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Abstract: SA-PO607

Fundamental Role for the Urothelial Plaque in Gram-Negative Urinary Tract Infections

Session Information

  • Pediatric Nephrology - II
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pediatric Nephrology

  • 1800 Pediatric Nephrology

Authors

  • Li, Birong, Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Cortado, Hanna H., Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Gupta, Sudipti, Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Ching, Christina B., Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Jackson, Ashley R., Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Becknell, Brian, Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Group or Team Name

  • Kidney and Urinary Tract Center
Background

Over 90% of human urinary tract infections (UTI) are caused by Gram-negative bacteria, most commonly, uropathogenic Escherichia coli (UPEC). Superficial cells in the bladder produce Uroplakin (Upk) containing urothelial plaques that bind to type I fimbriae of UPEC in a mannose-dependent manner. The role of the urothelial plaque in bladder epithelial cell invasion and triggering the host inflammatory response remains unclear. We hypothesized that a functional urothelial plaque is absolutely required for Gram-negative cystitis to occur.

Methods

We established acute cystitis in urothelial plaque-deficient female Upk1b-/- and wild-type (Upk1b+/+) mice by transurethral inoculation of UPEC strain UTI89 or Enterococcus faecalis strain 0852. Bacterial burden was measured by plating tissue homogenates and enumeration of bacterial CFU. Intracellular bacterial communities were detected on the basis of b-galactosidase activity and immunofluorescence microscopy. Upk protein expression was localized by immunofluorescence microscopy, and plaque ultrastructure was visualized by electron microscopy. UPEC elicitation of cytokines and chemokines was measured by QPCR.

Results

Upk1b deletion results in failure of superficial bladder epithelial cells to assemble a functional urothelial plaque, as evinced by absence of plaque ultrastructure and increased permeabilization of FITC-Dextran. In response to UPEC inoculation, Upk1b-/- mice exhibited reduced bacterial burden throughout the urinary tract, absence of intracellular bacterial communities, less cytokine and chemokine mRNA production induction, and decreased neutrophil infiltration, when compared to Upk1b+/+ mice. Conversely, Upk1b-/- and Upk1b+/+ mice displayed equal susceptibility to infection with E. faecalis.

Conclusion

The urothelial plaque is essential to facilitate UPEC invasion of the bladder mucosa and establishment of cystitis, but this structure is dispensable for Enterococcus infection. This study demonstrates the primacy of the plaque for Gram-negative UTI and further strengthens the rationale for targeted therapies such as mannosides to disrupt UPEC-plaque interaction and serve as anti-infective agents.

Funding

  • NIDDK Support