Natural Immunities’ Genetic Suspects

 

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

hyattjn@gmail.com www.Jeffersongroverva.com

Bitcoin GtjoZgxE7WpTkWRE6JiEiXfUpqbWKxH4g

https://substack.com/discover/pharmacoconuts

Further Reading and References

Nifedipine and Amlodipine Are Associated With Improved Mortality and Decreased Risk for Intubation and Mechanical Ventilation in Elderly Patients Hospitalized for COVID-19 (nih.gov)

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

Calcium channel blocker amlodipine besylate therapy is associated with reduced case fatality rate of COVID-19 patients with hypertension (nih.gov)

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

Analyzing host-viral interactome of SARS-CoV-2 for identifying vulnerable host proteins during COVID-19 pathogenesis (nih.gov)

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.

Identification of Required Host Factors for SARS-CoV-2 Infection in Human Cells (nih.gov)

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.

An Outbreak of Covid-19 on an Aircraft Carrier (nih.gov)

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.

Black Plague’s quirky genetics, 700 years later | Genetic Literacy Project

Plague Masks: A Brief History Of The Strangest Medical Mask We Ever Used | History Daily

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  1. Mark Alexander Coolidge
    Mark Alexander
    @MarkAlexander

    My wife and I have not had a flu vaccine in decades because, simply put, we have not had the flu in all that time. Our gamma delta T cells must rock. And at this time it makes no sense to risk our immune systems by taking the vaccine.

    • #1
  2. EHerring Coolidge
    EHerring
    @EHerring

    I am confused. Do I need to eat more bacon or less bacon.

    • #2
  3. Stina Member
    Stina
    @CM

    EHerring (View Comment):

    I am confused. Do I need to eat more bacon or less bacon.

    Brain says more :p

     

    • #3
  4. Hang On Member
    Hang On
    @HangOn

    Stina (View Comment):

    EHerring (View Comment):

    I am confused. Do I need to eat more bacon or less bacon.

    Brain says more :p

     

    You can have all mine.

    • #4
  5. Jules PA Member
    Jules PA
    @JulesPA

    JacobHyatt: Many of these genes are also associated with cholesterol and lipid functioning. Viral resistance may also come with increased cholesterol expression.

    Can you expand on this idea?

    • #5
  6. Ontheleftcoast Member
    Ontheleftcoast
    @Ontheleftcoast

    Jules PA (View Comment):

    JacobHyatt: Many of these genes are also associated with cholesterol and lipid functioning. Viral resistance may also come with increased cholesterol expression.

    Can you expand on this idea?

    This is not my specialty, but off the top of my head, cholesterol serves a number of important functions:

    • Hormone precursor (it’s somewhat metabolically “expensive” to make in terms of ATP, though not as much as making pregnenolone from cholesterol. Pregnenolone can go down two synthetic pathways; one to the sex hormones and the other to cortisol and related hormones.

    When stress is chronic, the economy that regulates the balance of the four “f”s of the hypothalamus (feeding, fleeing, fighting, and reproduction) is altered; the reproductive steroid hormone pathways are to a greater or lesser extent deemphasized in favor of reducing inflammation via cortisol, as are the related glucocorticoid driven changes in fluid balance and energy metabolism. In addition, cortisol interacts with medium- and long-chain fatty acid derivatives such as eicosanoid and (long chain only) endocannabinoid (see below) compounds in regulating cell mediated immunity, a regulation which is critical to a healthy response to viral and other infections.

    • Cholesterol is also important at the cellular level; many of the membrane crossing transport and signalling proteins live in more rigid cholesterol rafts embedded in the more fluid unsaturated and polyunsaturated long chain fatty acids of the phospoholipid bilayer of other regions of the cell membranes (and, IIRC, the nuclear membranes) because they need cholesterol’s 3D stability to work properly.

    Cholesterol does not work in isolation; there are key unsaturated fatty acid frameworks which we have to consume and cannot make. Even when we consume the essential (omega -3 and -6) skeletons from plants, there is substantial genetic and epigenetic variability in the efficiency of the conversion of the plant compounds into the compounds needed by mammalian cell membranes—and also as the precursors to many regulatory compounds (hormones and inflammation modulators such as the eicosanoids. and also the endocannabinoids) which are hugely important modulators of many important functions from mood to immunity and beyond. This conversion limitation is why many people do better consuming fish oil in foods and supplements than they do plant based omega-3 and omega-6 fatty acids; another important thing driven by nutrition is the presence or absence of a healthy balance between available omega-3 and omega-6 fatty acids.

    Also, all the above lipids need (highly ATP dependent) protection from free radical damage. Damage to the mitochondrial membranes hits ATP production hard, and the free radical damaged membrane lipids further damage ATP production in a vicious cycle.

    Many of the now notorious comorbidities predispose to failure of both the primary cell mediated immune response and the induction of the dangerous cytokine storms.

    Basically, if you can’t afford to make cholesterol (or, at least in some cases, your ability to do so has been excessively suppressed by drugs,) your ability to respond to many pathological insults is impaired.

    • #6
  7. Jules PA Member
    Jules PA
    @JulesPA

    Ontheleftcoast (View Comment):
    Basically, if you can’t afford to make cholesterol (or, at least in some cases, your ability to do so has been excessively suppressed by drugs,) your ability to respond to many pathological insults is impaired.

    Thanks for all that. Cholesterol rafts is my favorite imagery so far. 😉

    • #7
  8. Kelly B Member
    Kelly B
    @KellyB

    Ontheleftcoast (View Comment):
    Basically, if you can’t afford to make cholesterol (or, at least in some cases, your ability to do so has been excessively suppressed by drugs,) your ability to respond to many pathological insults is impaired.

    Your parenthetical remark is where my mind went right away – given that so many obese and/or diabetic people are also likely on a statin, could we maybe be looking at the wrong contributor to COVID death with comorbidity?

    • #8
  9. Front Seat Cat Member
    Front Seat Cat
    @FrontSeatCat

    You talk about, in your post, past diseases and cures. I argue that how many of those were man-made, created in a bioweapons lab, which may or may not have happened? So the cure = the shot – is a recreation of something that did not emerge naturally. 

    • #9
  10. I Walton Member
    I Walton
    @IWalton

    We’ll sort it out, overcome it, or at worse those who remain will develop immunities,  but we may not overcome our centralized reaction to it.  We could even get that matter straightened out if we’re in charge, but that is not at all clear.  Indeed, I’d guess the Chinese are and they’ll move fast unless we resist everything they and their witting and unwitting allies are doing.

    • #10
  11. EHerring Coolidge
    EHerring
    @EHerring

    Ontheleftcoast (View Comment):
    Basically, if you can’t afford to make cholesterol (or, at least in some cases, your ability to do so has been excessively suppressed by drugs,) your ability to respond to many pathological insults is impaired.

    Dang, I take a statin.

    • #11
  12. EHerring Coolidge
    EHerring
    @EHerring

    Kelly B (View Comment):

    Ontheleftcoast (View Comment):
    Basically, if you can’t afford to make cholesterol (or, at least in some cases, your ability to do so has been excessively suppressed by drugs,) your ability to respond to many pathological insults is impaired.

    Your parenthetical remark is where my mind went right away – given that so many obese and/or diabetic people are also likely on a statin, could we maybe be looking at the wrong contributor to COVID death with comorbidity?

    Something else to worry about.

    • #12
  13. Rodin Member
    Rodin
    @Rodin

    EHerring (View Comment):

    Ontheleftcoast (View Comment):
    Basically, if you can’t afford to make cholesterol (or, at least in some cases, your ability to do so has been excessively suppressed by drugs,) your ability to respond to many pathological insults is impaired.

    Dang, I take a statin.

    Terrible thought: If you were engineering a bioweapon (which is famously difficult to control) to target only a segment of the world population, what better could you do than to make people who take statins vulnerable? Skews older, incites panic, but maybe your population isn’t on statins? 

    • #13
  14. Ontheleftcoast Member
    Ontheleftcoast
    @Ontheleftcoast

    EHerring (View Comment):

    Ontheleftcoast (View Comment):
    Basically, if you can’t afford to make cholesterol (or, at least in some cases, your ability to do so has been excessively suppressed by drugs,) your ability to respond to many pathological insults is impaired.

    Dang, I take a statin.

    Dose is important. Some docs like to drive their patients’ cholesterol way down; at under 90 or 100 people are more likely to have steroid hormone related problems.

    • #14