Abstract
Recurrent urinary tract infections (UTIs) caused by uropathogenic E. coli (UPEC) are common and morbid infections with limited therapeutic options. Previous studies have demonstrated that persistent intracellular infection of bladder epithelial cells (BEC) by UPEC contributes to recurrent UTI in mouse models of infection. However, the mechanisms employed by UPEC to survive within BEC are incompletely understood. In this study we aimed to understand the role of host vesicular trafficking proteins in the intracellular survival of UPEC. Using a cell culture model of intracellular UPEC infection, we found that the small GTPase Rab35 facilitates UPEC survival in UPEC-containing vacuoles (UCV) within BEC. Rab35 plays a role in endosomal recycling of transferrin receptor (TfR), the key protein responsible for transferrin–mediated cellular iron uptake. UPEC enhance the expression of both Rab35 and TfR and recruit these proteins to the UCV, thereby supplying UPEC with the essential nutrient iron. Accordingly, Rab35 or TfR depleted cells showed significantly lower intracellular iron levels and reduced ability to support UPEC survival. In the absence of Rab35, UPEC are preferentially trafficked to degradative lysosomes and killed. Furthermore, in an in vivo murine model of persistent intracellular infection, Rab35 also colocalizes with intracellular UPEC. We propose a model in which UPEC subverts two different vesicular trafficking pathways (endosomal recycling and degradative lysosomal fusion) by modulating Rab35, thereby simultaneously enhancing iron acquisition and avoiding lysosomal degradation of the UCV within bladder epithelial cells. Our findings reveal a novel survival mechanism of intracellular UPEC and suggest a potential avenue for therapeutic intervention against recurrent UTI.
Highlights
Urinary tract infections (UTIs) are one of the most common bacterial infections in humans, affecting at least 50% of women at some point in their lifetime
Our study demonstrates a novel mechanism by which uropathogenic E. coli (UPEC) exploit a host endocytic recycling pathway protein (Rab35) to acquire the critical nutrient iron and to prevent lysosomal degradation, thereby promoting intracellular survival within bladder epithelial cells (BEC)
To identify host cell molecules and pathways utilized by UPEC for intracellular survival within BEC, we first focused on membrane trafficking pathway proteins
Summary
Urinary tract infections (UTIs) are one of the most common bacterial infections in humans, affecting at least 50% of women at some point in their lifetime. 25% of patients suffer a recurrence within 6 months, with 68% of these UTIs apparently caused by the original strain, despite appropriate antibiotic therapy [4,5]. Infected mice suffer episodes of recurrent UTI subsequent to clearance of bacteriuria following antibiotic therapy [9]. These recurrent infections are due to UPEC that persist within urinary bladder epithelial cells. QIRs, in particular, cause persistent infections lasting for months in mice [11], while IBCs and other intracellular bacteria have been detected in the urine of both adult and pediatric human UTI patients [12,13,14,15].
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