Link to Pubmed [PMID] – 40440389
Link to HAL – pasteur-05095696
Link to DOI – 10.1126/science.adt3880
Science, 2025, 388 (6750), pp.eadt3880. ⟨10.1126/science.adt3880⟩
INTRODUCTION The Plague of Justinian and the Black Death represent two of the greatest mortality events in recorded human history and are herald waves of the first and second plague pandemics. Genomes of the plague bacterium Yersinia pestis, reconstructed from ancient human remains from about a century into each pandemic, show evidence of a depletion in the copy number of the virulence gene pla, which resides on the high-copy number plasmid (pPCP1) and encodes a plasminogen activator (Pla) protease that is responsible for virulence and pathogenicity in bubonic and pneumonic models of plague. RATIONALE: To determine the effects of the pla depletion on virulence in mice, we tested modern (third pandemic) strains of Y. pestis from Vietnam that contain the same depletion as ancient strains using models of bubonic, pneumonic, and septicemic plague. We also investigated the genomes of the ancient and modern Y. pestis strains to characterize the molecular basis of the pla depletion. RESULTS: De novo reconstruction of the ancient and modern strains of Y. pestis that contain lower-copy number pla show transfer from the high-copy number plasmid (pPCP1) to single-copy genomic features in the modern (pCD1) and ancient (chromosome) strains. A common pla deletion mechanism is likely mediated by xrs sites present in pPCP1. Depletion in pla copy number led to an attenuation of virulence in bubonic models of plague (but not pneumonic or septicemic models), with lowered overall mortality (100 to 85%) and a longer time to death (by ~2 days). CONCLUSION: We hypothesize that natural selection for pla-reduced strains reflects the metapopulation structure of rat populations, supporting epidemiological models in which pathogen attenuation enables disease persistence in small and fragmented populations through frequent, reinitiated epidemics after population recovery. The massive rat mortality that presumably occurred during the first and second pandemics likely led to suppressed rodent densities. By increasing population fragmentation, this created an environment that favored pla-reduced, attenuated strains of Y. pestis over their more virulent wild-type pla relatives. Specifically, a decreased mortality rate and longer time to host death would allow for the continued movement of rodents between existing populations, now more distantly spaced than early in the pandemic, allowing for the continued persistence, and hence increased transmission, of Y. pestis and the slow continual burn of the epidemic.