Attenuation of virulence inacross three plague pandemics.

Abstract

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 geneoccurred in later-dated strains of the first and second pandemics, yet the biological relevance of thedeletion has been difficult to test. We identified modernstrains that independently acquired the samedepletion as ancient strains and herein show that excision offrom the multicopy pPCP1 plasmid is accompanied by the integration of a separate full pPCP1 harboringinto the single-copy pCD1 plasmid, reducingdosage. 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 thatdepletion may have been selectively advantageous in bubonic plague, owing to rodent fragmentation after pandemic-induced mortality.