title: Toll-like receptor 9 deficiency protects mice against Pseudomonas aeruginosa lung infection.
abstract: Pseudomonas aeruginosa is an opportunistic pathogen involved in nosocomial infections. While a number of studies have demonstrated the roles of TLR2, TLR4 and TLR5 in host defense againt P. aeruginosa infection, the implication of TLR9 in this process has been overlooked. Here, we show that P. aeruginosa DNA stimulates the inflammatory response through TLR9 pathway in both a cell line and primary alveolar macrophages (AMs). This activation requires asparagine endopeptidase- and endosomal acidification. Interestingly, TLR9-/- mice resisted to lethal lung infection by P. aeruginosa, compared to WT C57BL/6 mice. The resistance of TLR9-/- mice to P. aeruginosa infection was associated with: (i) a higher ability of TLR9-/- AMs to kill P. aeruginosa; (ii) a rapid increase in the pro-inflammatory cytokines such as TNFα, IL-1β and IL-6 production; and (iii) an increase in nitric oxide (NO) production and inductible NO synthase expression in AMs. In addition, inhibition of both IL-1β and NO production resulted in a significant decrease of P. aeruginosa clearance by AMs. Altogether these results indicate that TLR9 plays a detrimental role in pulmonary host defense toward P. aeruginosa by reducing the AMs clearance activity and production of IL-1β and NO necessary for bacteria killing.
authors.affiliation: Unité de Défense Innée et Inflammation, Institut Pasteur, Paris, France; INSERM, U.874, Paris, France.
authors.forename: Fatima
authors.initials: F
authors.lastname: Benmohamed
authors.affiliation: Unité de Défense Innée et Inflammation, Institut Pasteur, Paris, France; INSERM, U.874, Paris, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Medina
authors.affiliation: Unité de Défense Innée et Inflammation, Institut Pasteur, Paris, France; INSERM, U.874, Paris, France.
authors.forename: Yong-Zheng
authors.initials: YZ
authors.lastname: Wu
authors.affiliation: INSERM, U.1013, Paris, France.
authors.forename: Sophia
authors.initials: S
authors.lastname: Maschalidi
authors.affiliation: Unité d'histopathologie humaine et modèles animaux, Institut Pasteur, Paris, France.
authors.forename: Gregory
authors.initials: G
authors.lastname: Jouvion
authors.affiliation: Unité de Défense Innée et Inflammation, Institut Pasteur, Paris, France; INSERM, U.874, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Guillemot
authors.affiliation: Unité de Défense Innée et Inflammation, Institut Pasteur, Paris, France; INSERM, U.874, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Chignard
authors.affiliation: INSERM, U.1013, Paris, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Manoury
authors.affiliation: Unité de Défense Innée et Inflammation, Institut Pasteur, Paris, France; INSERM, U.874, Paris, France.
authors.forename: Lhousseine
authors.initials: L
authors.lastname: Touqui
mesh_terms: D000818:Animals; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis; D004269:DNA, Bacterial / Q000378:metabolism; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006863:Hydrogen-Ion Concentration; D007113:Immunity, Innate / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000382:microbiology* / Q000473:pathology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D050296:Microbial Viability / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D011014:Pneumonia / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D011552:Pseudomonas Infections / Q000276:immunology / Q000382:microbiology* / Q000473:pathology / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000172:deficiency* / Q000378:metabolism
chemical_list: C408982:CPG-oligonucleotide; D016207:Cytokines; D004269:DNA, Bacterial; D009838:Oligodeoxyribonucleotides; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II