Genome wide association study of Escherichia coli bloodstream infection isolates identifies genetic determinants for the portal of entry but not fatal outcome

Escherichia coli is an important cause of bloodstream infections (BSI), which is of concern given its high mortality and increasing worldwide prevalence. Finding bacterial genetic variants that might contribute to patient death is of interest to better understand infection progression and implement diagnostic methods that specifically look for those factors. E. coli samples isolated from patients with BSI are an ideal dataset to systematically search for those variants, as long as the influence of host factors such as comorbidities are taken into account. Here we performed a genome-wide association study (GWAS) using data from 912 patients with E. coli BSI from hospitals in Paris, France. We looked for associations between bacterial genetic variants and three patient outcomes (death at 28 days, septic shock and admission to intensive care unit), as well as two portals of entry (urinary and digestive tract), using various clinical variables from each patient to account for host factors. We did not find any association between genetic variants and patient outcomes, potentially confirming the strong influence of host factors in influencing the course of BSI; we however found a strong association between the papGII operon and entrance of E. coli through the urinary tract, which demonstrates the power of bacterial GWAS when applied to actual clinical data. Despite the lack of associations between E. coli genetic variants and patient outcomes, we estimate that increasing the sample size by one order of magnitude could lead to the discovery of some putative causal variants. Given the wide adoption of bacterial genome sequencing of clinical isolates, such sample sizes may be soon available. Author summaryEscherichia coli is a human gut commensal but also a main opportunistic pathogen responsible for extra-intestinal infections such as bloodstream infections. These infections are particularly severe and have been increasing in frequency. Furthermore, E. coli has become more resistant to antibiotics, rendering treatment difficult. To decipher whether bacterial genetic traits are linked to infection establishment and outcomes, we carried out a genome-wide association study for a collection of almost one thousand of E. coli bloodstream infection isolates from the Paris area, France. We did not find genetic variants linked to infection severity, but we identified a gene cluster (papGII) associated with the establishment of bloodstream infection through the urinary tract. Our simulations indicate that the failure to identify variants linked to infection severity could be due to an insufficient sample size, which could be easily solved in the future as pathogen genome sequencing becomes common in clinical practice.