Phenotypic and genotypic charaterzation of UPEC E.coli. Iron regulates contrasting toxicity of uropathogenic Eschericia coli in macrophages and epithelial cells

By far most urinary tract infections are caused by genetically diverse uropathogenic Escherichia coli(UPEC). Knowledge of the virulence mechanisms of UPEC is critical for drug development, but most studies focus on only a single strain of UPEC. In this study, we compared the virulence mechanisms of four antibiotic-resistant and highly pathogenic UPEC isolates in human blood monocyte-derived macrophages and a bladder epithelial cell (BEC) line: ST999, ST131, ST1981 and ST95. We found that while non-pathogenic E. colistrains are efficiently killed by macrophages in bactericidal single membrane vacuoles, the UPEC strains survive within double-membrane vacuoles. On side-by-side comparison, we found that whereas ST999 only carries Fe3+importers, ST95 carries both Fe2+and Fe3+importers and the toxins haemolysin and colibactin. Moreover, we found that ST999 grows in the Fe3+rich vacuolesof BECs and macrophageswith concomitant increasedexpression of haem receptor chuAandthehydrogen peroxide sensoroxyR. In contrast, ST95 produces toxins iniron-depletedconditions similar to that of the urinary tract. WhereasST95 also persist in the iron rich vacuoles of BECs, it produces colibactinin response to lowFe3+contributing to macrophage death. Thus, iron regulates the contrasting toxicitiesof UPEC strains in macrophages and bladder epithelial cellsdue to low and high labile iron concentrations, respectively.