title: Clinical Isolates of Pseudomonas aeruginosa from Chronically Infected Cystic Fibrosis Patients Fail To Activate the Inflammasome during Both Stable Infection and Pulmonary Exacerbation.
abstract: Immune recognition of pathogen-associated ligands leads to assembly and activation of inflammasomes, resulting in the secretion of inflammatory cytokines IL-1β and IL-18 and an inflammatory cell death called pyroptosis. Inflammasomes are important for protection against many pathogens, but their role during chronic infectious disease is poorly understood. Pseudomonas aeruginosa is an opportunistic pathogen that persists in the lungs of cystic fibrosis (CF) patients and may be responsible for the repeated episodes of pulmonary exacerbation characteristic of CF. P. aeruginosa is capable of inducing potent inflammasome activation during acute infection. We hypothesized that to persist within the host during chronic infection, P. aeruginosa must evade inflammasome activation, and pulmonary exacerbations may be the result of restoration of inflammasome activation. We therefore isolated P. aeruginosa from chronically infected CF patients during stable infection and exacerbation and evaluated the impact of these isolates on inflammasome activation in macrophages and neutrophils. P. aeruginosa isolates from CF patients failed to induce inflammasome activation, as measured by the secretion of IL-1β and IL-18 and by pyroptotic cell death, during both stable infection and exacerbation. Inflammasome evasion likely was due to reduced expression of inflammasome ligands and reduced motility and was not observed in environmental isolates or isolates from acute, non-CF infection. These results reveal a novel mechanism of pathogen adaptation by P. aeruginosa to avoid detection by inflammasomes in CF patients and indicate that P. aeruginosa-activated inflammasomes are not involved in CF pulmonary exacerbations.
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada; Department of Biology, Faculty of Science, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada;
authors.forename: Kelsey E
authors.initials: KE
authors.lastname: Huus
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada;
authors.forename: Julie
authors.initials: J
authors.lastname: Joseph
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada;
authors.forename: Li
authors.identifier: http://orcid.org/0000-0002-4396-5545
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Biology, Faculty of Science, Carleton University, Ottawa, Ontario K1N 6N5, Canada; and.
authors.forename: Alex
authors.initials: A
authors.lastname: Wong
authors.affiliation: Ottawa Hospital Research Institute, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Aaron
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada;
authors.forename: Thien-Fah
authors.initials: TF
authors.lastname: Mah
authors.affiliation: Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada; subash.sad@uottawa.ca.
authors.forename: Subash
authors.initials: S
authors.lastname: Sad
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D003550:Cystic Fibrosis / Q000150:complications* / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D005798:Genes, Bacterial; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D008024:Ligands; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D011552:Pseudomonas Infections / Q000209:etiology* / Q000378:metabolism* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification; D013183:Sputum / Q000382:microbiology; D000069296:Type III Secretion Systems / Q000235:genetics
chemical_list: D016207:Cytokines; D058847:Inflammasomes; D008024:Ligands; D000069296:Type III Secretion Systems; D020169:Caspases