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The wide spectrum of symptoms and variance of severity would indicate that COVID-19 affects us all a little differently. This will range from those horribly predisposed to viral infection to the rare few that simply don’t even get the virus. In the middle is most of us who are susceptible to varying degrees. If you had it and recovered then: Congratulations! You now have what should be the 2nd most coveted of all the immunities: naturally-acquired immunity. The best if you could win the genetic lottery would be to never catch COVID at all; pure natural immunity.
Humanity’s survival through the ages has depended upon our ability to defeat viruses, bacteria, parasites and a variety of other microbiological hazards that you cannot see but certainly know are there. Prior to modern antibiotics, infections would regularly ravage the population; the Black Death is estimated to have killed about a third of Europe, and that’s the moderate estimate. Masks were popular then too but they were far more fashionable.
Seven centuries later, through genetic testing, we can track down the positive genetic mutation Delta 32 that would confer resistance to not just the plague, but HIV as well. Herd immunity was eventually achieved because there were only three groups left; those that had it, those that would never get it, and the dead.
Unexplained cases of immunity to COVID-19 have been documented with married partners who confessed to being intimate during their infection, and yet, their partner did not contract the most transmissible virus ever (discordant infections). Furthermore, they would produce no antibodies that would indicate that an asymptomatic or less severe infection ever took place.
In 2019, on the USS Theodore Roosevelt, a COVID outbreak occurred. Of the 4779 crew members 1271 (26%) tested positive. It’s hard to imagine that the other 3,508 (74%) sailors aboard were not exposed to the virus, maybe a few were able to isolate, but certainly not all of them. It would be fair to say that in a healthy patient population there is a chunk of natural innate immunity of some sort going on. The size of that chunk is important and their mechanisms of resistance need to be understood in order to facilitate us in the development of better therapeutics.
A CRISPR loss of function screen was done to try and determine which human genes were most vital to COVID-19. Several genes were identified, each one affecting one step or another of viral entry and pathogenesis. The virus is very dependent upon much of our own cellular machinery in order to replicate itself and spread. Many of these genes affect our endosome function and regulation.
Attachment and endocytosis – ACE2, RAB7A, ACTR2, ACTR3, ARPC3, and ARPC4
Spike protein cleavage – CTSL, ATP6AP1, ATP6AP2, ATP6V0B ATP6V0C, ATP6V0D1, ATP6V1A, ATP6V1B2, ATP6V1C1, ATP6V1E1, ATP6V1G1, ATP6V1H, TMEM199, and TOR1AIP1
Endosome recycling – VPS26A, VPS29, VPS35, and SNX27
Endosomal trafficking – COMMD2, COMMD3, COMMD3-BMI1, COMMD4, dPIK3C3/VPS34, WDR81, and ACP5
Golgi trafficking – DPM3, ERMP1, PPID, and CHST14
Transcriptional Modulators – SLTM and SPEN
These are like your unwitting employees who spread malicious computer code by clicking on the wrong email. They were just doing their job and the virus takes advantage of that. Many of these genes are also associated with cholesterol and lipid functioning. Viral resistance may also come with increased cholesterol expression. Amlodipine, a calcium channel blocker commonly used for hypertension was shown to upregulate cholesterol levels and block infection in a lab study. Some studies have suggested a reduced Covid-19 fatality rate with amlodipine or other dihydropyridine calcium channel inhibitors.
Jacob Hyatt Pharm D.
Father of three, pharmacist, Realtor, Landlord, freelance health and medicine reporter
Further Reading and References
Solaimanzadeh I. Nifedipine and Amlodipine Are Associated With Improved Mortality and Decreased Risk for Intubation and Mechanical Ventilation in Elderly Patients Hospitalized for COVID-19. Cureus. 2020;12(5):e8069. Published 2020 May 12. doi:10.7759/cureus.8069
Zhang LK, Sun Y, Zeng H, et al. Calcium channel blocker amlodipine besylate therapy is associated with reduced case fatality rate of COVID-19 patients with hypertension [published correction appears in Cell Discov. 2021 May 3;7(1):29]. Cell Discov. 2020;6(1):96. Published 2020 Dec 22. doi:10.1038/s41421-020-00235-0
Das JK, Roy S, Guzzi PH. Analyzing host-viral interactome of SARS-CoV-2 for identifying vulnerable host proteins during COVID-19 pathogenesis. Infect Genet Evol. 2021 Sep;93:104921. doi: 10.1016/j.meegid.2021.104921. Epub 2021 May 15. PMID: 34004362; PMCID: PMC8123524.
Daniloski Z, Jordan TX, Wessels HH, Hoagland DA, Kasela S, Legut M, Maniatis S, Mimitou EP, Lu L, Geller E, Danziger O, Rosenberg BR, Phatnani H, Smibert P, Lappalainen T, tenOever BR, Sanjana NE. Identification of Required Host Factors for SARS-CoV-2 Infection in Human Cells. Cell. 2021 Jan 7;184(1):92-105.e16. doi: 10.1016/j.cell.2020.10.030. Epub 2020 Oct 24. PMID: 33147445; PMCID: PMC7584921.
Kasper MR, Geibe JR, Sears CL, Riegodedios AJ, Luse T, Von Thun AM, McGinnis MB, Olson N, Houskamp D, Fenequito R, Burgess TH, Armstrong AW, DeLong G, Hawkins RJ, Gillingham BL. An Outbreak of Covid-19 on an Aircraft Carrier. N Engl J Med. 2020 Dec 17;383(25):2417-2426. doi: 10.1056/NEJMoa2019375. Epub 2020 Nov 11. PMID: 33176077; PMCID: PMC7675688.Published in