[R01] The urothelial glycosaminoglycan layer: composition and contribution to pathogen fitness during catheter-associated urinary tract infection
Ente: National Institute of Diabetes and Digestive and Kidney Diseases
Scadenza: 2029-04-30
Importo max: 601.105 EUR
Paese: US
Descrizione
Project Summary/Abstract
Urinary tract infection (UTI) is one of the most common infections worldwide and a leading cause of
morbidity and healthcare expenditures across all ages. Older adults and individuals with catheters have a
particularly high risk of UTI sequelae, including kidney infection, permanent renal damage, and urosepsis.
The average mortality rate for urosepsis is 20-40%, but ranges as high as 66% for patients with catheter-
associated UTI (CAUTI). Catheterization also promotes polymicrobial colonization and infection by a wide
range of understudied microbes, including multidrug-resistant organisms that threaten the utility of last-
resort antibiotics, and there is a substantial gap in knowledge regarding the host-microbe interactions that
impact progression from initial colonization to urosepsis. The urothelium is the site of initial host-pathogen
interactions in the urinary tract, a major component of which is the glycosaminoglycan (GAG)-rich glycocalyx
that coats the apical surface of the umbrella cells. The GAG layer protects the urothelium in part by shielding
bacterial surface receptors and contributing to immune surveillance. However, our preliminary data
demonstrate that two of the most common CAUTI pathogens, Proteus mirabilis and Enterococcus faecalis,
encode six putative GAG-degrading enzymes (GAGases). Our initial study of two of these GAGases found
that they facilitate bladder colonization, kidney infection, and urosepsis during experimental infection, and
one allowed P. mirabilis to use GAGs as a carbon source. We hypothesize that the six GAGases facilitate
CAUTI and urosepsis by supporting bacterial growth, urothelial invasion, and immune modulation, and that
differences in GAG composition will influence CAUTI susceptibility and severity. In Aim 1, we will conduct a
comprehensive examination of the GAG composition throughout the urinary tract in mice, a three-
dimensional urine-tolerant human urothelial model, and urine specimens from catheterized patients to
determine the impact of age, sex, and catheterization on composition. In Aim 2, we will define the expression
profile and substrate specificity of all six GAGases, including degradation product size and
immunomodulatory capacity. In Aim 3, we will determine the contribution of GAGases to CAUTI progression
and severity, including polymicrobial infection, as well as the role of GAGs in sex- and age-based differences
in UTI susceptibility and severity. The proposed research will substantially further our understanding of how
catheterization facilitates bacteriuria and urosepsis, and provide insight into a previously unexplored target
for intervention in this patient population.
Istituzione: STATE UNIVERSITY OF NEW YORK AT BUFFALO
PI: Chelsie Elizabeth Armbruster
Progetto: 5R01DK136875-03
Settori: National Institute of Diabetes and Digestive and Kidney Diseases
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