Single gene may help explain the plague's persistence throughout human history

Scientists have discovered how adaptations in a single gene helped the plague survive for hundreds of years.

Responsible for the deadliest pandemic in history, the bacterium that causes the plague, Yersinia pestis, has existed in varying strains from ancient times until today.

Now, scientists have unearthed a genetic clue as to how the infamous disease has persisted for millennia, with devastating outbreaks smoldering across centuries. They published their findings Thursday (May 29) in the journal Science.

"This is one of the first research studies to directly examine changes in an ancient pathogen, one we still see today, in an attempt to understand what drives the virulence [disease severity], persistence and/or eventual extinction of pandemics," study co-senior author Hendrik Poinar, director of the Ancient DNA Centre at McMaster University in Ontario, Canada, said in a statement.

Y. pestis has been infecting humans since before recorded history began. The most common form of the disease is known as "bubonic" and most often enters the body through bites from infected fleas, although people can less commonly catch it directly from infected animals, including rats and cats. Once inside the body, the bacterium travels to the lymph nodes and replicates. As it multiplies, it triggers the formation of painful, pus-filled "buboes," for which the bubonic plague is named.

The plague bacterium can also cause a blood infection, called septicemic plague, and lung infection called pneumonic plague.

Related: Oregon's 1st bubonic plague case in 8 years tied to patient's pet cat

The three major plague pandemics are among the deadliest outbreaks in human history. The first pandemic, the Justinian Plague (which occurred roughly between A.D. 542 and 750), slashed the population in parts of the Mediterranean to by an estimated 40% by the end of the sixth century.

The second, and most infamous, outbreak of the disease was the 14th-century Black Death that ravaged Europe and the Middle East. The single deadliest pandemic in recorded history, the Black Death killed approximately 25 million people in Europe alone — between 33% and 50% of its population.

A third, lesser-known global plague pandemic began in 1855 in China's Yunnan province and killed more than 12 million people in India and China alone. This pandemic was considered active until 1960, after which plague deaths dropped to lower levels. Plague epidemics continue to this day, with the Democratic Republic of the Congo, Madagascar and Peru being the most endemic countries, according to the World Health Organization.

Besides the staggering death counts associated with the pathogen, what's perhaps most remarkable about Y. pestis is the longevity of its strains. Strains of the Justinian Plague bacterium took 300 years to go extinct after outbreaks were first recorded, and one of the two lineages from the Black Death re-emerged in waves for 500 years before its disappearance, while the other became the ancestor of all present-day strains.

To investigate the genetic toolkit Y. pestis uses to persist for so long, researchers conducted an analysis of a plague gene known as pla across hundreds of samples collected from ancient and modern victims of the disease.

The pla gene codes for an enzyme that helps Y. pestis move through the body undetected by the host's immune system. Previous studies have suggested that pla is a key factor that modulates both the lethality of a given plague strain and its ability to spark outbreaks in humans. However, one plague strain can carry a different number of pla genes than the next, and it wasn't clear how this copy number might impact their biology, the researchers noted.

To investigate, they collected multiple modern strains of Y. pestis from Vietnam that had varying numbers of copies of pla inside their genomes; carrying more copies of the gene means that the bacteria can crank out more copies of the enzyme. After injecting these different plague strains into mice, they found that the strains with fewer copies of pla led to longer infections but reduced the disease's mortality rate by up to 20%.

Across the ancient plague genomes they analyzed — 20 of which dated to the first plague pandemic and 94 of which were from the second — the researchers noted a pattern where the plague strains lost copies of pla over time, namely in later stages of each pandemic. Among the modern genomes, they found three strains that hint that the same pattern is unfolding today.

They theorized this adaptation likely made infections less virulent, or harmful to the host's body, over time. This suggests that the evolutionary change helped the disease to keep its hosts — be they rat or human — alive for longer, thereby enabling it to spread more widely. This adaptation may have been especially necessary after populations of the plague's primary hosts, rats, were killed off en masse during outbreaks.

"The reduction of pla may reflect the changing size and density of rodent and human populations," Poinar said. "It's important to remember that plague was an epidemic of [flea-ridden] rats, which were the drivers of epidemics and pandemics. Humans were accidental victims."

The scientists say that further research into both ancient and contemporary plague strains could reveal more pla depletions and help them to better understand how such changes to the germ's genome have shaped its virulence through history.

Nowadays, Y. pestis infections can be cured with antibiotics, though some strains have shown troubling signs of antibiotic resistance. To head off the threat of a superbug plague outbreak, scientists in the U.K. have already started developing a bubonic plague vaccine to add to stockpiles.