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urothelial cells can exfoliate in response to infection. Recent observations, however, suggest that UPEC is able to flux into and out of bladder epithelial cells (M.A.M., J.D.S., and S.J.H., unpublished data). This may allow invading uropathogens to multiply and subsequently escape from their host bladder cells before the host cells can complete the exfoliation process. This could also facilitate the dissemination of UPEC within the urinary tract and help bacteria evade both innate and adaptive host defenses. Furthermore, exfoliation of bladder epithelial cells could leave lower layers of the urothelium more susceptible to infection. It is in the underlying epithelial layers that UPEC may be able to persist for long intervals, sequestered within host bladder epithelial cells, possibly in a quiescent state and undetectable within the urine. These bacteria could potentially serve as a source for recurrent infections, one of the more vexing problems associated with UTIs. A model depicting some of the key factors and events that appear to contribute to the pathogenesis of bladder infections is shown in Fig. 8. Future research is aimed at identifying bacterial and host factors that can exacerbate or attenuate the severity of UTIs. It is hoped that such studies will eventually lead to more efficacious antibacterial therapeutics.

We thank R. Roth and J. Heuser for their help with the high-resolution EM; M. Veith for assistance with scanning EM; and L. LaRose and M. Levy for help with transmission EM. This work was supported by National Institutes of Health Grants RO1AI29549 and RO1DK51406. M.A.M. was supported by National Institutes of Health Fellowship AI09787.

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