Mechanisms of Uropathogenic Escherichia coli Persistence and Eradication from the Urinary Tract

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 38; pp. 14170 - 14175
• Main Authors: Mysorekar, Indira U., Hultgren, Scott J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19.09.2006; National Acad Sciences
• Subjects: Animals; Anti-Infective Agents, Urinary - therapeutic use; Bacteria; Biological Sciences; Cell growth; Cell nucleus; Cells; Cellular differentiation; E coli; Endosomes - microbiology; Epithelial cells; Epithelium; Escherichia coli; Escherichia coli - cytology; Escherichia coli - genetics; Escherichia coli - metabolism; Escherichia coli - pathogenicity; Escherichia coli Infections - metabolism; Exfoliation; Female; Humans; Infections; Lysosomal Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Pathology; Urinary bladder; Urinary Tract - cytology; Urinary Tract - metabolism; Urinary Tract - microbiology; Urinary tract diseases; Urinary tract infections; Urinary Tract Infections - drug therapy; Urinary Tract Infections - metabolism; Urinary Tract Infections - microbiology; Women
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0602136103

Recurrent urinary tract infections (rUTIs) are a source of considerable morbidity in women. The infecting bacteria in both rUTIs and a de novo acute infection have been thought to originate from an extraurinary location. Here, we show in a murine model of UTI that uropathogenic Escherichia coli (UPEC) established quiescent intracellular reservoirs (QIRs) in Lamp1⁺ endosomes within the urinary bladder epithelium. Depending on the integrity of the urothelial barriers at the time of initial infection, these QIRs were established within terminally differentiated superficial facet cells and/or underlying transitional epithelial cells. Treatment of infected bladders harboring exclusively superficial facet cell QIRs with the cationic protein, protamine sulfate, led to epithelial exfoliation and eradication of bacteria in 100% of treated animals. However, when the bacterial QIRs were harbored in underlying transitional cells, stimulation of epithelial turnover triggered reemergence of viable organisms and recurrence of infection. Thus, our results suggest (i) that bacterial QIRs within the bladder may be a previously unappreciated source of recurrent UTIs and (ii) that inducing epithelial exfoliation may be a therapeutic avenue for treating this heretofore recalcitrant disease.