# Novel Type 1 Pilus Receptors in Pyelonephritis and Recurrent UTI

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $393,750

## Abstract

PROJECT SUMMARY / ABSTRACT
Bacterial adhesion to the urinary tract epithelium is a critical step in establishing urinary tract infections. During
infection of the mammalian bladder (cystitis), uropathogenic Escherichia coli (UPEC) are well described to
employ type 1 pili, bearing the tip adhesin FimH, to bind oligomannose-decorated uroplakins that coat the
luminal surfaces of superficial bladder epithelial cells. However, less detail is known about host-pathogen
interactions in the kidney that enable initiation of upper-tract UTIs, including pyelonephritis and renal abscess.
We have found that type 1 pili, previously thought to be essential only in cystitis, also mediate establishment of
pyelonephritis and the initiation of renal abscesses in C3H mice. Furthermore, in an in vitro model of UPEC
binding to renal collecting duct epithelium, we identified a candidate renal epithelial receptor for FimH, namely
the mannosylated cell-junctional protein desmoglein-2 (Dsg2). This protein is expressed throughout the
nephron but most highly in collecting duct epithelium, and bears typical N-linked mannose-containing glycans
as well as cadherin family-specific O-linked mannosylation. In this project, we will test the central hypothesis
that desmoglein-2 is an epithelial receptor for FimH that mediates establishment of UPEC pyelonephritis and
can bind FimH in gut and exfoliated bladder. First, we will use multiple genetic and pharmacologic systems to
interrogate the importance of FimH binding to mannosylated Dsg2 in recently published, optimized mouse
models of UPEC pyelonephritis. Among these systems will be newly generated C3H mice carrying renal
epithelial-specific deletion of Dsg2. Next, we will quantify the binding affinity of the FimH lectin domain to the
purified extracellular domain of human DSG2 by SPR, and co-crystallize the relevant FimH and DSG2 domains
to reveal the structural basis for the DSG2-FimH interaction. Controls in these experiments will include
FimHQ133K, which carries a mutation that abrogates mannose binding; mannosides, high-affinity small-molecule
inhibitors of FimH binding; enzymatic pre-treatment of purified protein and kidney tissue sections to eliminate
N- or O-linked glycans; and monoclonal antibodies generated against the key DSG2 peptides mediating
interaction with FimH. Third, desmoglein-2 is also expressed widely on other epithelial cell types (in both
humans and mice), raising the added possibility that it binds FimH in other niches relevant to UTI
pathogenesis. These include the bladder after exfoliation (a rapid response to initial UPEC infection that
eliminates the primary FimH receptor) and the colon (which serves as a UPEC reservoir to seed recurrent
UTI). Therefore, we will use mouse and human tissue sections, an in vivo gut colonization model, and
additional new conditional Dsg2 knockout mice to investigate whether Dsg2 can serve as a FimH receptor in
these tissues. At the conclusion of these studies, we will have ...

## Key facts

- **NIH application ID:** 10828889
- **Project number:** 5R01AI158418-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** DAVID HUNSTAD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $393,750
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828889

## Citation

> US National Institutes of Health, RePORTER application 10828889, Novel Type 1 Pilus Receptors in Pyelonephritis and Recurrent UTI (5R01AI158418-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10828889. Licensed CC0.

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