This interdisciplinary SCOR program seeks to understand the epidemiology, pathogenic strategies, and resultant host responses of urinary tract infections (DTI) caused by uropathogenic E. coli (UPEC), one of the most common diseases affecting women. This knowledge will be applied to critically evaluate all aspects of clinical UTI management, including diagnosis, treatment, and prevention. We have proposed an integrative and translational set of experiments that capitalizes on the complementary expertise found in each of the three projects. Basic scientists in Projects 1 and 3 have access to uropathogenic strains collected from women in Project 2 at different clinical stages of UTI. Working together, Projects 1, 2, and 3 will identify genetic and molecular markers and correlates of the different clinical UTI syndromes associated with UPEC infection. These will be pursued both in humans (Project 2) and mice (Project 1) for prognostic indicators of disease outcome: bacterial clearance, asymptomatic infection, chronic colonization, or recurrence. Genotypic and phenotypic profiles of UPEC strains from well-characterized UTI cases will be generated in Project 1 and 3 by blending a powerful genetic system with functional and comparative genomics, defined in vitro and murine models, comparative immunoproteomics, biochemistry, cell biology, laser capture microdissection, antigen discovery techniques, and high resolution electron microscopy. The host response to intracellular bacterial communities (IBCs) and quiescent intracellular reservoirs (QIRs) formed by different UPEC isolates will be examined in detail both in a mouse model (Project 1), using gene and cytokine expression profiling, and in humans (Project 2), by monitoring the adaptive immune response and metabolite profiles in human urine. In addition, exfoliated bladder epithelial cells in mouse and human urine will be screened for evidence of IBC formation, allowing parallel correlation of microscopic assays with clinical outcome in both mice and humans. These efforts promise to connect specific measurements made at the bench to clinical outcomes observed at the bedside. Project 3 will also address primary prevention of UTI by using comparative pan-genomics to study the mechanism by which UPEC emerge from the distal gastrointestinal tract and traverse the perineum to the urethra to cause infection. Completion of these interwoven projects promises to address questions in the clinical management of this ubiquitous disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Specialized Center (P50)
Project #
5P50DK064540-08
Application #
7668593
Study Section
Special Emphasis Panel (ZRG1-HOP-U (40))
Program Officer
Mullins, Christopher V
Project Start
2002-09-30
Project End
2012-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
8
Fiscal Year
2009
Total Cost
$1,177,300
Indirect Cost
Name
Washington University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Yarbrough, Melanie L; Briden, Kelleigh E; Mitsios, John V et al. (2018) Mass spectrometric measurement of urinary kynurenine-to-tryptophan ratio in children with and without urinary tract infection. Clin Biochem 56:83-88
Spaulding, Caitlin N; Schreiber 4th, Henry Louis; Zheng, Weili et al. (2018) Functional role of the type 1 pilus rod structure in mediating host-pathogen interactions. Elife 7:
Shen, Jiangchuan; Walsh, Brenna J C; Flores-Mireles, Ana Lidia et al. (2018) Hydrogen Sulfide Sensing through Reactive Sulfur Species (RSS) and Nitroxyl (HNO) in Enterococcus faecalis. ACS Chem Biol 13:1610-1620
Rosen, David A; Twentyman, Joy; Hunstad, David A (2018) High Levels of Cyclic Di-GMP in Klebsiella pneumoniae Attenuate Virulence in the Lung. Infect Immun 86:
Olson, Patrick D; McLellan, Lisa K; Hreha, Teri N et al. (2018) Androgen exposure potentiates formation of intratubular communities and renal abscesses by Escherichia coli. Kidney Int 94:502-513
Ohlemacher, Shannon I; Giblin, Daryl E; d'Avignon, D André et al. (2017) Enterobacteria secrete an inhibitor of Pseudomonas virulence during clinical bacteriuria. J Clin Invest 127:4018-4030
Schreiber 4th, Henry L; Spaulding, Caitlin N; Dodson, Karen W et al. (2017) One size doesn't fit all: unraveling the diversity of factors and interactions that driveE. coliurovirulence. Ann Transl Med 5:28
Koh, Eun-Ik; Robinson, Anne E; Bandara, Nilantha et al. (2017) Copper import in Escherichia coli by the yersiniabactin metallophore system. Nat Chem Biol 13:1016-1021
Olson, Patrick D; McLellan, Lisa K; Liu, Alice et al. (2017) Renal scar formation and kidney function following antibiotic-treated murine pyelonephritis. Dis Model Mech 10:1371-1379
Spaulding, Caitlin N; Klein, Roger D; Ruer, Ségolène et al. (2017) Selective depletion of uropathogenic E. coli from the gut by a FimH antagonist. Nature 546:528-532

Showing the most recent 10 out of 140 publications