Impact of Pseudomonas aeruginosa quorum sensing on biofilm persistence in an in vivo intraperitoneal foreign-body infection model

Abstract

Pseudomonas aeruginosa is an opportunistic human pathogen that causes chronic biofilm-based infections in host organisms. P. aeruginosa employs quorum sensing (QS) to control expression of its virulence, and to establish and maintain chronic infections. Under such conditions, the biofilm mode of growth contributes significantly to P. aeruginosa tolerance to the action of the innate and adaptive defence system and numerous antibiotics. In the present study, an in vivo foreign-body infection model was established in the peritoneal cavity of mice. Experimental data showed that QS-deficient P. aeruginosa are cleared more rapidly from silicone implants as compared to their wild-type counterparts. Concurrently, treatment with the QS inhibitor furanone C-30 of mice harbouring implants colonized with the wild-type P. aeruginosa resulted in a significantly faster clearing of the implants as compared to the placebo-treated group. These results were obtained with both an inbred (BALB/c) and an outbred (NMRI) mouse strain. The present results support a model by which functional QS systems play a pivotal role in the ability of bacteria to resist clearing by the innate immune system and strongly suggest that the efficiency of the mouse innate defence against biofilm-forming P. aeruginosa is improved when the bacteria are treated with QS drugs that induce QS deficiency. INTRODUCTIONIn the USA, microbial infections on medical implants occur in more than 2 million surgical cases each year and infection is the main cause of biomedical implant failure (Emerson & Camesano, 2004;Gristina, 1987;Verkerke et al., 1997). One explanation gaining momentum is that the biofilm mode of growth protects the colonizing bacteria and enables them to withstand host immune responses and exhibit high tolerance to treatment with the highest deliverable doses of antibiotics Costerton et al., 1999;Hentzer et al., 2003; Høiby et al., 2001; Middleton et al., 2002;Singh et al., 2002). In general, infections on foreign bodies will not be cleared until the implants have been removed from the body (Neut et al., 2005), and unfortunately reimplantation has a high failure rate and is prone to recolonization by similar problem-causing bacteria (Cherney & Amstutz, 1983).One particularly notorious biofilm former that is known to cause infections on medically implanted foreign bodies is Pseudomonas aeruginosa (Braxton et al., 2005; Neut et al., 2005). P. aeruginosa uses cell-to-cell communication or quorum sensing (QS) to control the production and secretion of virulence factors, which, deployed at the right time and place, enables evasion of the host defences (Fuqua et al., 1994). By producing and receiving small diffusible Nacyl-L-homoserine lactone (AHL) signal molecules, the bacteria are able to monitor their own population size and Abbreviations: AHL, N-acyl-L-homoserine lactone; BAL, bronchoalveolar lavage; C4-HSL, N-butanoyl-L-homoserine lactone; CLSM, confocal laser scanning microscopy; GFP, green fluorescent protein; 3-oxo-C12-HSL, N-(3-oxododecanoyl)-L...

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

“…Diverse sets of furanone compounds have been generated by chemical synthesis (237,238), yielding inhibitors tested most frequently and rigorously on P. aeruginosa quorum sensing and on the V. fischeri LuxR protein heterologously expressed in E. coli, where compounds C-30 and C-56 (Table 3) were the most effective inhibitors (134,237,(239)(240)(241)(242)(243). More recently, additional synthetic schemes have led to new varieties of furanones, but their inhibitory properties remain relatively untested (244,245).…”

The quorum quenching antibody RS2-1G9 protects macrophages from the cytotoxic effects of the Pseudomonas aeruginosa quorum sensing signalling molecule N-3-oxo-dodecanoyl-homoserine lactone

“…QS-deficient P. aeruginosa strains show a clear reduction in overall pathogenicity (Christensen et al, 2007;Mittal et al, 2006). It has also been shown that in clinical P. aeruginosa isolates various components of the QS circuit have been lost due to mutations.…”

Role of quorum sensing by Pseudomonas aeruginosa in microbial keratitis and cystic fibrosis

“…based on the implantation of silicone chips pre-colonized with P. aeruginosa into lungs of mice has also demonstrated that a functional QS system is critical for the establishment of infection (Christensen et al, 2007). However, a number of studies have demonstrated that QS mutants can be isolated from CF samples.…”