Reply to Kaye and Sobel

Abstract

To the Editor—In their letter [1], Kaye and Sobel express concern regarding the model described in our recent review [2] in which we suggest that recurrent urinary tract infections (UTIs) may in part be attributable to the ability of uropathogenic Escherichia coli (UPEC) to invade and persist within the bladder epithelium. This idea is based on results from numerous studies dating back to 1998 that used bladder cell cultures and mouse models of UTI [3]. In mice, persistent bacterial populations within the bladder are often intracellular, as assessed by gentamicin protection assays and microscopy, and unfazed by antibiotic treatments that effectively sterilize the urine. Ongoing studies in our lab and published work using mice indicate that these intracellular bacteria can reemerge sporadically and grow to high titers within the bladder lumen days to weeks after the cessation of antibiotic treatments (eg, [4–6]). The statement in our review that UPEC can persist intracellularly within the bladders of mice “without any overt clinical symptoms” was not the best choice of words and was perhaps too anthropomorphic [2]. We simply meant that mice could harbor intracellular UPEC reservoirs without displaying any obvious signs of inflammation and in the absence of any detectable bacteria within the urine. Epidemiological studies support the possibility that intracellular bacterial reservoirs within the urinary tract are responsible for many recurrent UTIs in women, but these data may also be explained by the persistence of UPEC reservoirs within local environments outside of the urinary tract (discussed in [7]). Ex vivo assays show that UPEC can invade human urothelial cells in tissue explants from volunteers, and the analysis of shed human urothelial cells collected from the urine of women with UTI symptoms indicates the presence of intracellular E. coli [8, 9]. Together, these sorts of observations suggest that intracellular UPEC reservoirs are likely more than a mouse-specific laboratory phenomenon. However, Kaye and Sobel are correct in noting that the ability of UPEC to persist long-term intracellularly within the human urinary tract has not been established. Determining if intracellular UPEC reservoirs contribute to recurrent UTIs within the human population is a daunting task, plagued by issues of tissue procurement and contamination, possible reinoculation of the bladder by UPEC from niches outside of the urinary tract, and limited means to accurately detect small numbers of bacteria within a relatively enormous tissue. Ultimately, defining the relevance of intracellular UPEC reservoirs to the etiology of recurrent UTIs may only come to light with the development of approaches that can eradicate the reservoirs. We of course agree with Kaye and Sobel that it is premature to alter treatment protocols for recurrent or chronic UTIs outside of controlled clinical investigations based solely on results from mice, but we also feel that it is important to consider alternate rational explanations for recalcitrant UTIs, whether or not they gibe with the traditional view that UPEC act as strictly extracellular pathogens.