Quorum Sensing Is Accompanied by Global Metabolic Changes in the Opportunistic Human Pathogen Pseudomonas aeruginosa

Davenport, Peter W.; Griffin, Julian L.; Welch, Martin

doi:10.1128/jb.02557-14

Cited by 77 publications

(79 citation statements)

References 70 publications

(78 reference statements)

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“…Thus, the levels of important reduction-related agents (NADP + and glutathione disulfide) that protect cells from toxic reactive oxygen species were significantly higher in QS mutants than in wild type cells [38] (Figure 3), consistent with data from a previous study indicating that the key catalase gene katG is positively controlled by QS [62]. In P. aeruginosa, the concentrations of polyamines, multifunctional molecules associated with responses to oxidative stress, are elevated in the lasI/rhlI mutant (which is unable to make AHL-QS signaling molecules) because QS activates the expression of katA and superoxide dismutase, which are involved in the detoxification of reactive oxygen species [63,64].…”

Section: Influence Of Persistent Cooperativity On Primary Metabolismsupporting

confidence: 88%

“…Recently published results from GC-and LC-MSbased analyses of intracellular metabolites in P. aeruginosa showed that a deficiency in QS perturbed the cellular concentrations of TCA cycle intermediates, amino acids, and fatty acids [63]. TCA cycle intermediates, including citrate, malate, and succinate, were more abundant in QS mutant cells compared to wild type cells, as reported previously in B. glumae [38,63].…”

Section: Influence Of Persistent Cooperativity On Primary Metabolismmentioning

confidence: 52%

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Control of bacterial metabolism by quorum sensing

Goo

Kang

et al. 2015

Trends in Microbiology

129

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Section: Influence Of Persistent Cooperativity On Primary Metabolismsupporting

confidence: 88%

Section: Influence Of Persistent Cooperativity On Primary Metabolismmentioning

confidence: 52%

Control of bacterial metabolism by quorum sensing

Goo

Kang

et al. 2015

Trends in Microbiology

129

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“…It is not yet clear whether redox sensing by QS regulators is important in responding to the burst of reactive oxidative species generated by the host immune system or whether this type of redox switch allows regulators to balance up-regulation of QS pathways with the potentially damaging reactive oxidative species produced through heightened metabolic activity resulting from QS activation. QS in P. aeruginosa has been linked to the expression of catalase and superoxide dismutase genes for protection against H 2 O 2 (45), and other recent reports provide increased evidence for the close connection between QS and central metabolism in P. aeruginosa (46). Although it will be interesting to know precisely how oxidative sensing by LasR might serve P. aeruginosa, it is perhaps more valuable to have learned more about this protein at the chemical level, noting multiple critical cysteines that may prove to be useful targets in working toward effective treatment of this pathogen.…”

Section: Discussionmentioning

confidence: 99%

Molecular Insights into the Impact of Oxidative Stress on the Quorum-Sensing Regulator Protein LasR

Kafle¹,

Amoh²,

Reaves³

et al. 2016

Journal of Biological Chemistry

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The LasR regulator protein functions at the top of the Pseudomonas aeruginosa quorum-sensing hierarchy and is implicated in promoting bacterial virulence. Of note is recent evidence that this transcription factor may also respond to oxidative stress. Here, all cysteines in LasR were inspected to deduce their redox sensitivity and to probe the connection between stress response and LasR activity using purified LasR and individual LasR domains. Cys 79 in the ligand binding domain of LasR appears to be important for ligand recognition and folding of this domain to potentiate DNA binding but does not seem to be sensitive to oxidative stress when bound to its native ligand. Two cysteines in the DNA binding domain of LasR do form a disulfide bond when treated with hydrogen peroxide, and formation of this Cys 201 -Cys 203 disulfide bond appears to disrupt the DNA binding activity of the transcription factor. Mutagenesis of either of these cysteines leads to expression of a protein that no longer binds DNA. A cell-based reporter assay linking LasR function with ␤-galactosidase activity gave results consistent with those obtained with purified LasR. This work provides a possible mechanism for oxidative stress response by LasR and indicates that multiple cysteines within the protein may prove to be useful targets for disabling its activity.The Gram-negative bacterium Pseudomonas aeruginosa is an opportunistic human pathogen that establishes chronic infections in immunocompromised patients, with persistent pulmonary colonization in individuals with cystic fibrosis (1-3). Like many bacteria, P. aeruginosa employs quorumsensing (QS) 4 machinery to communicate local population density through the exchange of self-produced signaling molecules (4). QS contributes to the development of acute infections by coordinating the production of multiple virulence factors, including elastase and pyocyanin, and the formation of biofilms (5-7). QS in P. aeruginosa is largely mediated by N-acyl L-homoserine lactone autoinducer molecules, biosynthesized by LuxI-type synthases, and detected by LuxR-type regulator proteins (8). The two major systems responsive to acylhomoserine lactones (AHLs) in P. aeruginosa are LasI/LasR and RhlI/RhlR. LasI and RhlI are LuxI-type synthases, whereas LasR and RhlR are LuxR-type regulatory proteins. These AHL-dependent systems are also closely connected to signaling governed by 2-alkyl-4-quinolones in P. aeruginosa (9).The regulator protein LasR, with its cognate synthase LasI, functions at the top of the P. aeruginosa quorum-sensing hierarchy (10). Like other LuxR-type proteins, this transcription factor is composed of two domains (11). The amino-terminal ligand binding domain (LBD) specifically recognizes its autoinducer, N-(3-oxo-dodecanoyl)-L-homoserine lactone (3O-C 12 -HSL), promoting protein folding and dimerization, whereas the DNA binding domain (DBD) recognizes target sites to activate downstream gene expression. There has been significant interest in understanding LasR, as its inhibition represents a...

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“…utilization and nutrient transport genes were the most abundant representatives (60). A more recent study in the same species demonstrated a global impact of QS on the metabolome and proposed that QS plays a key role in metabolic rewiring of the cell under certain conditions (61). A study examining the targets of LuxR homologues in Brucella, an intracellular pathogen, identified a large number of proteins involved in metabolic pathways, such as central metabolism or amino acid metabolism, respiration, and transport of amino acids and sugars that were under the control of QS regulators (62).…”

Section: Figmentioning

confidence: 99%

Quorum Sensing Regulators Are Required for Metabolic Fitness in Vibrio parahaemolyticus

et al. 2017

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Quorum sensing (QS) is a process by which bacteria alter gene expression in response to cell density changes. In Vibrio species, at low cell density, the sigma 54-dependent response regulator LuxO is active and regulates the two QS master regulators AphA, which is induced, and OpaR, which is repressed. At high cell density the opposite occurs: LuxO is inactive, and therefore OpaR is induced while AphA is repressed. In Vibrio parahaemolyticus, a significant enteric pathogen of humans, the roles of these regulators in pathogenesis are less known. We examined deletion mutants of luxO, opaR, and aphA for in vivo fitness using an adult mouse model. We found that the luxO and aphA mutants were defective in colonization compared to levels in the wild type. The opaR mutant did not show any defect in vivo. Colonization was restored to wild-type levels in a luxO opaR double mutant and was also increased in an opaR aphA double mutant. These data suggest that AphA is important and that overexpression of opaR is detrimental to in vivo fitness. Transcriptome sequencing (RNA-Seq) analysis of the wild type and luxO mutant grown in mouse intestinal mucus showed that 60% of the genes that were downregulated in the luxO mutant were involved in amino acid and sugar transport and metabolism. These data suggest that the luxO mutant has a metabolic disadvantage, which was confirmed by growth pattern analysis using phenotype microarrays. Bioinformatics analysis revealed OpaR binding sites in the regulatory region of 55 carbon transporter and metabolism genes. Biochemical analysis of five representatives of these regulatory regions demonstrated direct binding of OpaR in all five tested. These data demonstrate the role of OpaR in carbon utilization and metabolic fitness, an overlooked role in the QS regulon.KEYWORDS Vibrio parahaemolyticus, carbon metabolism, intestinal colonization, quorum sensing V ibrio parahaemolyticus is the leading cause of bacterial seafood-borne gastroenteritis worldwide, resulting in mild to severe inflammatory gastroenteritis (1-5). The completed genome sequence of V. parahaemolyticus RIMD2210633, an O3:K6 serotype associated with pandemic disease, demonstrated the presence of two type III secretion systems (T3SS-1 and T3SS-2), one on each chromosome, which led to the identification of several effector proteins associated with inflammatory diarrhea (6-8). Studies have shown that T3SS-2 is the major contributing factor to enterotoxicity and that inflammatory diarrhea and intestinal epithelium cell disruption are dependent upon a functional T3SS-2 (9-12).Much less is known about how V. parahaemolyticus initially colonizes and survives within the host gastrointestinal tract. This lack of knowledge is in part due to a lack of animal models to study colonization and infection in vivo. The development of a streptomycin-pretreated adult mouse model that removes microbiota colonization resistance and allows V. parahaemolyticus to colonize has uncovered a number of

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Quorum Sensing Is Accompanied by Global Metabolic Changes in the Opportunistic Human Pathogen Pseudomonas aeruginosa

Cited by 77 publications

References 70 publications

Control of bacterial metabolism by quorum sensing

Control of bacterial metabolism by quorum sensing

Molecular Insights into the Impact of Oxidative Stress on the Quorum-Sensing Regulator Protein LasR

Quorum Sensing Regulators Are Required for Metabolic Fitness in Vibrio parahaemolyticus

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