In-host evolution of Yersinia enterocolitica during a chronic human infection

Following a pacemaker implantation, a 75-years-old patient suffered from five successive bacteremia episodes between in 1999 and 2013, during which five bacterial strains were isolated. Phenotypic and whole-genome sequencing analysis of four isolates identified the strains as Yersinia enterocolitica bioserotype 4/O:3. Phylogenetic reconstruction showed that the patient was chronically infected by the same strain, which evolved within the host during 14 years. Single-nucleotide polymorphhism (SNP) analysis indicates that the last two isolates which displayed severe growth defects in vitro and acquired resistance to quinolones, evolved in parallel and formed two independent lineages within the host. Pan-genome analysis and genome comparison showed that their common evolution was characterized by 41 small insertion/deletion events and loss of three large DNA fragments. These mutations, which may account for the observed growth defect and also for the appearance of vegetations on the pacemaker, support antibiotics tolerance. Quinolone resistance was acquired through a so far undescribed deletion in the gyrA gene. 140 genes containing mutations vertically acquired from a common ancestor were also identified in the two lineages. A phylogenetic analysis by maximum likelihood identified two genes presenting a positive selection signal, suggesting that these mutations provided a survival advantage to bacteria during chronic infection. This is the first report allowing identification of genetic changes associated to within-host adaptation of a pathogenic Yersinia species.