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How the Black Death has plagued our immune systems to this day

A study, published in Nature, has unveiled how the Black Death changed the frequency of certain immune-related genetic variants in the human population and continues to affect our susceptibility to disease today.

It was a very bad plague

The global bubonic plague pandemic of the 1340s – otherwise known as the “Black Death” – is notorious for wiping out almost half of the population of Europe in just five years, with its effects reaching as far as North Africa and Asia. Scientists are well-aware of the type of selective pressure this single event may have placed on the human race, but it has been difficult to categorically prove that any resulting changes are linked to this one pandemic. That is, until now.

“People have speculated for a long time that the Black Death might be a strong cause of selection, but it’s hard to demonstrate that when looking at modern populations, because humans had to face many other selective pressures between then and now,” explained Luis Barreiro, Professor of Genetic Medicine at the University of Chicago and co-senior author on the study. “The only way to address the question is to narrow the time window we’re looking at.”

Their approach involved analysing 516 ancient DNA samples from the bones of over 200 British and Danish individuals who died before, during, or after the plague. Targeted sequencing of a set of 300 immune-related genes allowed them to identify 4 genes that either protected or increased the individual’s susceptibility to Yersinia pestis – the bacterium that causes bubonic plague.

It’s in the genes

One gene in particular stood out from the crowd – ERAP2. It appears that anyone with two copies of the genetic variant rs2549794 was able to produce full length copies of the ERAP2 transcript and in turn create a functional form of the related protein. This protein helps the immune system recognize the presence of an infection.

“When a macrophage encounters a bacterium, it chops it into pieces for them to be presented to other immune cells signalling that there’s an infection,” said Barreiro. “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 make a person about 40% more likely to survive the Black Death than those who had two copies of the non-functional variant.”

Figure 1: ERAP2 genotype is associated with cytokine response to Y. pestis stimulation. a–d, Effect of genotype upon cytokine levels for granulocyte colony-stimulating factor (G-CSF) (a), interleukin-1β (IL-1β) (b), interleukin 10 (IL-10) (c) and C-C motif chemokine ligand 3 (CCL3) (d). e, Boxplots showing the percentage of bacteria killed (y axis) by macrophages infected for 24 h as a function of ERAP2 genotype (x axis).

To further validate their results, the team went on to test how live human macrophage cells with two copies of the specific variant would fare against the plague. They found that these macrophages were more efficient at neutralizing Y pestis.

“Examining the effects of the ERAP2 variants in vitro allows us to functionally test how the different variants affect the behavior of immune cells from modern humans when challenged with living Yersinia pestis,” said Javier Pizarro-Cerda, Head of the Yersinia Research Unit and Director of the World Health Organization Collaborating Centre for Plague at Institut Pasteur. “The results support the ancient DNA evidence that rs2549794 is protective against the plague.”

A lasting impact

Intriguingly, the story doesn’t end there. It seems that while ERAP2 is protective against the Black Death, selection for the variants is also associated with a higher risk of autoimmune disease in modern populations. In fact, it is a known risk factor for Crohn’s disease.

The work provides the first insight into how pandemics could influence our genomes for years to come, and how this relationship might not always be clear-cut. “A hyperactive immune system may have been great in the past but in the environment today it might not be as helpful,” adds Hendrik Poinar, Professor of Anthropology at McMaster University and co-senior author on the study. 

As for next steps, the team hopes to expand their work to look at the entire genome instead of a few selected immune-related genes. “There is a lot of talk about how pathogens have shaped human evolution, so being able to formally demonstrate which pathways and genes have been targeted really helps us understand what allowed humans to adapt and exist today,” said Barreiro. “This tells us about the mechanisms that allowed us to survive throughout history and why we’re still here today.”