Pseudomonas aeruginosa Exotoxin Pyocyanin Causes Cystic Fibrosis Airway Pathogenesis

Caldwell, Charles C.; Chen, Yi; Goetzmann, H.; Hao, Yonghua; Borchers, Michael T.; Hassett, Daniel J.; Young, Lisa R.; Mavrodi, Dmitri V.; Thomashow, Linda S.; Lau, Gee W.

doi:10.2353/ajpath.2009.090166

Cited by 147 publications

(186 citation statements)

References 71 publications

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“…radicis lycopersici (Chin-A- Woeng et al, 1998). The phenazine pyocyanin produced by Pseudomonas aeruginosa is suggested to be involved in lung infection of cystic fibrosis patients (Caldwell et al, 2009). However, recent evidence indicates that pyocyanin also acts as a signal molecule in P. aeruginosa (Dietrich et al, 2006) and may probably even interfere with central metabolism (Dietrich et al, 2008;Price-Whelan et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Role of the phenazine-inducing protein Pip in stress resistance of Pseudomonas chlororaphis

Girard

Rigali

2011

Microbiology

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The triggering of antibiotic production by various environmental stress molecules can be interpreted as bacteria's response to obtain increased fitness to putative danger, whereas the opposite situation – inhibition of antibiotic production – is more complicated to understand. Phenazines enable Pseudomonas species to eliminate competitors for rhizosphere colonization and are typical virulence factors used for model studies. In the present work, we have investigated the negative effect of subinhibitory concentrations of NaCl, fusaric acid and two antibiotics on quorum-sensing-controlled phenazine production by Pseudomonas chlororaphis. The selected stress factors inhibit phenazine synthesis despite sufficient cell density. Subsequently, we have identified connections between known genes of the phenazine-inducing cascade, including PsrA (Pseudomonas sigma regulator), RpoS (alternative sigma factor), Pip (phenazine inducing protein) and PhzI/PhzR (quorum-sensing system). Under all tested conditions, overexpression of Pip or PhzR restored phenazine production while overexpression of PsrA or RpoS did not. This forced restoration of phenazine production in strains overexpressing regulatory genes pip and phzR significantly impairs growth and stress resistance; this is particularly severe with pip overexpression. We suggest a novel physiological explanation for the inhibition of phenazine virulence factors in pseudomonas species responding to toxic compounds. We propose that switching off phenazine-1-carboxamide (PCN) synthesis by attenuating pip expression would favour processes required for survival. In our model, this ‘decision’ point for promoting PCN production or stress resistance is located downstream of rpoS and just above pip. However, a test with the stress factor rifampicin shows no significant inhibition of Pip production, suggesting that stress factors may also target other and so far unknown protagonists of the PCN signalling cascade.

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Section: Introductionmentioning

confidence: 99%

Role of the phenazine-inducing protein Pip in stress resistance of Pseudomonas chlororaphis

Girard

Rigali

2011

Microbiology

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“…Very little is known about the phenotypic variant subpopulation of persister cells in A. baumannii. In view of coinfection by A. baumannii and P. aeruginosa in respiratory tract infections, especially in cystic fibrosis patients, where pyocyanin has been detected in the sputum and pulmonary secretions (16), it is pertinent to study the mechanism(s) by which A. baumannii survives oxidative stress caused by pyocyanin exposure and also its effect with regard to persistence. This work reports that A. baumannii and P. aeruginosa can coexist in mixedspecies biofilms, as the oxidative stress caused by P. aeruginosa pyocyanin induced protective antioxidative enzymes in A. baumannii and enhanced its tolerance to antibiotics.…”

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confidence: 99%

Pyocyanin Stimulates Quorum Sensing-Mediated Tolerance to Oxidative Stress and Increases Persister Cell Populations in Acinetobacter baumannii

2014

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Acinetobacter baumannii and Pseudomonas aeruginosa are nosocomial pathogens with overlapping sites of infection. This work reports that the two can coexist stably in mixed-culture biofilms. In a study intended to improve our understanding of the mechanism of their coexistence, it was found that pyocyanin, produced by P. aeruginosa that generally eliminates competition from other pathogens, led to the generation of reactive oxygen species (ROS) in A. baumannii cells, which in response showed a significant (P < 0.05) increase in production of enzymes, specifically, catalase and superoxide dismutase (SOD). This work shows for the first time that the expression of catalase and SOD is under the control of a quorum-sensing system in A. baumannii. In support of this observation, a quorum-sensing mutant of A. baumannii (abaI::Km) was found to be sensitive to pyocyanin compared to its wild type and showed significantly (P < 0.001) lower levels of the antioxidant enzymes, which increased on addition of 5 M N-(3-hydroxydodecanoyl)-L-homoserine lactone. Likewise, in wild-type A. baumannii, there was a significant (P < 0.01) decrease in the level of anti-oxidant enzymes in the presence of salicylic acid, a known quencher of quorum sensing. In the presence of amikacin and carbenicillin, A. baumannii formed 0.07 and 0.02% persister cells, which increased 4-and 3-fold, respectively, in the presence of pyocyanin. These findings show that pyocyanin induces a protective mechanism in A. baumannii against oxidative stress and also increases its persistence against antibiotics which could be of clinical significance in the case of coinfections with A. baumannii and P. aeruginosa.

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“…Its pathogenicity, to a large extent, is attributable to its ability to secrete a broad arsenal of virulence determinants, including effector proteins secreted through a type III secretion system (T3SS) (3,8,59). P. aeruginosa is also well known to possess high intrinsic antibiotic resistance and is capable of developing multidrug resistance, posing serious therapeutic problems (21).…”

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MexT Regulates the Type III Secretion System through MexS and PtrC in Pseudomonas aeruginosa

et al. 2011

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The type III secretion system (T3SS) is the most important virulence factor in Pseudomonas aeruginosa, and its expression level varies in different isolates. We studied the molecular basis for such differences in two laboratory strains, PAK and PAO1. A chromosomal clone library from the high-T3SS-producer strain PAK was introduced into the low-producer strain PAO1, and we found that a mexS gene from PAK confers high T3SS expression in the PAO1 background. Further tests demonstrated that both mexS and its neighboring mexT gene are required for the repression of the T3SS in PAO1, while the PAK genome encodes a defective MexS, accounting for the derepression of the T3SS in PAK and the dominant negative effect when it is introduced into PAO1. MexS is a probable oxidoreductase whose expression is dependent on MexT, a LysR-type transcriptional regulator. Various genetic data support the idea that MexS modulates the transcriptional regulator function of MexT. In searching for the MexT-dependent repressor of the T3SS, a small gene product of PA2486 (ptrC) was found effective in suppressing the T3SS upon overexpression. However, deletion of ptrC in the PAO1 background did not result in derepression of the T3SS, indicating the presence of another repressor for the T3SS. Interestingly, overexpression of functional mexS alone was sufficient to repress T3SS even in the absence of MexT, suggesting that MexS is another mediator of MexT-dependent T3SS repression. Overexpression of mexS alone had no effect on the well-known MexT-dependent genes, including those encoding MexEF efflux pump, elastase, and pyocyanin, indicating alternative regulatory mechanisms. A model has been proposed for the MexS/MexT-mediated regulation of the T3SS, the MexEF efflux pump, and the production of elastase and pyocyanin.

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Pseudomonas aeruginosa Exotoxin Pyocyanin Causes Cystic Fibrosis Airway Pathogenesis

Cited by 147 publications

References 71 publications

Role of the phenazine-inducing protein Pip in stress resistance of Pseudomonas chlororaphis

Role of the phenazine-inducing protein Pip in stress resistance of Pseudomonas chlororaphis

Pyocyanin Stimulates Quorum Sensing-Mediated Tolerance to Oxidative Stress and Increases Persister Cell Populations in Acinetobacter baumannii

MexT Regulates the Type III Secretion System through MexS and PtrC in Pseudomonas aeruginosa

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