P. aeruginosa Burn Infections: Pathogenesis and Treatment

Holder, Ian Alan

doi:10.1007/978-1-4615-3036-7_14

Cited by 25 publications

(26 citation statements)

References 85 publications

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“…In humans, P. aeruginosa chronically infects the lungs of most cystic fibrosis patients, causes serious infections of burn wounds and eye lesions, and causes systemic infections of immunocompromised individuals (21,29,33,39). The bacterium's pathogenic versatility is reflected in its large arsenal of secreted and surface-associated virulence factors and in the complexity of the regulatory circuitry with which it controls these factors.…”

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confidence: 99%

Pseudomonas aeruginosa PAO1 Kills Caenorhabditis elegans by Cyanide Poisoning

2001

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In this report we describe experiments to investigate a simple virulence model in which Pseudomonas aeruginosa PAO1 rapidly paralyzes and kills the nematode Caenorhabditis elegans. Our results imply that hydrogen cyanide is the sole or primary toxic factor produced by P. aeruginosa that is responsible for killing of the nematode. Four lines of evidence support this conclusion. First, a transposon insertion mutation in a gene encoding a subunit of hydrogen cyanide synthase (hcnC) eliminated nematode killing. Second, the 17 avirulent mutants examined all exhibited reduced cyanide synthesis, and the residual production levels correlated with killing efficiency. Third, exposure to exogenous cyanide alone at levels comparable to the level produced by PAO1 killed nematodes with kinetics similar to those observed with bacteria. The killing was not enhanced if hcnC mutant bacteria were present during cyanide exposure. And fourth, a nematode mutant (egl-9) resistant to P. aeruginosa was also resistant to killing by exogenous cyanide in the absence of bacteria. A model for nematode killing based on inhibition of mitochondrial cytochrome oxidase is presented. The action of cyanide helps account for the unusually broad host range of virulence of P. aeruginosa and may contribute to the pathogenesis in opportunistic human infections due to the bacterium.Pseudomonas aeruginosa is a ubiquitous gram-negative bacterium that is virulent towards a wide range of organisms, including bacteria, plants, nematodes, insects, and mammals (5,9,17,19,35,36,41,48,49,62). In humans, P. aeruginosa chronically infects the lungs of most cystic fibrosis patients, causes serious infections of burn wounds and eye lesions, and causes systemic infections of immunocompromised individuals (21,29,33,39). The bacterium's pathogenic versatility is reflected in its large arsenal of secreted and surface-associated virulence factors and in the complexity of the regulatory circuitry with which it controls these factors. Among the specific virulence factors that it produces are adhesins, such as pili and filamentous hemagglutinin (14, 39); protein toxins, such as phospholipase, proteases, and ADP-ribosylating enzymes (39, 64); and small-molecule poisons, such as phenazines, rhamnolipid biosurfactant, and cyanide (4,8,44). Additionally, the genome of P. aeruginosa boasts the highest proportion of predicted regulatory genes of any of the bacterial genomes sequenced to date (61), which is indicative of the bacterium's remarkable ability to adapt and thrive in numerous pathogenic and nonpathogenic environments.Several model systems for Pseudomonas pathogenesis have been developed recently, and numerous genes required for virulence towards model hosts are also required for virulence towards mammals. For example, mutants of P. aeruginosa PA-14 exhibiting reduced virulence towards Arabidopsis or Caenorhabditis elegans also exhibit reduced virulence in a burned-mouse infection model (49,50,62). In addition, a putative Pseudomonas signal transduction gene cluster requi...

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Pseudomonas aeruginosa PAO1 Kills Caenorhabditis elegans by Cyanide Poisoning

2001

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“…Pseudomonas aeruginosa is a gram-negative bacterium that can cause serious infections in patients suffering from cystic fibrosis, cancer, infection with human immunodeficiency virus, or severe burn wounds (16,29). The pathogenesis of P. aeruginosa infections is due to the production of both cell-associated and extracellular virulence factors.…”

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Transcriptional Control of the Hydrogen Cyanide Biosynthetic Genes hcnABC by the Anaerobic Regulator ANR and the Quorum-Sensing Regulators LasR and RhlR in Pseudomonas aeruginosa

2000

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Virulence factors of Pseudomonas aeruginosa include hydrogen cyanide (HCN). This secondary metabolite is maximally produced at low oxygen tension and high cell densities during the transition from exponential to stationary growth phase. The hcnABC genes encoding HCN synthase were identified on a genomic fragment complementing an HCN-deficient mutant of P. aeruginosa PAO1. The hcnA promoter was found to be controlled by the FNR-like anaerobic regulator ANR and by the quorum-sensing regulators LasR and RhlR. Primer extension analysis revealed two transcription starts, T1 and T2, separated by 29 bp. Their function was confirmed by transcriptional lacZ fusions. The promoter sequence displayed an FNR/ANR box at ؊42.5 bp upstream of T2 and a lux box centered around ؊42.5 bp upstream of T1. Expression of the hcn genes was completely abolished when this lux box was deleted or inactivated by two point mutations in conserved nucleotides. The lux box was recognized by both LasR [activated by N-(oxododecanoyl)-homoserine lactone] and RhlR (activated by N-butanoyl-homoserine lactone), as shown by expression experiments performed in quorum-sensing-defective P. aeruginosa mutants and in the N-acyl-homoserine lactone-negative heterologous host P. fluorescens CHA0. A second, less conserved lux box lying 160 bp upstream of T1 seems to account for enhanced quorum-sensing-dependent expression. Without LasR and RhlR, ANR could not activate the hcn promoter. Together, these data indicate that expression of the hcn promoter from T1 can occur under quorum-sensing control alone. Enhanced expression from T2 appears to rely on a synergistic action between LasR, RhlR, and ANR.

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“…The phenomenon manifests itself in the apparent change of the behaviour (phenotype) of an entire population when the bacterial density has reached a threshold level. Such density dependent behavioural changes include the "switching on" of bioluminescence of Vibrio fischeri (a species that resides in certain deep sea squid, [11]), conjugal transfer in Agrobacterium tumefaciens (a form of sexual reproduction, [22]), swarming behaviour in Serratia liquefacians (presumably as a means of population expansion) and production of virulence factors in Burkholderia cepacia and Pseudomonas aeruginosa (both with significant medical implications for sufferers of cystic fibrosis [10] and, in the latter case, for patients with severe open wounds or burn injuries [14]). In some cases, rather than QS "switching on" a given phenotype, it may instead function by de-repressing a phenotype which is actively repressed at low densities [2,17].…”

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Cell-signalling repression in bacterial quorum sensing

Ward

King²,

Koerber³

et al. 2004

Mathematical Medicine and Biology

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In this paper we expand on two mathematical models for investigating the role of three distinct repression mechanisms within the so called quorum sensing (QS) cell-signalling process of bacterial colonies growing (1) in liquid cultures and (2) in biofilms. The repression mechanisms studied are (i) reduction of cell signalling molecule (QSM) production by a constitutively produced agent degrading the messenger RNA of a crucial enzyme (QSE), (ii) lower QSM production rate due to a negative feedback process and (iii) loss of QSMs by binding directly to a constitutively produced agent; the first two mechanisms are known to be employed by the pathogenic bacterium Pseudomonas aeruginosa and the last is relevant to the plant pathogen Agrobacterium tumefaciens. The modelling approach assumes that the bacterial colony consists of two sub-populations, namely down-and up-regulated cells, that differ in the rates at which they produce QSMs, while QSM concentration governs the switching between sub-populations. Parameter estimates are obtained by curve-fitting experimental data (involving P. aeruginosa growth in liquid culture, obtained as part of this study) to solutions of model (1). Asymptotic analysis of the model (1) shows that mechanism (i) is necessary, but not sufficient, to predict the observed saturation of QSM levels in an exponentially growing colony; either mechanism (ii) or (iii) also needs to be incorporated to obtain saturation. Consequently, only a fraction of the population will become up-regulated. Furthermore, only mechanisms (i) and (iii) effect the main timescales for up regulation. Repression was found to play less significant role in a biofilms, but mechanisms (i)-(iii) were nevertheless found to reduce the ulitimate up-regulated cell fraction and mechanisms (i) and (iii) increase the timescale for substantial up regulation and decrease the wave speed of an expanding front of QS activity.

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P. aeruginosa Burn Infections: Pathogenesis and Treatment

Cited by 25 publications

References 85 publications

Pseudomonas aeruginosa PAO1 Kills Caenorhabditis elegans by Cyanide Poisoning

Pseudomonas aeruginosa PAO1 Kills Caenorhabditis elegans by Cyanide Poisoning

Transcriptional Control of the Hydrogen Cyanide Biosynthetic Genes hcnABC by the Anaerobic Regulator ANR and the Quorum-Sensing Regulators LasR and RhlR in Pseudomonas aeruginosa

Cell-signalling repression in bacterial quorum sensing

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