The bacterial genetic determinants of Escherichia coli capacity to cause bloodstream infections in humans

Escherichia coli is both a highly prevalent commensal and a major opportunistic pathogen causing bloodstream infections (BSI). A systematic analysis characterizing the genomic determinants of extra-intestinal pathogenic vs. commensal isolates in human populations, which could inform mechanisms of pathogenesis, diagnostic, prevention and treatment is still lacking. We used a collection of 912 BSI and 370 commensal E. coli isolates collected in France over a 17-year period (2000-2017). We compared their pangenomes, genetic backgrounds (phylogroups, STs, O groups), presence of virulence-associated genes (VAGs) and antimicrobial resistance genes, finding significant differences in all comparisons between commensal and BSI isolates. A machine learning linear model trained on all the genetic variants derived from the pangenome and controlling for population structure reveals similar differences in VAGs, discovers new variants associated with pathogenicity (capacity to cause BSI), and accurately classifies BSI vs. commensal strains. Pathogenicity is a highly heritable trait, with up to 69% of the variance explained by bacterial genetic variants. Lastly, complementing our commensal collection with an older collection from 1980, we predict that pathogenicity continuously increased through 1980, 2000, to 2010. Together our findings imply that E. coli exhibit substantial genetic variation contributing to the transition between commensalism and pathogenicity and that this species evolved towards higher pathogenicity. Author summaryEscherichia coli is a usually harmless bacteria typically found in the human gut. However, certain strains can cause severe bloodstream infections (BSIs) with high mortality rates, especially in older and fragile patients. To develop more effective prevention and treatment measures, understanding the genetic factors that determine a strain's capacity to cause infection is essential.In this study, we analyzed 912 BSI and 370 commensal E. coli isolates collected in France over 17 years (2000-2017). Through genetic comparison, we identified notable differences in their genetic backgrounds, as well as the presence of virulence-associated genes (VAGs) and antimicrobial resistance (AMR) genes. Using a machine learning model, we distinguished BSI from commensal strains, thereby discovering genetic factors linked to pathogenicity.Our findings indicate that E. coli exhibits significant genetic variation contributing to the switch between commensalism and pathogenesis. We also suggest that pathogenicity in France has steadily increased over time, presenting a potentially serious public health threat. Our work is an important step in guiding future research to enhance diagnostic, prevention, and treatment strategies.