Cyclic-di-GMP signaling contributes to Pseudomonas aeruginosa mediated catheter-associated urinary tract infection

Bis-(3' -5' ) cyclic dimeric guanosine monophosphate (c-di-GMP) controls the lifestyle transition between the sessile and motile state in many Gram-negative bacteria, including the opportunistic human pathogen Pseudomonas aeruginosa.

Under laboratory conditions, high concentrations of c-di-GMP decrease motility and promote biofilm formation while low concentrations of c-di-GMP promote motility and decease biofilm formation. Here we seek to determine the contribution of c-di-GMP signaling to biofilm formation during P. aeruginosa mediated catheter-associated urinary tract infection (CAUTI). Using a murine CAUTI model, a decrease in colony forming units (CFUs) was detected in the bladder and kidneys of mice infected with strains overexpressing the phosphodiesterases (PDEs) PA3947 and PA2133 compared to wild-type P. aeruginosa. Conversely, overexpression of the diguanylate cyclases (DGCs) PA3702 and PA1107 increased the number of bacteria in bladder and significantly increased dissemination of bacteria to the kidneys compared to wild type. To determine which of the DGCs and PDEs contribute to c-di-GMP signaling during infection, a panel of PA14 in-frame deletion mutants lacking DGCs and PDE-As were tested in the CAUTI model. Results from these infections revealed five mutants, three containing GGDEF domains (ΔPA14_26970, ΔPA14_72420 and ΔsiaD) and two containing dual GGDEF-EAL domains (ΔmorA and ΔPA14_07500), with decreased colonization of the bladder and dissemination to the kidneys. These results indicate that c-di-GMP signaling influences P. aeruginosa mediated biofilms during CAUTI.

Biofilm-based infections are an important cause of nosomial infections since they resist the immune response and traditional antibiotic treatment. Cyclic-di-GMP (c-di-GMP) is a second messenger that promotes biofilm formation in many Gram-negative pathogens, including Pseudomonas aeruginosa. Here we determine the contribution of c-di-GMP signaling to catheter-associated urinary tract infection (CAUTI), an animal model of biofilm-based infection. P. aeruginosa with elevated levels of c-di-GMP during the initial infection have increased bacterial burden in the bladder and kidneys. Conversely, low concentrations of c-di-GMP decreased bacterial burden in the bladder and kidneys. We screened a library of mutants in genes regulating c-di-GMP signaling and found several mutants that altered colonization of the urinary tract. This study implicates, c-di-GMP signaling during CAUTI.

Journal of bacteriology. 2015 Jul 20 [Epub ahead of print]

Stephanie J Cole, Vincent T Lee

Department of Cell Biology and Molecular Genetics, University of Maryland at College Park, College Park, Maryland, USA. , Department of Cell Biology and Molecular Genetics, University of Maryland at College Park, College Park, Maryland, USA

PubMed

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