Catheter-associated urinary tract infection (CAUTI) is one of the leading causes of nosocomial infections and the outcomes range from patient discomfort, pyelonephritis, morbidity and, in rare cases, death. Numerous pathogens cause CAUTI by forming biofilms on inserted catheters including Gram-negative bacteria, such as Escherichia coli and Pseudomonas aeruginosa, Gram-positive cocci, and fungi. The rise of P. aeruginosa induced CAUTI is of particularly concern because P. aeruginosa biofilms are highly refractory to oral antibiotic therapy. The molecular mechanisms that allow bacteria to form biofilms on the catheter during CAUTI are not well understood. To uncover those molecular events, we have utilized P. aeruginosa as a model pathogen in which in vitro biofilm formation is well characterized. We have recently developed a murine model of CAUTI. Using this murine CAUTI model, we have published results showing that isogenic polysaccharide-deficient mutants colonized catheters as efficiently as parental PA14 and PA01 strains. These surprising results indicate that P. aeruginosa formed during CAUTI is fundamentally different from biofilms characterized in laboratory conditions. Our recent RNA-seq data reveal that urine induces the down-regulation of the quorum signaling (QS) pathway and the up-regulation of the Entner- Doudoroff metabolic pathway. These results led us to hypothesize that changes to P. aeruginosa gene expression in response to host urine contributes to CAUTI. We will address our hypothesis by completing the following aims: 1) Identify the mechanism and requirement of urine suppression of QS during CAUTI, 2) Determine the requirement for Entner-Doudoroff pathway during CAUTI, and 3) Determine the selective pressure of chronic CAUTI on P. aeruginosa. Results from our proposed studies will characterize the molecular mechanism of QS repression by urine and determine the contribution of differentially regulated genes to CAUTI. Together, findings from these experiments will advance our understanding of chronic, biofilm-based infections by bacterial pathogens.

Public Health Relevance

Catheter associated urinary tract infections are a major cause of nosocomial infections by pathogens that form biofilms on the catheter surface. This proposal seeks to identify the requirement of altered bacterial response to the host to mediate biofilm formation on catheters. Results from these studies will yield insight into the molecular mechanisms leading to catheter associated urinary tract infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Ernst, Nancy Lewis
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Maryland College Park
Anatomy/Cell Biology
Earth Sciences/Resources
College Park
United States
Zip Code
Cole, Stephanie J; Hall, Cherisse L; Schniederberend, Maren et al. (2018) Host suppression of quorum sensing during catheter-associated urinary tract infections. Nat Commun 9:4436
Orr, Mona W; Weiss, Cordelia A; Severin, Geoffrey B et al. (2018) A subset of exoribonucleases serve as degradative enzymes for pGpG in c-di-GMP signaling. J Bacteriol :
Hall, Cherisse L; Lee, Vincent T (2018) Cyclic-di-GMP regulation of virulence in bacterial pathogens. Wiley Interdiscip Rev RNA 9:
Zhou, Eric; Seminara, Anna B; Kim, Soo-Kyoung et al. (2017) Thiol-benzo-triazolo-quinazolinone Inhibits Alg44 Binding to c-di-GMP and Reduces Alginate Production by Pseudomonas aeruginosa. ACS Chem Biol 12:3076-3085
Hendrick, William A; Orr, Mona W; Murray, Samantha R et al. (2017) Cyclic Di-GMP Binding by an Assembly ATPase (PilB2) and Control of Type IV Pilin Polymerization in the Gram-Positive Pathogen Clostridium perfringens. J Bacteriol 199:
Okegbe, Chinweike; Fields, Blanche L; Cole, Stephanie J et al. (2017) Electron-shuttling antibiotics structure bacterial communities by modulating cellular levels of c-di-GMP. Proc Natl Acad Sci U S A 114:E5236-E5245
Gr√ľndling, Angelika; Lee, Vincent T (2016) Old concepts, new molecules and current approaches applied to the bacterial nucleotide signalling field. Philos Trans R Soc Lond B Biol Sci 371:
Orr, Mona W; Galperin, Michael Y; Lee, Vincent T (2016) Sustained sensing as an emerging principle in second messenger signaling systems. Curr Opin Microbiol 34:119-126