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Scavenging of reactive oxygen species by tryptophan metabolites helps Pseudomonas aeruginosa escape neutrophil killing. | LitMetric

Scavenging of reactive oxygen species by tryptophan metabolites helps Pseudomonas aeruginosa escape neutrophil killing.

Free Radic Biol Med

TIMC/Therex Laboratory, UMR 5525 (CNRS-UJF), Faculty of Medicine, University of Grenoble Alpes, Grenoble F-38041, France; Chronic Granulomatous Disease Diagnosis and Research Center, Pôle Biologie, CHU de Grenoble, Grenoble F-38043, France. Electronic address:

Published: August 2014

AI Article Synopsis

  • Pseudomonas aeruginosa can persistently infect cystic fibrosis patients by evading their immune defenses, largely utilizing the kynurenine pathway to break down tryptophan.
  • Most strains of this bacterium from cystic fibrosis patients produce high levels of kynurenine, which activates a gene (kynA) upon contact with immune cells, especially neutrophils.
  • Kynurenine helps the bacteria survive by inhibiting reactive oxygen species production from activated neutrophils, not through phagocytosis defects or direct inhibition, but by scavenging harmful oxidants like hydrogen peroxide.

Article Abstract

Pseudomonas aeruginosa is responsible for persistent infections in cystic fibrosis patients, suggesting an ability to circumvent innate immune defenses. This bacterium uses the kynurenine pathway to catabolize tryptophan. Interestingly, many host cells also produce kynurenine, which is known to control immune system homeostasis. We showed that most strains of P. aeruginosa isolated from cystic fibrosis patients produce a high level of kynurenine. Moreover, a strong transcriptional activation of kynA (the first gene involved in the kynurenine pathway) was observed upon contact with immune cells and particularly with neutrophils. In addition, using coculture of human neutrophils with various strains of P. aeruginosa producing no (ΔkynA) or a high level of kynurenine (ΔkynU or ΔkynA pkynA), we demonstrated that kynurenine promotes bacterial survival. In addition, increasing the amount kynurenine inhibits reactive oxygen species production by activated neutrophils, as evaluated by chemiluminescence with luminol or isoluminol or SOD-sensitive cytochrome c reduction assay. This inhibition is due neither to a phagocytosis defect nor to direct NADPH oxidase inhibition. Indeed, kynurenine has no effect on oxygen consumption by neutrophils activated by PMA or opsonized zymosan. Using in vitro reactive oxygen species-producing systems, we showed that kynurenine scavenges hydrogen peroxide and, to a lesser extent, superoxide. Kynurenine׳s scavenging effect occurs mainly intracellularly after bacterial stimulation, probably in the phagosome. In conclusion, the kynurenine pathway allows P. aeruginosa to circumvent the innate immune response by scavenging neutrophil reactive oxygen species production.

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Source
http://dx.doi.org/10.1016/j.freeradbiomed.2014.06.003DOI Listing

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