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UropathogenicEscherichia coli(UPEC), the most frequent cause of urinary tract infection (UTI), is associated with an inflammatory response which includes the induction of cytokine/chemokine secretion by urothelial cells and neutrophil recruitment to the bladder. Recent studies indicate, however, that UPEC can evade the early activation of urothelial innate immune response in vitro. In this study, we report that infection with the prototypic UPEC strain NU14 suppresses tumor necrosis factor alpha (TNF-α)-mediated interleukin-8 (CXCL-8) and interleukin-6 (CXCL-6) secretion from urothelial cell cultures compared to infection with a type 1 piliatedE. coliK-12 strain. Furthermore, examination of a panel of clinicalE. coliisolates revealed that 15 of 17 strains also possessed the ability to suppress cytokine secretion. In a murine model of UTI, NU14 infection resulted in diminished levels of mRNAs encoding keratinocyte-derived chemokine, macrophage inflammatory peptide 2, and CXCL-6 in the bladder relative to infection with anE. coliK-12 strain. Furthermore, reduced stimulation of inflammatory chemokine production during NU14 infection correlated with decreased levels of bladder and urine myeloperoxidase and increased bacterial colonization. These data indicate that a broad phylogenetic range of clinicalE. coliisolates, including UPEC, may evade the activation of innate immune response in the urinary tract, thereby providing a pathogenic advantage.

Urinary tract infections (UTIs) are among the most common inflammatory diseases. Acute UTIs are typically caused by type 1-piliated Escherichia coli and result in urothelial apoptosis, local cytokine release, and neutrophil infiltration. To examine the urothelial apoptotic response, a human urothelial cell line was incubated with various E. coli isolates and was then characterized by flow cytometry. Uropathogenic E. coli (UPEC) induced rapid urothelial apoptosis that was strictly dependent upon interactions mediated by type 1 pili. Interestingly, nonpathogenic HB101 E. coli expressing type 1 pili induced apoptosis at approximately 50% of the level induced by UPEC, suggesting that pathogenic strains contribute to apoptosis by pilus-independent mechanisms. Consistent with this possibility, UPEC blocked activity of an NF-κB-dependent reporter in response to inflammatory stimuli, yet this effect was independent of functional type 1 pili and was not mediated by laboratory strains of E. coli . UPEC suppressed NF-κB by stabilizing IκBα, and UPEC rapidly altered cellular signaling pathways. Finally, blocking NF-κB activity increased the level of piliated HB101-induced apoptosis to the level of apoptosis induced by UPEC. These results suggest that UPEC blocks NF-κB and thereby enhances type 1 pili-induced apoptosis as a component of the uropathogenic program.

Urinary tract infections are most commonly caused by type 1-piliated Escherichia coli (UPEC) and result in urothelial apoptosis, local cytokine release and neutrophil infiltration. A human urothelial cell line was incubated with various E. coli isolates and was then characterized by flow cytometry. UPEC induced rapid urothelial apoptosis that was dependent upon interactions mediated by type 1 pili. Laboratory isolates expressing type 1 pili-induced approximately 50% less apoptosis. UPEC blocked activity of a NF-kappaB-dependent reporter in response to inflammatory stimuli by stabilizing IkappaBalpha and UPEC rapidly altered cellular signalling pathways. Finally, blocking NF-kappaB activity increased the level of the laboratory strain-induced apoptosis to the level of apoptosis induced by UPEC. These results suggest that UPEC blocks NF-kappaB and enhances type 1 pili-induced apoptosis as a component of the uropathogenic programme.

Colonization of the vaginal introitus by fecal Escherichia coli is thought to be a key initial event leading to acute urinary tract infection, yet the mannosylated receptor for type 1 pili on the squamous epithelium of vaginal mucosa is unknown. E. coli expressing type 1 pili adhered to sections of normal human vaginal epithelium in a gradient with greatest binding in upper cell layers was observed, which suggests that epithelial differentiation influences bacterial binding. Consistent with this observation, bacterial binding was enhanced in vaginal epithelial cultures that were induced to differentiate, and this enhanced bacterial binding was associated with increased K 13 expression levels and increased binding of the mannose-specific lectin Galanthus nivalis agglutinin. These results demonstrate that the binding of type 1-piliated E. coli to vaginal epithelial cells correlates with epithelial differentiation and suggest that the vaginal receptor for type 1 pili is up-regulated during differentiation.