# ANDROGEN INFLUENCE ON UTI SUSCEPTIBILITY AND SEVERITY

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $354,375

## Abstract

PROJECT SUMMARY
In this project, we will employ a new model of urinary tract infection (UTI) in female and male mice to illuminate
the influence exerted by androgens on susceptibility to, and severity of, these infections. Prior studies of the
influence of sex hormones on UTI have been limited to estrogen exposure only. However, our recent findings
indicate that the influence of sex, particularly androgen exposure, on these common bacterial infections is
more complex than previously appreciated. Until now, sex differences in UTI pathogenesis and host response
have not been examined in preclinical models, largely because technical (anatomic) considerations preclude
routine catheterization of the male mouse bladder. Thus, preclinical modeling of bladder infection (cystitis) and
kidney infection (pyelonephritis) has previously been performed almost exclusively in female mice. In
response to this deficit, we recently developed, optimized, and published a novel, innovative, minimally
invasive surgical bladder inoculation technique that allows first-ever studies of sex differences in UTI
pathogenesis and host response. Our method of direct bladder inoculation with uropathogenic Escherichia coli
(UPEC), which bypasses traditional anatomic differences between sexes, has already revealed strikingly
higher susceptibility of male and androgenized female mice to chronic cystitis, severe pyelonephritis,
ascending renal abscess formation, and tubulointerstitial fibrosis. These findings correlate with epidemiologic
data revealing higher morbidity and mortality in men who do suffer complicated UTI (compared with women),
and higher incidence of UTI in women with a common hyperandrogenic condition (polycystic ovary syndrome).
On the basis of these findings, we hypothesize that androgens enhance epithelial receptivity to uropathogenic
bacteria and/or influence the host immune response to bacterial infection of the urinary tract in both female and
male hosts. To interrogate this hypothesis, we propose to first prove that the observed phenotypes arise from
signaling through the androgen receptor; this will involve female mice androgenized with DHT (a specific AR
agonist) as well as pharmacologic AR inhibitors. Next, we will define and interrogate androgen effects on both
the soluble and cellular components of host immune responses to bladder and kidney infection, using a variety
of techniques and newly generated C3H/HeN conditional AR knockout mice. Finally, we will take multiple in
vitro and in vivo approaches to defining androgen effects on uroepithelial biology and interactions with
uropathogenic bacteria. Our results will illuminate the influence exerted by androgens, in both female and
male hosts, on pathogenesis and host response in both lower and upper-tract UTI. In addition, our preclinical
findings will also be translationally relevant to UTI risk in multiple human patient populations, including
otherwise healthy women.

## Key facts

- **NIH application ID:** 10137082
- **Project number:** 5R01DK111541-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** DAVID HUNSTAD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $354,375
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137082

## Citation

> US National Institutes of Health, RePORTER application 10137082, ANDROGEN INFLUENCE ON UTI SUSCEPTIBILITY AND SEVERITY (5R01DK111541-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10137082. Licensed CC0.

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