Forced Resurgence and Targeting of Intracellular Uropathogenic Escherichia coli Reservoirs

Matthew G Blango,Peter Veranic,Andreja Erman,Elizabeth M Ott,Matthew A Mulvey,Christophe Beloin

doi:10.1371/journal.pone.0093327

Matthew G Blango, Peter Veranic + Show 4 more

Open Access

https://doi.org/10.1371/journal.pone.0093327

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Journal: PloS one	Publication Date: Mar 25, 2014
Citations: 94	License type: CC BY 4.0

Affiliation: University of Utah, University of Ljubljana

Abstract

Intracellular quiescent reservoirs of uropathogenic Escherichia coli (UPEC), which can seed the bladder mucosa during the acute phase of a urinary tract infection (UTI), are protected from antibiotic treatments and are extremely difficult to eliminate. These reservoirs are a potential source for recurrent UTIs that affect millions annually. Here, using murine infection models and the bladder cell exfoliant chitosan, we demonstrate that intracellular UPEC populations shift within the stratified layers of the urothelium during the course of a UTI. Following invasion of the terminally differentiated superficial layer of epithelial cells that line the bladder lumen, UPEC can multiply and disseminate, eventually establishing reservoirs within underlying immature host cells. If given access, UPEC can invade the superficial and immature bladder cells equally well. As infected immature host cells differentiate and migrate towards the apical surface of the bladder, UPEC can reinitiate growth and discharge into the bladder lumen. By inducing the exfoliation of the superficial layers of the urothelium, chitosan stimulates rapid regenerative processes and the reactivation and efflux of quiescent intracellular UPEC reservoirs. When combined with antibiotics, chitosan treatment significantly reduces bacterial loads within the bladder and may therefore be of therapeutic value to individuals with chronic, recurrent UTIs.

Highlights

uropathogenic Escherichia coli (UPEC) strains are the primary cause of urinary tract infection (UTI), which rank among the most common of both community-acquired and nosocomial infections [1]
Microscopic analyses indicate that UPEC can replicate to high levels within the cytosol of apical terminally differentiated superficial bladder epithelial cells (BECs), forming large inclusions known as intracellular bacterial communities (IBCs) [8,9]
In assays using the UPEC reference strain UTI89 grown shaking in modified M9 minimal medium containing 0.002, 0.0002, or 0.00002% chitosan or carrier alone, we found that logarithmic growth of the pathogen was delayed by the higher concentration of chitosan, but otherwise normal (Fig. 1A)

Summary

Introduction

UPEC strains are the primary cause of UTIs, which rank among the most common of both community-acquired and nosocomial infections [1]. We reasoned that chitosan might be a useful means to artificially stimulate turnover of the bladder urothelium in order to promote the resurgence of UPEC from intracellular reservoirs, thereby rendering the pathogens more susceptible to antibiotic treatments.

Results

Conclusion