# Cellular and Molecular Basis of Sex Specificity in UTI Pathogenesis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $472,516

## Abstract

PROJECT SUMMARY
In the proposed work, the Hunstad laboratory at Washington University will employ new models of urinary tract
infection (UTI) in female, androgenized female, and male mice to determine molecular mechanisms by which
host androgen exposure promotes uropathogenic Escherichia coli (UPEC) pyelonephritis as well as renal
scarring, a common sequela of upper-tract UTI. Our recent findings indicate that the influence of sex, including
androgen exposure, on these common bacterial infections is more complex than previously appreciated.
Using newly developed and optimized models of UTI in mice, we recently demonstrated that androgen
exposure is associated with increased risk for chronic cystitis and high-titer pyelonephritis, as well as formation
of renal abscesses, in both male and female hosts. 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). Moreover,
we have demonstrated a separable effect of androgens on renal fibrosis (scarring), a common complication of
pyelonephritis in children that can contribute to long-term sequelae such as hypertension and risk for chronic
kidney disease. On the basis of these findings, we hypothesize that fundamental sex differences impact the
host-pathogen interaction and cellular responses in pyelonephritis, thereby influencing pathogenicity,
resolution, and subsequent renal scarring. To interrogate this hypothesis, and building on our published work,
we will first comprehensively define host-sex-specific virulence requirements and sex influences on the host-
pathogen interaction through single-nucleus RNA-seq, hybrid capture-enhanced bacterial RNA-seq, and
insertion-site sequencing experiments on the infected kidney, in collaboration with MPI Dr. Earl and
collaborator Dr. Humphreys. Candidate sex-discrepant host pathways and bacterial virulence factors will be
confirmed and interrogated using germline and conditional knockout mice, bacterial mutants, and an array of
bacterial pathogenesis studies. We will also define the molecular pathways underlying renal fibrosis following
pyelonephritis, and how these pathways are modulated by sex and/or by androgen exposure at varying times
before, during, and after UTI. In total, the proposed work will leverage new preclinical models and an array of
conventional and cutting-edge experimental techniques. Our results will illuminate sex-specific host-pathogen
interactions in the infected kidney and identify UPEC virulence factors important in sex-dependent outcomes of
upper-tract UTI. In addition, our preclinical findings will also be translationally relevant to recurrent UTI and
renal scarring in human patient populations.

## Key facts

- **NIH application ID:** 10264141
- **Project number:** 5R01DK126697-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Ashlee Miriam Earl
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $472,516
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10264141

## Citation

> US National Institutes of Health, RePORTER application 10264141, Cellular and Molecular Basis of Sex Specificity in UTI Pathogenesis (5R01DK126697-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10264141. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*