Attenuation of virulence in <i>Yersinia pestis</i> across three plague pandemics.

Abstract

<i>Yersinia pestis</i> has spilled over from wild rodent reservoirs to commensal rodents and humans, causing three historically recorded pandemics. Depletion in the copy number of the plasmid-encoded virulence gene <i>pla</i> occurred in later-dated strains of the first and second pandemics, yet the biological relevance of the <i>pla</i> deletion has been difficult to test. We identified modern <i>Y. pestis</i> strains that independently acquired the same <i>pla</i> depletion as ancient strains and herein show that excision of <i>pla</i> from the multicopy pPCP1 plasmid is accompanied by the integration of a separate full pPCP1 harboring <i>pla</i> into the single-copy pCD1 plasmid, reducing <i>pla</i> dosage. Moreover, we demonstrate that this depletion decreases the mortality of mice in models of bubonic plague but not in the pneumonic and septicemic forms of the disease. We hypothesize that <i>pla</i> depletion may have been selectively advantageous in bubonic plague, owing to rodent fragmentation after pandemic-induced mortality.