The Interaction of N-Acylhomoserine Lactone Quorum Sensing Signaling Molecules with Biological Membranes: Implications for Inter-Kingdom Signaling

Davis, Benjamin; Jensen, Rasmus O.; Williams, Paul; O'Shea, Paul

doi:10.1371/journal.pone.0013522

Cited by 76 publications

(84 citation statements)

References 51 publications

(78 reference statements)

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“…3OC12 was shown to bind PPAR␥ receptors, resulting in modulation of cytokine expression (16,17). Evidence has also been provided that direct interaction of 3OC12 with the plasma membrane may mediate some biological responses (41). PON2 will act to attenuate signaling through these pathways that are mediated by the lactone form of 3OC12.…”

Section: Discussionmentioning

confidence: 99%

Novel Paraoxonase 2-Dependent Mechanism Mediating the Biological Effects of the Pseudomonas aeruginosa Quorum-Sensing Molecule N -(3-Oxo-Dodecanoyl)- l -Homoserine Lactone

et al. 2015

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cPseudomonas aeruginosa produces N-(3-oxo-dodecanoyl)-L-homoserine lactone (3OC12), a crucial signaling molecule that elicits diverse biological responses in host cells thought to subvert immune defenses. The mechanism mediating many of these responses remains unknown. The intracellular lactonase paraoxonase 2 (PON2) hydrolyzes and inactivates 3OC12 and is therefore considered a component of host cells that attenuates 3OC12-mediated responses. Here, we demonstrate in cell lines and in primary human bronchial epithelial cells that 3OC12 is rapidly hydrolyzed intracellularly by PON2 to 3OC12 acid, which becomes trapped and accumulates within the cells. Subcellularly, 3OC12 acid accumulated within the mitochondria, a compartment where PON2 is localized. Treatment with 3OC12 caused a rapid PON2-dependent cytosolic and mitochondrial pH decrease, calcium release, and phosphorylation of stress signaling kinases. The results indicate a novel, PON2-dependent intracellular acidification mechanism by which 3OC12 can mediate its biological effects. Thus, PON2 is a central regulator of host cell responses to 3OC12, acting to decrease the availability of 3OC12 for receptor-mediated effects and acting to promote effects, such as calcium release and stress signaling, via intracellular acidification. P seudomonas aeruginosa is a common pathogen causing serious infections in immunocompromised and ill individuals due to the bacteria's ability to evade host immune responses and acquire antibiotic resistance (1). Many Gram-negative bacteria, including P. aeruginosa, produce acyl-homoserine lactone (AHL) signaling molecules which regulate the cell density-dependent expression of virulence factors in a process termed quorum sensing (QS) (1). The AHL N-(3-oxododecanoyl)-L-homoserine lactone (3OC12) is a key P. aeruginosa QS signal that has been shown to be necessary for biofilm maturation and full expression of virulence in P. aeruginosa animal infection models (2-5). Concentrations up to 600 M 3OC12 have been measured in P. aeruginosa biofilms in vitro (6). Concentrations of over 6 M 3OC12 have been detected in the sputum of individuals with pulmonary P. aeruginosa infections (7), suggesting active 3OC12 signaling in the human disease as well.In addition to modulating bacterial gene expression, 3OC12 elicits a multitude of biological responses in diverse mammalian cell types (8). Depending upon the cell type and dose, 3OC12 (10 to 100 M) can induce apoptosis, endoplasmic reticulum (ER) stress, chemotaxis, and proinflammatory gene expression (8-10). Conversely, 3OC12 inhibited lipopolysaccharide (LPS) induction of proinflammatory mediators in macrophages, fibroblasts, and epithelial cells and in vivo by repressing nuclear factor -light chain enhancer of activated B-cell (NF-B) signaling (11). In antigen-stimulated T-lymphocytes, 3OC12 inhibits cell proliferation and production of gamma interferon and interleukin-4 (IL-4), critical regulators of immunity (8,12). These diverse responses suggest that 3OC12 acts through multiple, and cell-...

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Section: Discussionmentioning

confidence: 99%

Novel Paraoxonase 2-Dependent Mechanism Mediating the Biological Effects of the Pseudomonas aeruginosa Quorum-Sensing Molecule N -(3-Oxo-Dodecanoyl)- l -Homoserine Lactone

et al. 2015

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“…In mammalian cells, long acyl chain AHL with an intact lactone ring are able to interact with phospholipids and diffuse across membrane systems, where membrane microdomains, such as caveolae and lipid rafts, may facilitate this process [94] via interactions with a sub-membrane organization of filamentous actin, actin-binding proteins, and anchoring membrane proteins. The overall plasma membrane fitness and the dynamic of these interactions, including those of the actin cytoskeleton, can influence the shape of microdomain compartments and the capacity of transport and receptor signaling [95].…”

Section: Traffic and Human Targets For P Aeruginosa 3o-c12-hslmentioning

confidence: 99%

Bacteria-Host Crosstalk: Sensing of the Quorum in the Context of <b><i>Pseudomonas aeruginosa</i></b> Infections

Turkina

Vikström

2018

J Innate Immun

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Cell-to-cell signaling via small molecules is an essential process to coordinate behavior in single species within a community, and also across kingdoms. In this review, we discuss the quorum sensing (QS) systems used by the opportunistic pathogen Pseudomonas aeruginosa to sense bacterial population density and fitness, and regulate virulence, biofilm development, metabolite acquisition, and mammalian host defense. We also focus on the role of N-acylhomoserine lactone-dependent QS signaling in the modulation of innate immune responses connected together via calcium signaling, homeostasis, mitochondrial and cytoskeletal dynamics, and governing transcriptional and proteomic responses of host cells. A future perspective emphasizes the need for multidisciplinary efforts to bring current knowledge of QS into a more detailed understanding of the communication between bacteria and host, as well as into strategies to prevent and treat P. aeruginosa infections and reduce the rate of antibiotic resistance.

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“…They trigger a diverse set of signaling pathways including MAPK, activation of Rho GTPases that are important in cell migration and the transcription factor NFκB that plays a central role in the expression of pro-inflammatory mediators [4,151,152]. 3O-C12-HSL may interact directly with phospholipids in membranes [153] and when entering the host cell [154], and use the peroxisome proliferator-activated receptor (PPAR) to interfere with NFκB signaling [155,156]. The IQ-motif-containing GTPase-activating protein IQGAP1 was identified as an allegeable target for 3O-C12-HSL [145].…”

Section: Quorum Sensing and The Hostmentioning

confidence: 99%

“…The P. aeruginosa AHL 3O-C12-HSL can diffuse into cells [153,154] and modulate immune responses [152,155,156]. To further investigate the impact of P. aeruginosa QS on host cells and assess in greater detail the bacteria-host cell communication, we investigated the effects of P. aeruginosa 3O-C12-HSL on cell morphology, area, volume and AQP9 characteristics of human primary macrophages.…”

Section: Water Flux Inhibitors Show Small Effects On the Phagocytosismentioning

confidence: 99%

Aquaporins in Infection and Inflammation

Holm¹

2016

Linköping University Medical Dissertations

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About the cover:The front cover displays a human, blood-derived macrophage stained for aquaporin 9.During the course of the research underlying this thesis, Angelika Holm was enrolled in Forum Scientium, a multidisciplinary doctoral programme at Linköping University Printed by LiU-Tryck, Linköping, Sweden, 2016 "Be brave, even if you're not, pretend to be. No one can tell the difference."To that young, awkward, tall girl who dared to dream of something else, something more:You did it. SUPERVISOR Elena VikströmDepartment of Clinical and Experimental Medicine Linköping University Linköping Sweden When cells of the innate immune system encounter pathogens they need to respond and prepare for migration and phagocytosis and do so through volume regulatory processes. The Gramnegative bacterium Pseudomonas aeruginosa utilizes a small molecule-based communication system, called quorum sensing (QS) to control the production of its virulence factors and biofilms. We found that P. aeruginosa with a complete QS system elicits a stronger phagocytic response in human blood-derived macrophages compared to its lasI-/rhlI-mutant lacking the production of the QS molecules N-butyryl-L-homoserine lactone (C4-HSL) and N-3-oxododecanoyl-L-homoserine lactone (3O-C12-HSL). Infection with P. aeruginosa further increases the expression of AQP9 and induces re-localisation of AQP9 to the front and trailing ends of macrophages. Moreover, the 3O-C12-HSL alone elevates the expression of AQP9, redistribute the water channel to the front and rear ends and increases the cell area and volume of macrophages. Both infection with the wild type P. aeruginosa and the treatment with 3O-C12-HSL change the nano-structural architecture of the AQP9 distribution in macrophages. ASSISTANT SUPERVISORS Karl-Eric MagnussonViruses use the intracellular machinery of the invaded cells to produce and assemble new viral bodies. Intracellular AQPs are localised in a membranes of cellular organelles to regulate their function and morphology. C3H10T1/2 fibroblasts transiently expressing green fluorescent protein (GFP)-AQP6 show a reduced expression of AQP6 after Hazara virus infection and an increased cell area. Overexpressing AQP6 in C3H10T1/2 cells reduces the infectivity of Hazara virus indicating that AQP6 expression has a protective role in virus infections.Ion and water channels in the epithelial cell lining tightly regulate the water homeostasis. In microscopic colitis (MC), patients suffer from severe watery diarrhoeas. For the first time, we have shown that the expression of AQP1, 8 and 11 and the sodium/hydrogen exchanger NHE1 are reduced in colonic biopsies from MC patients compared to healthy control individuals. Following treatment with the glucocorticoid budesonide the patients experienced a rapid recovery and we observed a restored or increased expression of the AQPs and NHE1 during treatment, suggesting a role for AQPs in the diarrhoeal mechanisms in MC.Taken together, this thesis provides new evidence on the importance of water homeostasis regulatio...

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The Interaction of N-Acylhomoserine Lactone Quorum Sensing Signaling Molecules with Biological Membranes: Implications for Inter-Kingdom Signaling

Cited by 76 publications

References 51 publications

Novel Paraoxonase 2-Dependent Mechanism Mediating the Biological Effects of the Pseudomonas aeruginosa Quorum-Sensing Molecule N -(3-Oxo-Dodecanoyl)- l -Homoserine Lactone

Novel Paraoxonase 2-Dependent Mechanism Mediating the Biological Effects of the Pseudomonas aeruginosa Quorum-Sensing Molecule N -(3-Oxo-Dodecanoyl)- l -Homoserine Lactone

Bacteria-Host Crosstalk: Sensing of the Quorum in the Context of <b><i>Pseudomonas aeruginosa</i></b> Infections

Aquaporins in Infection and Inflammation

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