Black Death bacterium has become less lethal after genetic tweak

Reducing the number of copies of one gene in the pathogen could also make it more transmissible

Black rats can carry fleas hosting the bacterium *Yersinia pestis*, which causes the plague.Credit: Tom McHugh/Science Photo Library

A small genetic change makes the bacterium that caused the plague less fatal but possibly more transmissible, allowing for greater disease spread in smaller populations¹, a study in Science reports.

The bacterium Yersinia pestis caused the Black Death — killing up to 50 million people in the mid-fourteenth century — as well as an earlier plague across the Mediterranean in the sixth century ad. The bacteria still circulate in low levels in parts of the United States, Africa and Asia, and are typically transmitted to humans by infected fleas carried by rats or other rodents.

Previous research found that some strains of Y. pestis had reduced amounts of pla², a gene associated with disease severity, but it was unclear why, says Ravneet Sidhu, a palaeogeneticist at McMaster University in Hamilton, Canada, and a co-author of the latest work. “Our findings in this study characterize a case in which a pandemic-causing pathogen has independently evolved to cause what we believe is a slightly weaker form of the disease,” she says.

Mice mortality

To understand the impact of the genetic change, the team infected mice with modern strains of Y. pestis that had normal levels of pla, had reduced levels of the gene or were unable to express it at all. When the bacteria were injected beneath the skin to mimic the form of plague that affects lymph nodes, mice infected with the reduced-pla strain lived for almost two days longer than did those infected with the normal strain. Mortality also decreased from 100% with the normal strain to 85% with the reduced-pla strain. However, when the team infected mice intravenously or through the nose to mimic blood- or lung-based infections, the pla-reduced strain was as fatal as the normal strain.

The team also looked at the genomes of ancient and modern strains of Y. pestis to find out how prevalent pla depletion was. Between 30% and 50% of ancient strains obtained from previously published studies showed signs of depletion, as did three modern strains, isolated from a human and two rats in 1994. Wanting to understand why pla was depleted, the researchers analysed the genetic data from these ancient and modern strains. They found that the reduction was caused by deletion of a 2,100-base-pair-long region of DNA containing the pla gene in one region of the genome, and the integration of a DNA molecule called a plasmid carrying the gene into other regions.

Sidhu says the team hypothesized that pla depletion occurred because repeated outbreaks of the plague decreased the density of rodent populations. Increasing the time for which rats were infectious would have given them more time to travel between fragmented populations, increasing the chance of them spreading the disease, she adds.