Chelsie E. Armbruster, PhD, holds a petri dish which contains the bacterium Proteus mirabilis, one of the understudied UTI pathogens her research team is currently working on in a NIH grant-funded study.
Study Focused on Aiming to Better Understand UTI
By Dirk Hoffman
Published December 17, 2024
Urinary tract infection (UTI) is one of the most common infections worldwide and a leading cause of morbidity and health care expenditures across all ages.
A Jacobs School of Medicine and Biomedical Sciences researcher has been awarded a five-year, $3 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases to help further understanding of how the urinary tract defends against infection and how understudied pathogens bypass these defenses.
One of the body’s defenses against UTI is a protective layer on the bladder surface that is made up of long chains of sugars called glycosaminoglcyans or “GAGs,” according to Chelsie E. Armbruster, PhD, associate professor of microbiology and immunology and principal investigator on the grant.
GAG Layer Composition Has Not Been Well Studied
Armbruster says the exact composition and function of the GAG layer has not been well studied, partly because the most common bacteria that cause UTI (E. coli) don’t have any of the known enzymes required for breaking down GAGs.
“However, other UTI pathogens that become more common as we age or when we require a urinary catheter do have enzymes that might be able to break down GAGs,” she says. Our preliminary data shows that these other pathogens can in fact break down components of the GAG layer, and may therefore remove a key defense of the bladder and increase risk of developing severe disease.”
For this study, Armbruster says the researchers need to first determine exactly which GAGs are present in different compartments of the urinary tract and whether this changes in patient groups that are at higher risk for developing severe disease.
They will accomplish this by using mass spectrometry to characterize the GAG composition of the bladder, ureters, and kidneys in female and male mice for each of the three mouse strains that are most commonly used for UTI research.
“We will also look across the lifespan using mice of different ages, and whether catheterization has an impact on GAG composition,” Armbruster says. “This work needs to be conducted in an animal model in order to get paired samples from each tissue and to control for as many variables as possible.”
Seeking Targets to Reduce Severe Disease Risk
Since GAG composition can be quite different in mice than in humans, the researchers will also determine GAG composition in a 3-dimensional bladder organoid model that is derived from human bladder cells, in human urine samples, and in human bladder tissue.
The researchers will also study the GAG-degrading enzymes from two of the most common non-E. coli UTI pathogens to see which GAGs they can degrade and what role GAG degradation plays in the ability of these bacteria to cause UTI and invasive disease.
“We will study contribution to infection in 3D bladder organoids, using imaging techniques to monitor the thickness and composition of the GAG layer, disruption of bladder cell tight junctions, and bacterial invasion into deeper layers of the organoid,” Armbruster says.
“We will then use a mouse model of UTI to study contribution to bacterial colonization of the bladder, dissemination from the bladder to the kidneys, development of urosepsis, and stimulation of the innate immune response.”
And because some patient populations tend to be infected by multiple types of bacteria at the same time, the researchers will determine if GAG degradation by one type of bacteria can allow a non-degrading bacteria like E. coli to cause more invasive disease.
“Our research will determine the contribution of GAGs and microbial GAGases to infection, urosepsis, and mortality, and provide insight into a previously unexplored target for intervention in this patient population,” Armbruster says.
Co-Investigators from UB, Texas and London
The grant is titled “The Urothelial Glycosaminoglycan Layer: Composition and Contribution to Pathogen Fitness During Catheter-Associated Urinary Tract Infection.”
Teresa L. Danforth, MD, clinical associate professor of urology, is a co-investigator from the Jacobs School on the study. She will provide clinical insight and additional specimens.
Other co-investigators are:
- Saptarshi Chakraborty, PhD, assistant professor of biostatistics in UB’s School of Public Health and Health Professions, who will provide statistical modeling
- Nicole De Nisco, PhD, associate professor of biological sciences at the University of Texas at Dallas, who will conduct the mass spectrometry portion of the study
- Jennifer Rohn, PhD, professional research fellow at the University College London, who will conduct the 3D organoid work