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Mechanisms of uropathogenic Escherichia coli persistence and eradication from the urinary tract.

ABSTRACT: 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.

SUBMITTER: Mysorekar IU

PROVIDER: S-EPMC1564066 | biostudies-literature | 2006 Sep

REPOSITORIES: biostudies-literature

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Mechanisms of uropathogenic Escherichia coli persistence and eradication from the urinary tract.

Mysorekar Indira U IU Hultgren Scott J SJ

Proceedings of the National Academy of Sciences of the United States of America 20060912 38

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 infecti ...[more]

PMID: 16968784

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Project description:In the present study, it is shown that although Escherichia coli CFT073, a human uropathogenic (UPEC) strain, grows in liquid glucose M9 minimal medium, it fails to grow on glucose M9 minimal medium agar plates seeded with ?10(6) CFU. The cells on glucose plates appear to be in a "quiescent" state that can be prevented by various combinations of lysine, methionine, and tyrosine. Moreover, the quiescent state is characteristic of ~80% of E. coli phylogenetic group B2 multilocus sequence type 73 strains, as well as 22.5% of randomly selected UPEC strains isolated from community-acquired urinary tract infections in Denmark. In addition, E. coli CFT073 quiescence is not limited to glucose but occurs on agar plates containing a number of other sugars and acetate as sole carbon sources. It is also shown that a number of E. coli CFT073 mini-Tn5 metabolic mutants (gnd, gdhA, pykF, sdhA, and zwf) are nonquiescent on glucose M9 minimal agar plates and that quiescence requires a complete oxidative tricarboxylic acid (TCA) cycle. In addition, evidence is presented that, although E. coli CFT073 quiescence and persistence in the presence of ampicillin are alike in that both require a complete oxidative TCA cycle and each can be prevented by amino acids, E. coli CFT073 quiescence occurs in the presence or absence of a functional rpoS gene, whereas maximal persistence requires a nonfunctional rpoS. Our results suggest that interventions targeting specific central metabolic pathways may mitigate UPEC infections by interfering with quiescence and persistence. IMPORTANCE Recurrent urinary tract infections (UTIs) affect 10 to 40% of women. In up to 77% of those cases, the recurrent infections are caused by the same uropathogenic E. coli (UPEC) strain that caused the initial infection. Upon infection of urothelial transitional cells in the bladder, UPEC appear to enter a nongrowing quiescent intracellular state that is thought to serve as a reservoir responsible for recurrent UTIs. Here, we report that many UPEC strains enter a quiescent state when ?10(6) CFU are seeded on glucose M9 minimal medium agar plates and show that mutations in several genes involved in central carbon metabolism prevent quiescence, as well as persistence, possibly identifying metabolic pathways involved in UPEC quiescence and persistence in vivo.

Dataset Information

Mechanisms of uropathogenic Escherichia coli persistence and eradication from the urinary tract.

Publications

Mechanisms of uropathogenic Escherichia coli persistence and eradication from the urinary tract.

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