How the plague evolved to persist

Scientists from the Institut Pasteur and McMaster University have discovered that the evolution of a gene in the bacterium responsible for bubonic plague, Yersinia pestis, may have prolonged the duration of the two major pandemics.

They highlight that adjusting the number of copies of a specific virulence gene increases the duration of infection in affected individuals. This genetic evolution would extend the contagious period in less densely populated environments where transmission between individuals necessarily takes longer. This genetic variation is observed independently in each of the two major plague pandemics, hundreds of years before they died out.


The study was published on May 29, 2025, in the journal Science.

Human history has been marked by three major plague pandemics. The first pandemic began in the Mediterranean basin in the 6th century.


The second pandemic emerged in the 14th century and resurged multiple times over more than 500 years in Europe. The first wave of this second pandemic, known as the "Black Death," remains to this day the deadliest event in human history, killing 30 to 50% of European populations between 1347 and 1352.

The third plague pandemic appeared in Asia in 1850. It spread to all continents and persists today in regions called "endemic," including countries like Uganda and the Democratic Republic of the Congo, as well as the United States and Mongolia.

The plague bacillus, Y. pestis, remains highly lethal due to the presence of various virulence factors, notably the pla factor, present in multiple copies in the bacterium's genome. This virulence factor allows the bacterium to reach the lymph nodes and proliferate before spreading to the rest of the body, causing rapid sepsis.

By studying hundreds of samples taken from ancient plague victims, researchers from McMaster University, specialists in ancient DNA, observed a decrease in the number of copies of the pla gene in the later phases of the first and second pandemics. To complement this observation, scientists from the Institut Pasteur focused on the third plague pandemic, whose samples are more recent and preserved alive.


"Our study is among the first to specifically examine the evolution of an ancient pathogen, still relevant today, to understand the factors of virulence, persistence, or extinction of pandemics," says Hendrik Poinar, co-senior author of the study, director of the McMaster Ancient DNA Centre, and holder of the Michael G. DeGroote Chair in Genetic Anthropology.


The National Reference Center for Plague and Other Yersinioses at the Institut Pasteur holds one of the richest collections of modern isolates of Y. pestis in the world. "Our international collaborators, who monitor local plague outbreaks worldwide, have provided us with unique bacterial samples for this project," explains Javier Pizarro-Cerdá, co-senior author of the study, head of the Yersinia research unit, and director of the WHO Collaborating Centre for Plague at the Institut Pasteur.

"We identified three samples of Y. pestis collected in the 1990s in Asia where the total number of pla genes had decreased," says Guillem Mas Fiol, co-first author of the study and researcher in the Yersinia unit at the Institut Pasteur.

"Thanks to these three samples, we were able to study in vitro and in vivo the biological effect of these pla gene deletions, bridging the gap with the paleogenomic observations of our Canadian colleagues," adds Javier Pizarro-Cerdá.

In murine models of bubonic plague, researchers observed that the decrease in the number of copies of the pla gene is linked to a 20% reduction in mortality and an increase in the duration of infection in affected individuals, with infected rats living longer.

The researchers suggest that rats infected with these bacteria could spread the infection further in an environment where mammal density was reduced. Indeed, the high mortality of rodents at the beginning of pandemic waves leads to a decrease in host proximity.

"The decrease in virulence would give the bacillus a selective advantage in the context of reduced population density," explains Javier Pizarro-Cerdá. The pandemics would eventually die out, likely due to the reduced virulence of these strains.

This genetic evolution appeared randomly and independently in each historical plague pandemic. "Our research sheds light on a key pattern in the evolutionary history of the plague. However, it should be noted that most strains still circulating today in Africa, America, and Asia are highly virulent strains, i.e., those once responsible for massive mortality," emphasizes Ravneet Sidhu, co-first author of the study and PhD student at the Ancient DNA Centre at McMaster University.


The lethality of infection by the plague bacillus, Y. pestis, is now better controlled thanks to antibiotics and diagnostic methods, making the evolutionary dynamics different.

"The plague remains a disease that, although rare today, is still a public health issue and serves as a model for understanding both the emergence and extinction of pandemics in the broadest sense. This example illustrates the virulence balance a pathogen can adopt to effectively transmit from one host to another," concludes Javier Pizarro-Cerdá.