One of 3,000 plague victims recently dug up in London. New research shows how the plague evolved from harmless to devastating. (AFP/Crossrail)

Without two genetic mutations, the Black Death would never have been more than a minor gastrointestinal annoyance. According to a study published Tuesday in Nature Communications, Yersinia pestis -- the bacterium that causes the three main forms of plague and has killed millions throughout history -- could never have been a killer if not for these mutations, which occurred relatively recently.

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There are actually three kinds of plague that Y. pestis can cause; bubonic, pneumonic, and septicemic. But pneumonic plague, which infects the lungs and killed millions as "The Black Death" during the 1300s, is considered the most serious, and has a fatality rate of close to 100 percent. Even today, when individual cases of the plagues are rare but not unheard of, the pneumonic plague often goes undetected for too long -- easily mistaken for the flu -- for antibiotics to be of use.

But how did the Black Death become so deadly?

In the new study lead by microbiologist Wyndham Lathem, researchers from the Northwestern University Feinberg School of Medicine found that a single gene for producing the protein Pla (acquired by Y. pestis early in its evolution) allowed the bacterium to infect the lungs. Until then, based on tests of bacteria altered to lack the gene, it may have been able to colonize the lungs, but wouldn't have caused a serious infection there.

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"Almost all ancestral strains of Y. pestis carry the gene for Pla, but there still exist a few that represent ancestral Y. pestis just prior to acquistion of Pla," the study authors wrote in an article for The Conversation. "We were able to test if these pre-Pla strains were able to cause pneumonic plague – and they did not. But as soon as Y. pestis picked up this gene, the bacteria could cause epidemics of pneumonic plague. No further changes were necessary, even though there are dozens of additional differences between these ancestral strains and modern Y. pestis. So Y. pestis was able to cause pneumonic plague much earlier in its history than had previously been thought – as soon as it acquired this single gene for Pla."

Traditionally, researchers have thought that lung infection was one of the last tools the plague added to its arsenal. But this new research suggests that it took its baby steps as a lung infection, since it probably had the Pla gene quite early in its 5,000-10,000 year lifespan.

But it was a mutation to that gene that gave the plague real potential.

Previous research had shown that a mutation in the Pla gene changed how Y. pestis expressed it, but Lathem and his colleagues tested how that shift changed the disease in rats.

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According to their observations, the modern version of the Pla gene allows the bacterium to infect deep tissues in the body 100 times more effectively. In other words, the mutation makes the plague bacteria much better at infecting the bloodstream and causing a full-body infection.

That second mutation almost certainly occurred just before the first major outbreak of plague 1,500 years ago. The researchers believe that this tiny mutation made the infection spread quickly enough to hit critical mass and cause epidemics.

"Our data suggests that the insertion and then subsequent mutation of Pla allowed for new, rapidly evolving strains of disease," Lathem said in a statement. "This information can show how new respiratory pathogens could emerge with only small genetic changes."

Even though the plague is still out there, no one expects it to make another genetic leap and turn super-deadly again. But it's important that scientists understand just how swiftly a harmless bacterium can turn itself into a killer -- because it could certainly happen again.

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