Oxygen levels rapidly modulate <i>Pseudomonas aeruginosa</i> social behaviours via substrate limitation of PqsH

Schertzer, Jeffrey W.; Brown, Stacie A.; Whiteley, Marvin

doi:10.1111/j.1365-2958.2010.07303.x

Cited by 145 publications

(165 citation statements)

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“…In contrast, our data suggested that PAO1 produced significantly suppressed levels of PAI-1 and nondetectable PAI-2 during anaerobic growth, respectively. Together with previous reports revealing that the production of PQS is also highly inhibited during anaerobic growth (43,51), these findings suggest that (i) the three major autoinducers mediating P. aeruginosa QS are either not produced or produced at significantly lower levels during anaerobic growth and (ii) QS may therefore not be functional in PAO1 growing under anaerobic conditions. It is of particular interest that the levels of PAI-1 and PAI-2 detected in sputum samples isolated from CF patients colonized with up to 10 8 CFU/ml of P. aeruginosa were significantly lower than those produced in laboratory aerobic cultures (46).…”

Section: Discussionsupporting

confidence: 78%

“…Schertzer and colleagues recently elucidated the molecular basis behind the abrogated synthesis of PQS during growth without oxygen (43). Because oxygen and NADH are required as cofactors for the enzymatic synthesis of PQS from its precursor, 2-heptyl-4-quinolone (HHQ), a lack of oxygen prevents the enzymatic conversion of HHQ to PQS from taking place.…”

Section: Discussionmentioning

confidence: 99%

“…Although the LasI/R QS system plays a dominant role in the complex QS hierarchy in P. aeruginosa (34), three QS systems, namely, LasI/R, RhlI/R, and PQS, all participate in a complex signaling network to regulate lasB gene expression (29). Recently, it was reported that production of PQS is completely abrogated during anaerobic growth of P. aeruginosa (43,51). Given the fact that synthesis of the PQS signal molecule is coordinately regulated by the LasI/R and RhlI/R components of the QS system (28), this finding suggests that these two QS systems might also be differentially modulated during anaerobic and aerobic growth.…”

Section: Cellmentioning

confidence: 99%

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Anaerobiosis-Induced Loss of Cytotoxicity Is Due to Inactivation of Quorum Sensing in Pseudomonas aeruginosa

et al. 2011

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Pseudomonas aeruginosa, an opportunistic pathogen of clinical importance, causes chronic airway infections in patients with cystic fibrosis (CF). Current literature suggests that pockets with reduced oxygen tension exist in the CF airway mucus. However, virulence features of this opportunistic pathogen under such conditions are largely unknown. Cell-free supernatant of the standard laboratory P. aeruginosa strain PAO1 obtained from anaerobic culture, but not aerobic culture, failed to kill A549 human airway epithelial cells. Further investigation revealed that this reduced cytotoxicity upon anaerobiosis was due to the suppressed secretion of elastase, a virulence factor controlled by P. aeruginosa quorum sensing (QS). Both a lacZ-reporter fusion assay and quantitative real-time PCR (RT-PCR) analysis demonstrated that transcription of the elastase-encoding lasB gene was substantially decreased during anaerobic growth compared with aerobic growth. Moreover, transcription of other genes controlled by the LasI/R QS system, such as rhlR, vqsR, mvfR, and rsaL, was also repressed under the same anaerobic growth conditions. Importantly, synthesis of 3-oxo-C 12 -HSL (PAI-1), an autoinducer molecule that mediates induction of the LasI/R QS system, was >22-fold decreased during anaerobic growth while C 4 -HSL (PAI-2), which mediates RhlI/R QS, was nondetectable under the same growth conditions. Transcription of the lasB gene was restored by exogenous supplementation with autoinducers, with PAI-2 more effective than PAI-1 or Pseudomonas quinolone signal (PQS) at restoring transcription of the lasB gene. Together, these results suggest that anaerobiosis deprives P. aeruginosa of the ability to regulate its virulence via QS and this misregulation attenuates the pathogenic potential of this important pathogen.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Cellmentioning

confidence: 99%

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Anaerobiosis-Induced Loss of Cytotoxicity Is Due to Inactivation of Quorum Sensing in Pseudomonas aeruginosa

et al. 2011

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“…3D). We reasoned that the lack of iron-regulated growth suppression of S. mutans could be due to reduced PQS production during static growth in the transwell plates, as PQS production is known to be dependent upon oxygen (50). However, iron-regulated AQ production not only was retained under these conditions but was significantly enhanced during static versus shaking growth (see Fig.…”

Section: Iron Regulates Pqsa-mediated Growth Suppression Of S Aureusmentioning

confidence: 99%

Iron Depletion Enhances Production of Antimicrobials by Pseudomonas aeruginosa

et al. 2015

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Cystic fibrosis (CF) is a heritable disease characterized by chronic, polymicrobial lung infections. While Staphylococcus aureus is the dominant lung pathogen in young CF patients, Pseudomonas aeruginosa becomes predominant by adulthood. P. aeruginosa produces a variety of antimicrobials that likely contribute to this shift in microbial populations. In particular, secretion of 2-alkyl-4(1H)-quinolones (AQs) contributes to lysis of S. aureus in coculture, providing an iron source to P. aeruginosa both in vitro and in vivo. We previously showed that production of one such AQ, the Pseudomonas quinolone signal (PQS), is enhanced by iron depletion and that this induction is dependent upon the iron-responsive PrrF small RNAs (sRNAs). Here, we demonstrate that antimicrobial activity against S. aureus during coculture is also enhanced by iron depletion, and we provide evidence that multiple AQs contribute to this activity. Strikingly, a P. aeruginosa ⌬prrF mutant, which produces very little PQS in monoculture, was capable of mediating iron-regulated growth suppression of S. aureus. We show that the presence of S. aureus suppresses the ⌬prrF1,2 mutant's defect in iron-regulated PQS production, indicating that a PrrF-independent iron regulatory pathway mediates AQ production in coculture. We further demonstrate that iron-regulated antimicrobial production is conserved in multiple P. aeruginosa strains, including clinical isolates from CF patients. These results demonstrate that iron plays a central role in modulating interactions of P. aeruginosa with S. aureus. Moreover, our studies suggest that established iron regulatory pathways of these pathogens are significantly altered during polymicrobial infections. IMPORTANCEChronic polymicrobial infections involving Pseudomonas aeruginosa and Staphylococcus aureus are a significant cause of morbidity and mortality, as the interplay between these two organisms exacerbates infection. This is in part due to enhanced production of antimicrobial metabolites by P. aeruginosa when these two species are cocultured. Using both established and newly developed coculture techniques, this report demonstrates that iron depletion increases P. aeruginosa's ability to suppress growth of S. aureus. These findings present a novel role for iron in modulating microbial interaction and provide the basis for understanding how essential nutrients drive polymicrobial infections.

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“…Subsequent investigations of these genes have yielded a wealth of knowledge about the precursors and biosynthesis of PQS in P. aeruginosa (20)(21)(22)(23). One of the mutants was found to have a disruption in gene PA5506 (hereafter referred to as qapR for quinolone alteration pathway regulator), which encodes an RpiR family transcriptional regulator homolog.…”

mentioning

confidence: 99%

QapR (PA5506) Represses an Operon That Negatively Affects the Pseudomonas Quinolone Signal in Pseudomonas aeruginosa

2013

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Pseudomonas aeruginosa is a Gram-negative, opportunistic pathogen that can cause disease in varied sites within the human body and is a significant source of morbidity and mortality in those afflicted with cystic fibrosis. P. aeruginosa is able to coordinate group behaviors, such as virulence factor production, through the process of cell-to-cell signaling. There are three intercellular signaling systems employed by P. aeruginosa, and one of these systems utilizes the small molecule 2-heptyl-3-hydroxy-4-quinolone (Pseudomonas quinolone signal [PQS]). PQS is required for virulence in multiple infection models and has been found in the lungs of cystic fibrosis patients colonized by P. aeruginosa. In this study, we have identified an RpiR family transcriptional regulator, QapR, which is an autoregulatory repressor. We found that mutation of qapR caused overexpression of the qapR operon. We characterized the qapR operon to show that it contains genes qapR, PA5507, PA5508, and PA5509 and that QapR directly controls the transcription of these genes in a negative manner. We also show that derepression of this operon greatly reduces PQS concentration in P. aeruginosa. Our results suggest that qapR affects PQS concentration by repressing an enzymatic pathway that acts on PQS or a PQS precursor to lower the PQS concentration. We believe that this operon comprises a novel mechanism to regulate PQS concentration in P. aeruginosa. Pseudomonas aeruginosa is a ubiquitous, Gram-negative bacterium that can infect a broad range of hosts, including insects, plants, and animals (1-3). This prevalent opportunistic pathogen is frequently acquired in the nosocomial setting and causes intractable infections in the lungs of cystic fibrosis patients (4-6). The ability of this organism to colonize and cause disease is tied to its vast array of virulence factors, such as pyocyanin, alkaline protease, hydrogen cyanide, elastase, and rhamnolipid, which are produced in response to intercellular signals (7-10).There are three cell-to-cell signaling systems that P. aeruginosa utilizes to coordinate expression of numerous genes for metabolic processes and virulence factor production (7, 9). The lasRI signaling system is at the top of the cell-to-cell signaling hierarchy and positively regulates the rhlRI and quinolone signaling systems (11). The las and rhl quorum sensing systems produce and respond to the acyl-homoserine lactone signals N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C 12 -HSL) and N-butyryl-L-homoserine lactone (C 4 -HSL), respectively (12, 13). The other cell-to-cell signaling system functions through the quinolone compound 2-heptyl-3-hydroxy-4-quinolone (the Pseudomonas quinolone signal [PQS]) (14). Production of PQS is mediated by the products of the pqsABCD operon and the pqsH gene and occurs through the condensation of the precursors anthranilate and ␤-ketodecanoic acid (15). PQS then interacts with and activates PqsR, which positively controls expression of the PQS biosynthetic operon (pqsABCDE) in an autoregulatory loop...

show abstract

Oxygen levels rapidly modulate Pseudomonas aeruginosa social behaviours via substrate limitation of PqsH

Cited by 145 publications

References 63 publications

Anaerobiosis-Induced Loss of Cytotoxicity Is Due to Inactivation of Quorum Sensing in Pseudomonas aeruginosa

Anaerobiosis-Induced Loss of Cytotoxicity Is Due to Inactivation of Quorum Sensing in Pseudomonas aeruginosa

Iron Depletion Enhances Production of Antimicrobials by Pseudomonas aeruginosa

QapR (PA5506) Represses an Operon That Negatively Affects the Pseudomonas Quinolone Signal in Pseudomonas aeruginosa

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