# Mucosal Immune Defense Mechanisms of the Urinary Bladder

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $594,739

## Abstract

ABSTRACT: Complex mucosal networks impact the outcome of a urinary tract infection (UTI). UTIs caused
mostly by uropathogenic E. coli (UPEC) are common, highly recurrent, and a leading cause of antibiotic therapy
for otherwise healthy adult women. Thus, with dire predictions of antibiotic resistance reaching a tipping point, it
is imperative to better understand the mechanisms of recurrent UTIs (rUTIs) to avoid a future where ordinarily
treatable infections become unmanageable. 20-30% of women have a recurrence within 6 months of their initial
infection. In fact, history of UTI is an independent risk factor for subsequent UTI. Mouse models have shown that
upon UPEC infection of the bladder, a long-term remodeling of the bladder mucosa occurs, the nature of which
depends upon the inflammatory and infection history, which alters susceptibility to subsequent infection. This
remodeling, or “memory” of a prior infection, can include i) “trained immunity” of the bladder epithelium through
epigenetic reprogramming; ii) an adaptive immune response, which is sometimes protective; and iii) disruptions
of the gut microbiota due to oral antibiotic therapy leading to dysbiosis. Primary epithelial stem cells cultured
from bladders of mice with a history of infection recapitulate many of the reprogrammed morphologic and gene
expression features present in the convalescent mouse bladder. In addition, depletion of CD4+ and CD8+ T-
cells alters susceptibility to same-strain recurrence. UPEC also interact with the gastrointestinal tract (GIT)
microbiota, which is directly influenced by immune functions in the GIT, such as production of the cytokine
interleukin 22 (IL-22), which regulates mucin production and induces the expression of antimicrobial factors that
prevent invasive colonization. The GIT microbiota in turn shapes the composition of mucus. Understanding how
the GIT microbiota and mucosa work in concert to restrict UPEC colonization is therefore key to understanding
UPEC's relationship with the host. This proposal seeks to investigate how a prior infection leads to trained
immunity that alters the response and outcome of subsequent infections by: i) using robust mouse infection
models as well as cultured primary cells to probe chromatin modifications between cell lines derived from mice
with differential UTI disease histories and susceptibilities to rUTI, with particular focus on Programmed Cell
Death-associated genes, as well as tumor necrosis factor alpha and cyclooxygenase-2 (Aim 1); ii) probing how
prior infection shapes the formation of adaptive immunity at the bladder mucosa and how that modulates
susceptibility to recurrent infection (Aim 2); and iii) identifying microbial and mucosal immune mechanisms by
which the gut mucosa restricts UPEC colonization in health and dysbiosis and the roles of IL-22 and its binding
partner IL-22 binding protein in regulating the microbiota and mucus quantity and quality (Aim 3). The strength
of this proposal is that...

## Key facts

- **NIH application ID:** 10786072
- **Project number:** 5R01DK132327-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** MARCO COLONNA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $594,739
- **Award type:** 5
- **Project period:** 2023-02-15 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10786072

## Citation

> US National Institutes of Health, RePORTER application 10786072, Mucosal Immune Defense Mechanisms of the Urinary Bladder (5R01DK132327-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10786072. Licensed CC0.

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