Exploring the Evolutionary History of Yersinia pestis: A Persistent Pandemic Pathogen

Abstract

Yersinia pestis, the causative agent of the Black Death (1346-1353), has caused three historical and ongoing pandemics. The first Plague pandemic (541-740 CE), for which the Plague of Justinian was its herald (541-549 CE), the second Plague pandemic (1346-1840 CE), beginning with the Black Death (1346-1353 CE), and the third Plague pandemic (1850 CE-present), which resulted in the dissemination of global reservoirs, and continues to cause outbreaks today. Within the past fifteen years, hundreds of ancient genomes have been sequenced from historical and pre-historical outbreaks of the disease to address questions related to the bacterium’s virulence, global spread, and long-term, persistent outbreaks. In this dissertation, I present 15 new ancient Y. pestis genomes from Denmark (n = 13) and Turkey (n = 2), dated to the second Plague pandemic. Using these ancient samples and several modern isolates from collections at the Institut Pasteur, I perform phylogenetic, genomic, and functional analyses to study the persistence of the bacterium during the second Plague pandemic with respect to its spread and virulence. Specifically, I describe recurrent epidemic waves of the Plague throughout Denmark over a three-hundred-year period and assess the relationship between ancient strains from Denmark and other European countries. I de novo assemble the PCP1 plasmids in ancient and modern strains, revealing for the first time the sequence of the PCP1∆pla plasmid, and hypothesize the genomic and molecular characteristics of pla-reduced Y. pestis strains. Using modern pla-reduced isolates from Vietnam, I show the decreased virulence and increased time-to-death in these later-dated, pla-reduced strains, found in varying extents in all three pandemics. Furthermore, I predict that pla-reduced strains arise following rounds of high-mortality outbreaks of Plague, as a way for the bacterium to persist in its scarcely populated rodent hosts. Finally, I turn my attention towards modern-day Turkey, situated near the Caucasus Mountains, a region long hypothesized to host Plague reservoirs which caused the re-emergent epidemic waves of the second Plague pandemic. Here, I show the first genomic evidence of Plague in the Ottoman Empire, provide an updated second pandemic phylogeny, and I discuss current limitations in synthesizing genomic and historical data.