foreign. However, the largest of these proteins, the Spike protein, is coated with sugar chains that fend off the human immune system, preventing it from recognizing the Spike as a foreign [1, 2].

In order to infect a cell in the human body, the viral Spike must “dock” with a normal protein found embedded in the cell wall of certain types of cells, the ACE2 receptor. This docking initiates the merging of the viral membrane with the cell wall, allowing the virus to drop its RNA into the cytoplasm of the human cell. The RNA does not enter the infected cell alone. It brings with it a protein that wraps and protects the RNA, called the nucleocapsid protein or N-protein. And the N-protein is not just along for the ride.

Inside the infected cell, the N-protein falls away from the viral RNA and begins its next task, to interfere with the “RNA silencing system” normally found in cells of the human body [5]. This system allows cells to stop making protein from RNA. The virus uses the N-protein to shut down that system, so that it can make its own viral proteins without restraint. In addition, the N-protein suppresses Interferon type I (IFN), disrupting the response of the immune system to the viral infection [8]. Shutting down the cell’s RNA silencing system and suppressing interferon are ways the virus fights the human immune system.

As the Covid-19 virus replicates within an infected cell, it has a quick and easy way to make a large number of viral proteins. The RNA codes for three sets of proteins, two long proteins (polypeptide 1a, polypeptide 1b), and then a set of structural and accessory proteins (including the Spike protein and the N-protein) [6]. The two long polypeptides are non-functional; they do nothing at all — until two viral proteases (enzymes that cut up proteins) cleave the peptides into a set of smaller working proteins [7].

These two proteases (PLpro and Mpro) have a second function. They cut up normal human proteins used in the immune system [9]. This sabotages the immune system at an early point in its biochemical processes. The viral proteases cleave three immune system proteins (called IRF3, NLRP12, TAB1), causing two effects. First, the response of the innate arm of the immune system, which is the first responder to a viral or bacterial infection, is blunted. Second, the inflammatory response is increased, by enhanced production of Interleukin-6, to a harmful extent, possibly causing a cytokine storm, as the disease progresses [9].

“A cytokine storm … is a physiological reaction in humans and other animals in which the innate immune system causes an uncontrolled and excessive release of pro-inflammatory signaling molecules called cytokines. Normally, cytokines are part of the body’s immune response to infection, but their sudden release in large quantities can cause multisystem organ failure and death.” [Wikipedia]

The Coronavirus cuts up immune system proteins to reduce one type of immune response, but also so as to initiate an excess of cytokines, by means of a different kind of immune response. That avalanche of cytokines can literally kill you by means of fluid in the lungs and harmful effects on other organs.

Then there are three more ways the virus fights against the immune system. Three of the viral proteins — called Nsp1, Nsp3c, and ORF7a — also attack the immune system. “SARS-CoV-2 produces three virulence factors Nsp1, Nsp3c and ORF7a to interfere with human immunity.” [12. cf. 10].

A certain cell protein, called BST-2, has the role of guarding cells from viral infection by preventing the cell from releasing any new viruses, replicated in the cell. ORF7a (Open Reading Frame 7a, basically the name of a stretch of genetic code) binds to BST-2 so that the cell will freely release newly-created viruses without interference [10].

Nsp1 is a Covid-19 viral protein that inhibits the production of interferon type-I proteins [10]. Interferons are part of the first line of defense against viral infection, the innate arm of the immune system. Inhibiting interferon type-I helps the virus by slowing the response to viral infection. Nsp1 also keeps the infected cell from breaking down the viral RNA [10, 11].

Then Nsp3c helps the coronavirus resist infected person’s innate immunity by binding to the infected cell’s ADP-ribose [10]. The ADP molecule is important in providing energy in cells As ADP-ribose, it helps defend against infection. Nsp3c is essentially an inhibitor of ADP-ribose, thereby removing another one of the cell’s defensive mechanisms.

Now that is a large number array of ways that the Covid-19 virus evades or attacks the human immune system. I know this is all very technical, but the bottom line is that the human immune system is facing a virus which doesn’t just infect the human body; it wages war against the immune system with both defensive and offensive weapons. So the immune system doesn’t always win the battle, especially in persons with weakened immune systems, such as the elderly and those with chronic illnesses (“co-morbidities”).

Treating a Hidden Disease

The ability of the Coronavirus to hide from the immune system creates a practical problem for patient and doctor: How do you treat a hidden disease?

The length of time from when you are infected to when you begin to have symptoms — called the incubation period — is longer for Covid-19 than for many other viral diseases. Half of patients with Covid-19 have an incubation period of 5.1 days or less; the other half, more than 5.1 days [13]. And 99% of persons will have an incubation period of 14 days or less; 97.5% for 11.5 days or less [13]. So a large percentage of persons infected with Covid-19 will not know that they are sick for far too long.

During this time, the incubation period, you are infected with SARS-CoV-2, but you don’t know it. There are no symptoms yet. And since you don’t know you are sick, your doctor doesn’t know. As a result, you won’t be taking any medications for Covid-19 during that time. Doctors do not prescribe medications to persons who are not sick (not usually).

Yet the longer a disease goes without being treated, the worse the outcome. The study “Timing of antiviral treatment initiation is critical to reduce SARS-Cov-2 viral load” found that in order to reduce the amount of virus in your system enough to overcome the infection (>2 logs), “drug efficacy needs to be greater than 80% if treatment is administered after symptom onset; an efficacy of 50% could be sufficient if treatment is initiated before symptom onset” [14]. And that is why many medications that seem to work against Covid-19, do not work very well. They are not given soon enough.

What is the solution to this problem? One way to treat Covid-19, before you have symptoms, is to have a massive testing program, so that you find the disease within a few days of infection. That might be a viable approach for high-risk frontline medical personnel, or for hospital patients with other diseases (in case of infection from staff or other patients). But it is impractical, if not impossible, for the general population.

The other way to treat Covid-19 before symptoms is to take medication for Covid-19 while you are well, or at least while you think you are well. This approach is suggested in the MATH+ protocol, under “prophylaxis” [15]. The protocol has a set of recommendations for persons who are not symptomatic and who probably have not yet been infected.

Prophylaxis
While there is extremely limited data, the following “cocktail” may have a role in the prevention/mitigation of COVID-19 disease. This cocktail is cheap, safe, and widely available.
• Vitamin C 500 mg BID and Quercetin 250-500 mg BID
• Zinc 75-100 mg/day (acetate, gluconate or picolinate). Zinc lozenges are preferred. After 1 month, reduce the dose to 30-50 mg/day.
• Melatonin (slow release): Begin with 0.3 mg and increase as tolerated to 2 mg at night
• Vitamin D3 1000-4000 IU/day
• Optional: Famotidine 20-40 mg/day
[Full Protocol Here]

The prophylaxis protocol is vitamin C, 500 milligrams, “BID” (twice a day); quercetin, a flavonoid found in onions, figs, buckwheat, and other foods, 250 to 500 mg twice a day; zinc, melatonin, and vitamin D, as stated above. For a faster correction of possible vitamin D deficiency, Grant et al. recommended 10,000 IU/day for a few weeks, followed by 5,000 IU/day [16]. Note that the “+” Plus in MATH+ is additional medications and treatments that might be added as time passes.

UPDATES

* Klemm, Theresa, et al. “Mechanism and inhibition of SARS-CoV-2 PLpro.” bioRxiv (2020). PLpro attacks the immune system and causes inflammation by cleaving proteins involved in the immune system.

* Turoňová, Beata, et al. “In situ structural analysis of SARS-CoV-2 spike reveals flexibility mediated by three hinges.” bioRxiv (2020). “We show that the stalk domain of S contains three hinges that give the globular domain unexpected orientational freedom. We propose that the hinges allow S to scan the host cell surface, shielded from antibodies by an extensive glycan coat.”

* Henderson, Rory, et al. “Glycans on the SARS-CoV-2 Spike Control the Receptor Binding Domain Conformation.” bioRxiv (2020). “The glycan shield of the beta-coronavirus (β-CoV) Spike (S) glycoprotein provides protection from host immune responses, acting as a steric block to potentially neutralizing antibody responses…. This indicates the glycan shield acts not only as a passive hinderance to antibody meditated immunity but also as a conformational control element.” They are saying that the sugar chains on the Spike protein evade the immune system, block antibodies, and also help the virus infect cells by controlling the Spikes “up” and “down” states (up means able to infect the cell via the ACE2 receptor).

* Schubert, K., et al. “SARS-CoV-2 Nsp1 binds ribosomal mRNA channel to inhibit translation.” bioRxiv (2020).
~ In infected cells, Nsp1 promotes host mRNA degradation and thereby suppresses host gene expression, including proteins involved in the innate arm of the immune system.

Summary

Covid-19 is a dangerous disease precisely because it has multiple ways to evade and attack the immune system. Perhaps treatments for Covid-19 need to be researched which will inhibit each of the viral components directed at the immune system. Then the virus would be much less dangerous.

Edited to add these studies:
Grant, Rogan A., et al. “Alveolitis in severe SARS-CoV-2 pneumonia is driven by self-sustaining circuits between infected alveolar macrophages and T cells.” bioRxiv (2020).

Pontelli, Marjorie C., et al. “Infection of human lymphomononuclear cells by SARS-CoV-2.” bioRxiv (2020).

Ronald L. Conte Jr.
Covid.us.org
Note: the author of this article is not a doctor, nurse, or healthcare provider.

1. Protein Data Bank, June Molecule of the Month, SARS-COV-2 Spike;

2. Casalino, Lorenzo, et al. “Shielding and Beyond: The Roles of Glycans in SARS-CoV-2 Spike Protein.” bioRxiv (2020).

3. Barros, Romulo O., et al. “Interaction of drugs candidates with various SARS-CoV-2 receptors: an in silico study to combat COVID-19.” (2020).

4. Wang, Xinling, et al. “SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion.” Cellular & Molecular Immunology (2020): 1-3.

5. Mu, Jingfang, et al. “SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells.” Science China Life Sciences (2020): 1-4.

6. Saadat, Shoab, et al. “Structure based drug discovery by virtual screening of 3699 compounds against the crystal structures of six key SARS-CoV-2 proteins.” (2020).

7. Kim, Dongwan, et al. “The architecture of SARS-CoV-2 transcriptome.” Cell (2020).

8. Chen, Jidang, and Hinh Ly. “Immunosuppression by viral N proteins.” Oncotarget 8.31 (2017): 50331.

9. Moustaqil, Mehdi, et al. “SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts.” bioRxiv (2020).

10. Wu, Canrong, et al. “Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods.” Acta Pharmaceutica Sinica B (2020).

11. Naqvi, Ahmad Abu Turab, et al. “Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach.” Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease (2020): 165878.

12. Brown, Alex. “BOC Sciences Adds Featured SARS-CoV-2 Inhibitors for Drug Discovery.” (2020).

13. Lauer, Stephen A., et al. “The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: estimation and application.” Annals of internal medicine 172.9 (2020): 577-582.

14. Gonçalves, A., J. Bertrand, and R. Ke. “Timing of antiviral treatment initiation is critical to reduce SARS-Cov-2 viral load. medRxiv.” Preprint 10.2020.04 (2020): 04-20047886.

15. EVMS Critical Care COVID-19 Protocol – developed by Dr. Paul Marik (June 17 update)

16. Grant, William B., et al. “Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths.” Nutrients 12.4 (2020): 988.

17. Sangith, Nikhil, and Xact Diagnotek. “Unique Fibrinogen-binding motifs in the Nucleocapsid Phosphoprotein of SARS CoV-2: Potential Implications in Host-Pathogen Interactions.” Medical Hypotheses (2020): 110030.

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