PR000831 (Project)

Description:Urinary tract infections (UTIs) represent a major burden across the population, although key facets of their pathogenesis challenge physicians and investigators alike. Escherichia coli epitomizes these obstacles: this Gram-negative bacterial species is the most prevalent agent of UTIs worldwide and can also colonize the urogenital tract in a phenomenon known as asymptomatic bacteriuria (ASB). Unfortunately, at the level of the organism, the relationship between symptomatic UTI and ASB is poorly defined, confounding our understanding of microbial pathogenesis and strategies for clinical management. Unlike diarrheagenic pathotypes of E. coli, the definition of uropathogenic E. coli (UPEC) remains phenomenologic, without conserved phenotypes and (known) genetic determinants that rigorously distinguish UTI- and ASB-associated strains. This manuscript provides a cross-disciplinary review of the current issues – from interrelated mechanistic and diagnostic perspectives – and describes new opportunities by which clinical resources can be leveraged to overcome molecular challenges. Specifically, we present our work harnessing a large collection of patient-derived isolates to identify features that do (and do not) distinguish UTI- from ASB-associated E. coli strains. Analyses of biofilm formation, previously reported to be higher in ASB strains, revealed extensive phenotypic heterogeneity that did not correlate with symptomatology. However, metabolomic experiments revealed distinct signatures between ASB and cystitis isolates, including species in the purine pathway (previously shown to be critical for intracellular survival during acute infection). Together, these studies demonstrate how large-scale, wild-type approaches can help dissect the physiology of colonization-versus-infection, suggesting that the molecular definition of UPEC may rest at the level of global bacterial metabolism.