Black Plague Left a Genetic Imprint in Four Genes in Europeans: Specific Genetic Variants Found in Survivors Indicate Plague Deaths Involved Metal-Based "Medical" Treatments

Was the Black Plague fatality rate just survival of the infection? There's a bit of a surprise in the responses of ERAP1/ERAP2 and two other genes to certain metals...

Bubonic plague, or the “Black Death” caused mass mortality which led to shifts in allele frequencies in four immune system-related genes: ERAP1/ERAP2, NFATC1, CTLA4, TICAM2/TMED7. We explore the function of these genes in detail and they tell a tale some will not want to hear.

When the Black Death, a plague caused by a bacterium called Yersinia pestis swept through Europe in the late 1340s, 50% of the population was wiped out over the course of a half-decade. Such a huge mortality rate is an extreme example of hard selection, the removal of individuals from the population who cannot survive the event.

But the data from a new study suggest (to me) that hard selection may have been due to another cause all together.

People trying to survive the Black Death were often treated with arsenic and mercury, which “killed them faster than the plague”.

Researchers at the University of Chicago, McMaster University, and the Institut Pasteur studied gene frequencies for evidence of changes in specific genetic variation in immune protein-coding genes associated with survivors of the Black Plague.

Their research suggests that the plague altered allele frequencies predominantly in four genes via hard selection due to Y. pestis-related deaths. Because these genes are involved in our immune system, the researchers speculated that the surviving variation might impact our immune responses to other pathogens.

The data involved sequences collected from bones from 300 individuals in two sites, London, and Denmark, to assess reproducibility of the findings. Changes in the frequencies of specific genetic variants over the course of the epidemic were studied by comparing sequences from individuals who died before, during, and after the epidemic.

The Four Proteins

1. Endoplasmic Reticulum Aminopeptidases 1 and 2 (ERAP1/ERAP2)

Our ERAP1 and ERAP2 proteins encode proteins that are responsible for proper trimming of HLA class I epitope precursor peptides involved in antigen presentation. These precursor peptides are from bacterial proteins digested by macrophages and presented on the surface of the macrophages to activate CD8+ T cells.

The trimming process involves concerted action by both ERAP1 and ERAP2 in a final trimming step in the endoplasmic reticulum.

In the study, genes from the 300 persons studied who had two copies of a particular genetic variant (rs2549794) could produce fully functioning ERAP2 transcripts. This would lead to a protein that was ready to work with ERAP1.

Interestingly, the study could not trace the survival directly to the protein-trimming functions of the ERAP1/ERAP2 dynamic duo.

It has been known for some time now that thimerosal selectively inhibits ERAP1. Thimerosal is mercury-based preservative used to allow multi-dose vials of some vaccines, including about 60% of influenza vaccines in the US, and US-made pediatric vaccines shipped overseas.

The inhibition of ERAP1 will prevent proper antigen presentation to many if not most infectious pathogens. In 2012, Ben Cowling et al. reported a two-year increase in the risk of noninfluenza respiratory virus infections in patients who accepted thimerosal-containing influenza vaccines. In other words… they tended to get influenza-like infections for two years following injection with thimerosal.

2. NFATC1

This gene plays a role in the inducible expression of cytokine genes in T-cells, especially in the induction of the IL-2 or IL-4 gene transcription. Combined, IL-2 and IL-4 reduce asthma-like pulmonary morbidity

NFATC1 is a protein involved in a pathway (Syk-> NFAT-> IL-2) that is activated by aluminum salt-based vaccine adjuvants. Aluminum from vaccines is long-lasting - much longer than most infections - and thus chronic NFAT activation via cumulative doses of vaccines will likely lead to chronic IL-2 activation. IL-2 is a pro-inflammatory cytokine secreted by activated CD4+ and CD8+ T-cells; chronic IL-2 expression means chronic inflammation. In the brain, chronic inflammatory cytokine expression can be expected to lead to schizophrenia.

3. CTLA4

Cytotoxic T-lymphocyte associated protein 4 gene encodes a protein that inhibits T-cells. Downregulation of CTLA-4 in immune checkpoint cancer treatments caused autoimmune diseases.

It turns out that arsenic influences the expression of CTLA4. When CTLA4 is blocked by anti-CTLA4 antibodies in mice, they are more susceptible to autoimmunity induced by mercury.

4. TICAM2/TMED7 (Toll-like receptor adaptor molecule 2/Transmembrane P24 Trafficking Protein 7 Read-through)

TICAM2/TMED7, part of our innate immune system, is an unusual “gene”. Sometimes, genes previously identified are expressed together in a way that was not anticipated when the genes were first discovered. They can be "read", or transcribed, in a way that the end of one gene overlaps with another (readthrough transcription). TICAM2/TMED7 is a naturally-occurring example of this type of read-through expression.

There are number of possible connections between TICAM2/TMED7 and each gene individually with metals, notably the functional link between TMED7, Toll-Like Receptor 4 (TLR4) responses to a variety of metals, but I found no direct connection to mercury, arsenic or aluminum.

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Notably, other outlets covering this study merely reference ERAP2. But the study itself reports on ERAP1/ERAP2. And that’s what prompted this article. There is not sufficient awareness of the damage thimerosal visits on a very important function of our immune system.

The reference that should be better appreciated is:

Stamogiannos A, Papakyriakou A, Mauvais FX, van Endert P, Stratikos E. Screening Identifies Thimerosal as a Selective Inhibitor of Endoplasmic Reticulum Aminopeptidase 1. ACS Med Chem Lett. 2016 May 31;7(7):681-5. doi: 10.1021/acsmedchemlett.6b00084. PMID: 27437077; PMCID: PMC4948014.

The other articles quote one of the study authors: “When a macrophage encounters a bacterium, it chops it into pieces for them to be presented to other immune cells signaling that there’s an infection,” said Barreiro.

This process can’t happen if the macrophages are poisoned by thimerosal because thimerosal inhibits ERAP1.

(Barreiro, cont.) “Having the functional version of the gene, appears to create an advantage, likely by enhancing the ability of our immune system to sense the invading pathogen. By our estimate, possessing two copies of the rs2549794 variant would have make a person about 40% more likely to survive the Black Death than those who had two copies of the non-functional variant.”

Of course, inhibiting ERAP1 would have the opposite effect.

Black Death, or Mercury and Arsenic treatments of Black Death? Or maybe both. Or more than both.

The study also examined the ability of living people infected with other pathogens to mount an effective immune response. The study found the same four genes are involved in responses protective against a variety of infections.

In science, often the answer is multifactorial (i.e., not either/or). The exact portion of the risk of death to iatrogenic disease (disease caused by treatment) vs. infection might not be known. But one thing is certain: the mercury and arsenic likely made the Y. pestis infections far worse by impairing the immune reactions.

If the infection interacted with the treatment in more than a linear manner, the interaction may have been multiplicative.

So… who had the bright idea to treat people who had black plague with arsenic and mercury in the 1350’s? Not so bright.

But then who had the bright idea to inject ethylmercury into billions of human beings last century? That would be Eli Lilly, in the 1930’s. Not so bright.

This is a fascinating read… authority-driven treatments with doctors treating patients causing harm since the middle ages! Infected? Get your arsenic, mercury, and ground-up emeralds…

Keep in mind as you read the article, of course that the bacterium that causes plague was and is spread by fleas that fed on infected rodents. Isolation will keep people from being bit by the same fleas. So would a flea bath.

Quacks have been using mercury in medicine for a long, long time. In the book “Quackery”, authors Lydia Kang, MD & Nate Pedersen tell the story of how US President Abraham Lincoln was being sickened by blue pills that contained mercury because he associated the pills with the symptoms of mercury poisoning he was suffering (N=1).

My hypothesis is that the reason why black plague ended was in large part due to immunity, but also due to survival by people refusing arsenic- and mercury-based treatments because the association was so obvious everyone could see it.

See “Mercury was considered a cure — until it killed you”.

Another key reference to be remembered is Ben Cowling’s study. There will be a quiz.

Cowling BJ, Fang VJ, Nishiura H, Chan KH, Ng S, Ip DK, Chiu SS, Leung GM, Peiris JS. Increased risk of non-influenza respiratory virus infections associated with receipt of inactivated influenza vaccine. Clin Infect Dis. 2012 Jun;54(12):1778-83. doi: 10.1093/cid/cis307. Epub 2012 Mar 15. PMID: 22423139; PMCID: PMC3404712.