# Exploiting microbial exposure to study the immune response to uropathogenic E. coli

> **NIH NIH R21** · UNIVERSITY OF MINNESOTA · 2022 · $193,750

## Abstract

The bladder is a frequent site of infection, as ~50% of women aged 18-50 years will have at least one urinary
tract infection (UTI) and ~40% of hospital-acquired nosocomial infections are UTIs after urinary catheter
introduction. Most UTIs are caused by uropathogeneic E. coli (UPEC), starting with bladder colonization and
then ascension to the kidneys. In severe cases of pyelonephritis, the bacteria can enter the bloodstream –
causing bacteremia, sepsis (urosepsis), and death. Importantly, the immune system is involved in the
development of these pathologies and response to treatment. The dominant in vivo mammalian model used in
biomedical research is the mouse. However, environmental microbial exposure is an important difference
between basic human and laboratory mouse biology that must be considered when using mouse models to
evaluate the fitness of the immune system. Humans are naturally exposed to commensal and pathogenic
microbes from birth, and the immune system of adult humans consequently becomes trained by each
encounter. In contrast, laboratory mice are often housed under specific pathogen-free (SPF) conditions. While
SPF housing has been key in increasing experimental reproducibility, it has simultaneously further distanced
the mouse model from humans, largely because SPF mice live their lives with limited microbial exposure.
This proposal leverages a novel mouse model that mimics a critical aspect of human biology – exposure to
multiple ongoing and resolved infections trains the immune system for robust responses to new pathogens.
Our central hypothesis holds that the matured immune system in microbially-experienced dirty mice will
respond with a more robust immune response in the bladder after local UPEC infection and accelerated UTI
clearance, but an exaggerated inflammatory response and increased mortality during systemic urosepsis.
The overall goal of this project is to study how changing the “starting point” of the immune system (i.e., naïve,
neonate-like immune system of SPF mice vs. mature, adult-like immune system in ‘dirty’ mice after
physiological microbial exposure) affects the immune response local and systemic UPEC infections. Our
rationale for the studies with ‘dirty’ mice is that we will amass a valuable new foundation of information
regarding UTI and urosepsis-induced immune responses and pathophysiology. Ultimately, the data obtained
from the proposed studies will be of great relevance to the understanding UTIs. It is important to emphasize
our ‘dirty’ mouse model is meant to be a novel complement to, rather than a replacement of, the SPF mice
typically used in research, and serve as a valuable tool to discover new efficacious therapies that may be
sensitive to unique environmental perturbations resulting from physiological microbial exposure.

## Key facts

- **NIH application ID:** 10413143
- **Project number:** 5R21AI154527-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Thomas S Griffith
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $193,750
- **Award type:** 5
- **Project period:** 2021-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10413143

## Citation

> US National Institutes of Health, RePORTER application 10413143, Exploiting microbial exposure to study the immune response to uropathogenic E. coli (5R21AI154527-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10413143. Licensed CC0.

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