TY - JOUR

T1 - Pseudomonas aeruginosa tolerance to tobramycin, hydrogen peroxide and polymorphonuclear leukocytes is quorum-sensing dependent

AU - Bjarnsholt, Thomas

AU - Jensen, Peter Østrup

AU - Burmølle, Mette

AU - Hentzer, Morten

AU - Haagensen, Janus A J

AU - Hougen, Hans Petter

AU - Calum, Henrik

AU - Madsen, Kit G

AU - Moser, Claus

AU - Molin, Søren

AU - Høiby, Niels

AU - Givskov, Michael

PY - 2005/2

Y1 - 2005/2

N2 - The opportunistic human pathogen Pseudomonas aeruginosa is the predominant micro-organism of chronic lung infections in cystic fibrosis (CF) patients. P. aeruginosa colonizes the CF lungs by forming biofilm structures in the alveoli. In the biofilm mode of growth the bacteria are highly tolerant to otherwise lethal doses of antibiotics and are protected from bactericidal activity of polymorphonuclear leukocytes (PMNs). P. aeruginosa controls the expression of many of its virulence factors by means of a cell-cell communication system termed quorum sensing (QS). In the present report it is demonstrated that biofilm bacteria in which QS is blocked either by mutation or by administration of QS inhibitory drugs are sensitive to treatment with tobramycin and H2O2, and are readily phagocytosed by PMNs, in contrast to bacteria with functional QS systems. In contrast to the wild-type, QS-deficient biofilms led to an immediate respiratory-burst activation of the PMNs in vitro. In vivo QS-deficient mutants provoked a higher degree of inflammation. It is suggested that quorum signals and QS-inhibitory drugs play direct and opposite roles in this process. Consequently, the faster and highly efficient clearance of QS-deficient bacteria in vivo is probably a two-sided phenomenon: down regulation of virulence and activation of the innate immune system. These data also suggest that a combination of the action of PMNs and QS inhibitors along with conventional antibiotics would eliminate the biofilm-forming bacteria before a chronic infection is established.

AB - The opportunistic human pathogen Pseudomonas aeruginosa is the predominant micro-organism of chronic lung infections in cystic fibrosis (CF) patients. P. aeruginosa colonizes the CF lungs by forming biofilm structures in the alveoli. In the biofilm mode of growth the bacteria are highly tolerant to otherwise lethal doses of antibiotics and are protected from bactericidal activity of polymorphonuclear leukocytes (PMNs). P. aeruginosa controls the expression of many of its virulence factors by means of a cell-cell communication system termed quorum sensing (QS). In the present report it is demonstrated that biofilm bacteria in which QS is blocked either by mutation or by administration of QS inhibitory drugs are sensitive to treatment with tobramycin and H2O2, and are readily phagocytosed by PMNs, in contrast to bacteria with functional QS systems. In contrast to the wild-type, QS-deficient biofilms led to an immediate respiratory-burst activation of the PMNs in vitro. In vivo QS-deficient mutants provoked a higher degree of inflammation. It is suggested that quorum signals and QS-inhibitory drugs play direct and opposite roles in this process. Consequently, the faster and highly efficient clearance of QS-deficient bacteria in vivo is probably a two-sided phenomenon: down regulation of virulence and activation of the innate immune system. These data also suggest that a combination of the action of PMNs and QS inhibitors along with conventional antibiotics would eliminate the biofilm-forming bacteria before a chronic infection is established.

KW - Animals

KW - Anti-Bacterial Agents

KW - Bacterial Proteins

KW - Biofilms

KW - Cystic Fibrosis

KW - DNA-Binding Proteins

KW - Female

KW - Gene Expression Regulation, Bacterial

KW - Humans

KW - Hydrogen Peroxide

KW - Mice

KW - Mice, Inbred BALB C

KW - Neutrophils

KW - Pseudomonas Infections

KW - Pseudomonas aeruginosa

KW - Signal Transduction

KW - Tobramycin

KW - Trans-Activators

KW - Virulence

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1099/mic.0.27463-0

DO - 10.1099/mic.0.27463-0

M3 - Journal article

C2 - 15699188

VL - 151

SP - 373

EP - 383

JO - Microbiology

JF - Microbiology

SN - 1350-0872

IS - Pt 2

ER -