Mechanisms of uropathogenic Escherichia coli persistence and eradication from the urinary tract.
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.
Mysorekar
Indira U
IU
Department of Molecular Microbiology, Washington University School of Medicine, Box 8230, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Hultgren
Scott J
SJ
D000818:Animals; D000892:Anti-Infective Agents, Urinary / Q000627:therapeutic use*; D011992:Endosomes / Q000382:microbiology; D004926:Escherichia coli / Q000166:cytology / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000378:metabolism*; D005260:Female; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D014551:Urinary Tract / Q000166:cytology / Q000378:metabolism / Q000382:microbiology; D014552:Urinary Tract Infections / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D052118:Lysosomal-Associated Membrane Protein 1
D000892:Anti-Infective Agents, Urinary; D051907:Lysosomal Membrane Proteins; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1