# Molecular Determinants of Gastrointestinal Colonization and Persistence in Uropathogenic E. coli

> **NIH NIH F32** · WASHINGTON UNIVERSITY · 2021 · $48,600

## Abstract

PROJECT SUMMARY/ABSTRACT
Uropathogenic Escherichia coli (UPEC) is the main etiological agent of urinary tract infections (UTI) and primarily
affects otherwise healthy women. A third of women diagnosed with a UTI will experience a recurrent UTI (rUTI)
in the following months, with some women suffering as many as six or more rUTIs per year. Further, more than
60% of rUTIs are caused by the same strain of E. coli that caused the initial infection, arguing that host-
associated UPEC reservoirs are recalcitrant to antibiotic treatment and can seed rUTIs. One major reservoir for
E. coli is the gastrointestinal tract (GIT). At the time of a UTI, the causal E. coli strain is most often the
predominant E. coli strain in the GIT, and the same strain can persist within the GIT even after antibiotic therapy.
A healthy GIT microbiota maintains homeostasis with the host immune system and prevents colonization by
bacterial pathogens. Ironically, antibiotic treatments meant to clear the UTI can also disrupt the microbiota and
expose individuals to an increased risk of colonization by bacterial pathogens in the GIT. Previous studies
performed with Salmonella enterica serovar Typhimurium have demonstrated that the type VI secretion system
(T6SS) is critical for colonization and infection within the mouse gut. Interestingly, UPEC cystitis isolate, UTI89,
possesses two T6SS; and my data reveals that deletion of either T6SS cluster decreases the relative GIT fitness
of UTI89 in our streptomycin (STM) mouse model. Moreover, comparative genomics data analyses of diverse
E. coli strains reveal that a specific subtype of T6SS is enriched in clade B2 E. coli (the predominant clade
causing UTIs in the western hemisphere), suggesting that B2 E. coli may share functions and gene content that
promote GIT colonization. Despite numerous studies demonstrating the GIT to be an important reservoir for
UPEC in humans, UPEC determinants critical for productive GIT colonization have yet to be fully investigated. I
hypothesize that UPEC possess an arsenal of fitness factors and gene regulatory programs that enhance GIT
colonization and persistence increasing UTI susceptibility and rUTIs. To test this, I will use: i) the established
prototypical human cystitis isolate, UTI89, and clinically relevant UPEC and E. coli isolates; ii) complementary in
vivo and in vitro experimentation; and iii) robust computational and bioinformatic analyses. Aim 1 will assess the
relative fitness of T6SS mutants in our STM model, compare GIT microbiota profiles and inflammatory
responses, and determine the cellular targets of the T6SS. Aim 2 will assess the relative fitness of 30 diverse E.
coli clinical isolates from healthy and rUTI patients in our STM model, compare their transcriptional profiles and
genetic content using newly developed multi-omic analyses, and perform targeted deletions to confirm
phenotypes in our STM model. This two-pronged research strategy provides both a targeted (Aim 1) and
unbi...

## Key facts

- **NIH application ID:** 10141524
- **Project number:** 1F32AI157152-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Vanessa Munoz
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $48,600
- **Award type:** 1
- **Project period:** 2021-06-01 → 2022-01-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10141524

## Citation

> US National Institutes of Health, RePORTER application 10141524, Molecular Determinants of Gastrointestinal Colonization and Persistence in Uropathogenic E. coli (1F32AI157152-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10141524. Licensed CC0.

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