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Both toxic and beneficial effects of pyocyanin contribute to the lifecycle of Pseudomonas aeruginosa.

ABSTRACT: Pseudomonas aeruginosa, an opportunistic pathogen, produces redox-active pigments called phenazines. Pyocyanin (PYO, the blue phenazine) plays an important role during biofilm development. Paradoxically, PYO auto-poisoning can stimulate cell death and release of extracellular DNA (eDNA), yet PYO can also promote survival within biofilms when cells are oxidant-limited. Here, we identify the environmental and physiological conditions in planktonic culture that promote PYO-mediated cell death. We demonstrate that PYO auto-poisoning is enhanced when cells are starved for carbon. In the presence of PYO, cells activate a set of genes involved in energy-dependent defenses, including: (i) the oxidative stress response, (ii) RND efflux systems and (iii) iron-sulfur cluster biogenesis factors. P. aeruginosa can avoid PYO poisoning when reduced carbon is available, but blockage of adenosine triphosphate (ATP) synthesis either through carbon limitation or direct inhibition of the F0 F1 -ATP synthase triggers death and eDNA release. Finally, even though PYO is toxic to the majority of the population when cells are nutrient limited, a subset of cells is intrinsically PYO resistant. The effect of PYO on the producer population thus appears to be dynamic, playing dramatically different yet predictable roles throughout distinct stages of growth, helping rationalize its multifaceted contributions to biofilm development.

SUBMITTER: Meirelles LA

PROVIDER: S-EPMC6281804 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Both toxic and beneficial effects of pyocyanin contribute to the lifecycle of Pseudomonas aeruginosa.

Meirelles Lucas A LA Newman Dianne K DK

Molecular microbiology 20181023 6

Pseudomonas aeruginosa, an opportunistic pathogen, produces redox-active pigments called phenazines. Pyocyanin (PYO, the blue phenazine) plays an important role during biofilm development. Paradoxically, PYO auto-poisoning can stimulate cell death and release of extracellular DNA (eDNA), yet PYO can also promote survival within biofilms when cells are oxidant-limited. Here, we identify the environmental and physiological conditions in planktonic culture that promote PYO-mediated cell death. We d ...[more]

PMID: 30230061

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Project description:RationaleCystic fibrosis lung disease is characterized by accumulation of apoptotic neutrophils, indicating impaired clearance of dying cells. Pseudomonas aeruginosa, the principal microbial pathogen in cystic fibrosis, manipulates apoptosis induction via production of toxic metabolites. Whether these metabolites, particularly pyocyanin, can also modulate apoptotic cell engulfment is unknown.ObjectivesTo assess the effects of pyocyanin on apoptotic cell engulfment by macrophages in vitro and in vivo and to investigate potential mechanisms of the observed effects.MethodsHuman monocyte-derived macrophages were treated with pyocyanin before challenge with apoptotic neutrophils, apoptotic Jurkat cells, or latex beads, and phagocytosis was assessed by light microscopy and flow cytometry. Effects of pyocyanin production on apoptotic cell clearance in vivo were assessed in a murine model, comparing infection by wild-type or pyocyanin-deficient P. aeruginosa. Oxidant production was investigated using fluorescent probes and pharmacologic inhibition and Rho GTPase signaling by immunoblotting and inhibitor studies.Measurements and main resultsPyocyanin treatment impaired macrophage engulfment of apoptotic cells in vitro, without inducing significant macrophage apoptosis, whereas latex bead uptake was preserved. Macrophage ingestion of apoptotic cells was reduced and late apoptotic/necrotic cells were increased in mice infected with pyocyanin-producing P. aeruginosa compared with the pyocyanin-deficient strain. Inhibition of apoptotic cell uptake involved intracellular generation of reactive oxygen species (ROS) and effects on Rho GTPase signaling. Antioxidants or blockade of Rho signaling substantially restored apoptotic cell engulfment.ConclusionsThese studies demonstrate that P. aeruginosa can manipulate the inflammatory microenvironment through inhibition of apoptotic cell engulfment, and suggest potential strategies to limit pulmonary inflammation in cystic fibrosis.

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Both toxic and beneficial effects of pyocyanin contribute to the lifecycle of Pseudomonas aeruginosa.

Publications

Both toxic and beneficial effects of pyocyanin contribute to the lifecycle of Pseudomonas aeruginosa.

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