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Publication

Characterization of invasive versus non-invasive uropathogenic **Escherichia coli** through comparative and population genomics

Book - Dissertation

Escherichia coli is a usually innocuous member of the human intestinal microbiota but can cause infections when reaching other body sites. In the urinary tract E. coli is the dominant pathogen and can cause various syndromes ranging from asymptomatic bacteriuria to life-threatening urosepsis. Underlying pathogenesis mechanisms of uropathogenic E. coli (UPEC) are however incompletely understood. In this thesis, we aimed to explore the virulence determinants, population structure, and evolution of UPEC using phylogenomic approaches. We analyzed 907 whole genome sequences of E. coli isolates associated with invasive urinary tract infections (pyelonephritis, urinary-source bacteremia), non-invasive urinary tract colonization (asymptomatic bacteriuria, cystitis), or isolates from fecal samples. Invasive and non-invasive UPEC isolates were observed to have segregated phylogenetically into distinct lineages, suggesting distinct genetically determined pathogenesis mechanisms. Genome-wide association studies identified the P fimbrial adhesin PapGII as a key virulence determinant of invasive UPEC lineages and the siderophore aerobactin as an important virulence-enhancing determinant. Long-read sequencing in combination with phylogenetic analyses revealed long-term and globally distributed invasive UPEC lineages which emerged after horizontal acquisition of diverse papGIIĀ­-containing pathogenicity islands (papGII+ PAIs). Comparative analyses of these papGII+ PAIs identified six major families, which differed in their gene content and preferential chromosomal integration site. Analyses of isolates belonging to the pandemic lineage ST131 revealed recent horizontal transfer events of papGII+ PAIs in the E. coli population resulting in the formation of additional invasive UPEC lineages. Moreover, papGII+ ST131 isolates harbored a significantly higher AMR-conferring gene content than ST131 isolates lacking papGII. This finding suggests a joint evolution of virulence and AMR phenotypes. Genotype-to-phenotype predictions suggest that the papGII+ ST131 lineages are both highly urovirulent and resistant to commonly used antibiotics, including fluoroquinolones and 3rd-generation cephalosporines. In summary, the work offers novel insights into the evolution and key virulence determinants of invasive UPEC and provides a framework that contributes to the surveillance of invasive UPEC isolates.
Number of pages: 154
Publication year:2020
Keywords:Doctoral thesis
Accessibility:Open