title: Pyocyanin production by Pseudomonas aeruginosa induces neutrophil apoptosis and impairs neutrophil-mediated host defenses in vivo.
abstract: Clearance of neutrophils from inflamed sites is critical for resolution of inflammation, but pathogen-driven neutrophil apoptosis can impair host defenses. We previously showed that pyocyanin, a phenazine toxic metabolite produced by Pseudomonas aeruginosa, accelerates neutrophil apoptosis in vitro. We compared wild-type and pyocyanin-deficient strains of P. aeruginosa in a murine model of acute pneumonia. Intratracheal instillation of either strain of P. aeruginosa caused a rapid increase in bronchoalveolar lavage neutrophil counts up to 18 h after infection. In wild-type infection, neutrophil numbers then declined steadily, whereas neutrophil numbers increased up to 48 h in mice infected with pyocyanin-deficient P. aeruginosa. In keeping with these differences, pyocyanin production was associated with reduced bacterial clearance from the lungs. Neutrophil apoptosis was increased in mice infected with wild-type compared with the phenazine-deficient strain or two further strains that lack pyocyanin production, but produce other phenazines. Concentrations of potent neutrophil chemokines (MIP-2, KC) and cytokines (IL-6, IL-1beta) were significantly lower in wild-type compared with phenazine-deficient strain-infected mice at 18 h. We conclude that pyocyanin production by P. aeruginosa suppresses the acute inflammatory response by pathogen-driven acceleration of neutrophil apoptosis and by reducing local inflammation, and that this is advantageous for bacterial survival.
authors.affiliation: Division of Clinical Sciences (North), University of Sheffield, Sheffield, United Kingdom.
authors.forename: Lucy
authors.initials: L
authors.lastname: Allen
authors.forename: David H
authors.initials: DH
authors.lastname: Dockrell
authors.forename: Theresa
authors.initials: T
authors.lastname: Pattery
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Lee
authors.forename: Pierre
authors.initials: P
authors.lastname: Cornelis
authors.forename: Paul G
authors.initials: PG
authors.lastname: Hellewell
authors.forename: Moira K B
authors.initials: MK
authors.lastname: Whyte
mesh_terms: D000818:Animals; D017209:Apoptosis; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology*; D010619:Phenazines / Q000378:metabolism; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D011552:Pseudomonas Infections / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity*; D011710:Pyocyanine / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018925:Chemokines; D016207:Cytokines; D010619:Phenazines; D011710:Pyocyanine