Abstract
TLRs are required for generation of protective lung mucosal immune responses against microbial pathogens. In this study, we evaluated the effect of the TLR5 ligand flagellin on stimulation of antibacterial mucosal immunity in a lethal murine Pseudomonas aeruginosa pneumonia model. The intranasal pretreatment of mice with purified P. aeruginosa flagellin induced strong protection against intratracheal P. aeruginosa-induced lethality, which was attributable to markedly improved bacterial clearance, reduced dissemination, and decreased alveolar permeability. The protective effects of flagellin on survival required TLR5 and were observed even in the absence of neutrophils. Flagellin induced strong induction of innate genes, most notably the antimicrobial peptide cathelicidin-related antimicrobial peptide. Finally, flagellin-induced protection was partially abrogated in cathelicidin-related antimicrobial peptide-deficient mice. Our findings illustrate the profound stimulatory effect of flagellin on lung mucosal innate immunity, a response that might be exploited therapeutically to prevent the development of gram-negative bacterial infection of the respiratory tract.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Administration, Intranasal
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Animals
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Antimicrobial Cationic Peptides
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Blotting, Western
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Cathelicidins / genetics
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Cathelicidins / immunology*
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Cathelicidins / metabolism
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Cells, Cultured
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Epithelial Cells / drug effects
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Epithelial Cells / immunology
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Epithelial Cells / metabolism
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Female
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Flagellin / administration & dosage
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Flagellin / immunology*
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Gene Expression / drug effects
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Gene Expression / immunology
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Immunity, Mucosal / drug effects
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Immunity, Mucosal / genetics
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Immunity, Mucosal / immunology*
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Leukocytes / drug effects
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Leukocytes / immunology
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Leukocytes / metabolism
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Lung / immunology*
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Lung / metabolism
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Lung / microbiology
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Macrophages / drug effects
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Macrophages / immunology
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Macrophages / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Nude
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Pneumonia, Bacterial / immunology
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Pneumonia, Bacterial / prevention & control
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Pseudomonas Infections / immunology
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Pseudomonas Infections / prevention & control
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Pseudomonas Vaccines / administration & dosage
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Pseudomonas Vaccines / immunology
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Reverse Transcriptase Polymerase Chain Reaction
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Survival Analysis
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Toll-Like Receptor 5 / genetics
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Toll-Like Receptor 5 / immunology*
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Toll-Like Receptor 5 / metabolism
Substances
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Antimicrobial Cationic Peptides
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Cathelicidins
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Pseudomonas Vaccines
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Toll-Like Receptor 5
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Flagellin