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Curli of Uropathogenic Escherichia coli Enhance Urinary Tract Colonization as a Fitness Factor.

ABSTRACT: Curli, a type of fimbriae widely distributed in uropathogenic Escherichia coli (UPEC), are involved in adhesion to human bladder cell surfaces and biofilm development. The role of UPEC curli was evaluated in a murine model of urinary tract infection. The aim of this study was to establish the role of curli in C57BL/6 mice transurethrally infected with curli-producing and non-curli-producing UPEC strains. We confirmed that curli enhanced UPEC colonization in the urinary tract, resulting in damage to both the bladder and kidney. Intranasal immunization with recombinant CsgA protein protected against colonization by curli-producing UPEC in the urinary tract. Quantification of cytokines from urinary tract organs showed increases in interleukin-6 and tumor necrosis factor (TNF) release in the kidneys 48 h postinfection with curli-producing UPEC. By contrast, mice infected with non-curli-producing UPEC showed the highest release of interleukin-6, -10, and -17A and TNF. Curli may obscure other fimbriae and LPS, preventing interactions with Toll-like receptors. When intranasal immunization with recombinant FimH and PapG proteins and subsequent infection with this strain were performed, cytokine quantification showed a decrease in the stimulation and release by the uroepithelium. Thus, curli are amyloid-like fimbriae that enhances colonization in the urinary tract and a possible fitness factor.

SUBMITTER: Luna-Pineda VM

PROVIDER: S-EPMC6733918 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Urinary tract infection (UTI) is among the most common infections treated worldwide each year and is caused primarily by uropathogenic Escherichia coli (UPEC). Rising rates of antibiotic resistance among uropathogens have spurred a consideration of alternative treatment strategies, such as bacteriophage (phage) therapy; however, phage-bacterial interactions within the urinary environment are poorly defined. Here, we assess the activity of two phages, namely, HP3 and ES17, against clinical UPEC isolates using in vitro and in vivo models of UTI. In both bacteriologic medium and pooled human urine, we identified phage resistance arising within the first 6 to 8 h of coincubation. Whole-genome sequencing revealed that UPEC strains resistant to HP3 and ES17 harbored mutations in genes involved in lipopolysaccharide (LPS) biosynthesis. Phage-resistant strains displayed several in vitro phenotypes, including alterations to adherence to and invasion of human bladder epithelial HTB-9 cells and increased biofilm formation in some isolates. Interestingly, these phage-resistant UPEC isolates demonstrated reduced growth in pooled human urine, which could be partially rescued by nutrient supplementation and were more sensitive to several outer membrane-targeting antibiotics than parental strains. Additionally, phage-resistant UPEC isolates were attenuated in bladder colonization in a murine UTI model. In total, our findings suggest that while resistance to phages, such as HP3 and ES17, may arise readily in the urinary environment, phage resistance is accompanied by fitness costs which may render UPEC more susceptible to host immunity or antibiotics. IMPORTANCE UTI is one of the most common causes of outpatient antibiotic use, and rising antibiotic resistance threatens the ability to control UTI unless alternative treatments are developed. Bacteriophage (phage) therapy is gaining renewed interest; however, much like with antibiotics, bacteria can readily become resistant to phages. For successful UTI treatment, we must predict how bacteria will evade killing by phage and identify the downstream consequences of phage resistance during bacterial infection. In our current study, we found that while phage-resistant bacteria quickly emerged in vitro, these bacteria were less capable of growing in human urine and colonizing the murine bladder. These results suggest that phage therapy poses a viable UTI treatment if phage resistance confers fitness costs for the uropathogen. These results have implications for developing cocktails of phage with multiple different bacterial targets, of which each is evaded only at the cost of bacterial fitness.

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Curli of Uropathogenic Escherichia coli Enhance Urinary Tract Colonization as a Fitness Factor.

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