One of the world’s most notorious pathogens has survived for centuries. Scientists say they now know why

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(CNN) — One of the bleakest periods in medieval Europe was the plague pandemic known as the Black Death, which killed at least 25 million people in just five years. But the disease didn’t stop there. The plague adapted to keep its hosts alive longer, so it could spread farther and keep infecting people for centuries, and researchers now say they’ve discovered how.

The disease is caused by the bacterium Yersinia pestis, which has been circulating among human populations for at least 5,000 years. The pathogen has fueled three major plague pandemics since the first century AD, and though its deadliest years appear to be behind us, plague hasn’t disappeared. Cases still occur a few times a year in Asia, South America and the United States and more commonly in parts of Africa, according to the Cleveland Clinic, and can be treated with antibiotics.

Scientists are still searching for answers about how Y. pestis evolved and dispersed, but recent analysis of ancient and modern Y. pestis samples revealed how plague managed to persist among humans for hundreds of years after pandemic waves petered out. After an initial period of high infection rates and rapid mortality — killing infected people within three days — changes to just one gene in the bacterium produced new strains that were less deadly and more transmissible, according to research published Thursday in the journal Science.

Those weakened strains eventually went extinct; the dominant lineage of today’s Y. pestis is the deadlier variety, the study authors reported. However, these findings about historic instances of Y. pestis adaptation could provide important clues to help scientists and physicians manage modern plague outbreaks.

Trio of outbreaks

Plague’s most common form is bubonic plague, which causes painful swelling in lymph nodes and spreads among people through bites from fleas hitchhiking on infected rats. An outbreak of bubonic plague from 1347 to 1352 in Europe famously killed about 30% to 50% of the continent’s population. But the earliest known bubonic plague outbreak — the Plague of Justinian — took hold in the Mediterranean Basin and lasted from AD 541 to AD 544. Another plague outbreak emerged in China in the 1850s and sparked a major epidemic in 1894. Scientists view modern plague cases as part of this third pandemic.

For the new study, scientists collected ancient samples of Y. pestis from human remains dating back to about 100 years after the appearance of the first and second plague pandemics, sampling remains from Denmark, Europe and Russia. After reconstructing the genomes of these plague strains, they compared them with older, ancient strains that dated back to the start of plague pandemics.

The researchers also examined more than 2,700 genomes of modern plague samples from Asia, Africa, and North and South America. One of the study coauthors, Jennifer Klunk, is a product scientist at Daciel Arbor Biosciences, a biotechnology company in Michigan that provided synthetically created molecules for the experiments, but there was no financial gain associated with the research.

The researchers found that their newly reconstructed genomes from 100 years into the first two plague pandemics had fewer copies of a gene called pla, which has been recognized for decades as one of the factors that made plague so deadly, according to the study’s co-lead author Ravneet Sidhu, a doctoral student in the McMaster Ancient DNA Centre at McMaster University in Ontario, Canada.

Pla encodes an enzyme that interacts with host proteins, “and one of the functions that it carries out is in breaking down blood clots,” Sidhu told CNN. This ability helps Y. pestis spread into the host’s lymph nodes, where it replicates before attacking the rest of the body.

“Not every function of this gene is fully known,” Sidhu added. However, prior studies by other researchers linked pla to severity of illness caused by both bubonic and pneumonic plague — an airborne form of the disease that affects the lungs, she said.

While the reconstructed strains showed fewer copies of the pla gene, the scientists were still uncertain whether that would directly affect how deadly the disease could be. So they tested strains of reduced-pla bubonic plague on mice, and found that survival rates for this type of plague were 10 to 20 percent higher in those experiment subjects than in mice infected with Y. pestis that had a normal amount of the pla gene. It also took the reconstructed bubonic strain about two days longer to kill its hosts.

“The paper presents a strong argument that depletion, but not total loss, of Pla (the enzyme produced by the pla gene) is part of the evolution of the plague pathogen and may help explain the decline of plague in the second pandemic commonly known as the Black Death,” said Dr. Deborah Anderson, a professor of veterinary pathobiology at the University of Missouri’s College of Veterinary Medicine. Anderson, who was not involved in the new research, investigates the virulence of plague, and these findings could shed light on transmission patterns in modern cases, she told CNN in an email.

“Our laboratory studies the flea-rodent cycle and we have collaborators who conduct field research in areas that experience annual or occasional plague outbreaks in the wild,” Anderson said.

“There are nearly 300 rodent species that can transmit Yersinia pestis, and today, burrowing rodents such as prairie dogs or ground squirrels are considered key animal hosts that experience outbreaks of disease,” she added. “After reading this paper, we will pay closer attention to Pla in the future to see if there continues to be a role for its expression in driving the explosive outbreaks of plague in the animal populations.”

‘Epidemic burnout’

Mathematical models suggested how this might have played out in human populations centuries ago, leading to an “epidemic burnout” about 100 years after a bubonic plague outbreak.

In a pandemic’s early stages, infections were swift, and death came quickly for both rats and humans. Over time, as dense rat populations thinned out, selective pressures favored the emergence of a less deadly strain of Y. pestis, with fewer copies of the pla gene. Rat hosts infected with this new strain would have a little more time to carry the disease, potentially enabling them to infect more rats — and more people.

“They suggest a model that can be readily pursued in the laboratory that may help explain the spread of plague today in the wild,” Anderson said.

These weaker strains of the disease eventually sputtered out and went extinct. In the modern samples, the researchers found just three examples of strains with reduced pla genes, from Vietnam: one from a human subject and two from black rats (Rattus rattus).

“We’ve been able to do this really cool interdisciplinary study between the modern and ancient data and marry these things that have been happening throughout (the plague’s) long evolutionary history,” Sidhu said. “It could be interesting to see how future researchers continue to try and bridge that gap between the modern third pandemic and those first and second ancient pandemics, to see other similarities. Because there aren’t a lot of ancient pathogens that we have as much data on, as we do for Yersinia pestis.”

One of the unusual features of plague pandemics is their persistence, and understanding how Y. pestis changed its infection patterns and survived over time could shed light on the adaptive patterns of modern pandemics such as Covid-19, she added.

“Even if we aren’t experiencing it to the amount that we were in 2020 or 2021, the pathogen is in the background — still evolving and persisting.”

Mindy Weisberger is a science writer and media producer whose work has appeared in Live Science, Scientific American and How It Works magazine. She is the author of “Rise of the Zombie Bugs: The Surprising Science of Parasitic Mind Control” (Hopkins Press).

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