Attenuation of virulence in Yersinia pestis across three plague pandemics

Yersinia pestis has spilled over from rodent reservoirs to humans causing three historically recorded pandemics. Depletion in the copy number of the plasmid encoded virulence gene pla occur in later dated strains of the first and second pandemics, and has been suggested to attenuate virulence and lead to localized bacterial extinction. However, the evolutionary processes associated with pla depletion, as well as its effects on mortality and time to death in the bubonic and pneumonic forms of the disease, have been difficult to test. We curated genomic data from ancient and modern Y. pestis samples for pla depletion, from which we identified modern strains that independently acquired the same depletion as ancient strains. In vitro and in vivo experimentation using these strains revealed that pla depletions had marked effects on virulence and time to death. Notably, the pla depletion decreased the mortality rate in murine models of the bubonic forms of disease, but had no impact on the progression of the pneumonic and septicaemic forms. These findings suggest that the pla depletion was selectively advantageous in bubonic plague, particularly following high mortality outbreaks and sparse host metapopulation structures associated with the first and second pandemics.