title: Pseudomonas aeruginosa lipid A diversity and its recognition by Toll-like receptor 4.
abstract: Lipid A is the pro-inflammatory component of bacterial lipopolysaccharide, the major surface component of Gram-negative bacteria. Gram-negative bacteria alter the structure of lipid A in response to specific environmental conditions including those found upon colonization of a host. The opportunistic pathogen Pseudomonas aeruginosa synthesizes a unique hexa-acylated lipid A containing palmitate and aminoarabinose during adaptation to the cystic fibrosis airway. Different lipid A species are observed in P. aeruginosa isolated from non-cystic fibrosis associated infections. Here we report that P. aeruginosa isolates from the airway of a cystic fibrosis patient with severe pulmonary disease synthesized a novel hepta-acylated lipid A. Cystic fibrosis-specific P. aeruginosa lipid A modifications result in resistance to host antimicrobial peptides and increased recognition by human Toll-like receptor 4 (TLR4). Using P. aeruginosa lipid A with different levels of acylation, we identified a 222 amino acid region in the extracellular portion of human TLR4 that is required for the differential recognition of cystic fibrosis-specific lipid A. P. aeruginosa adaptation to the human airway may, therefore, play a fundamental role in the progressive lung damage associated with cystic fibrosis.
authors.affiliation: Department of Medicine, HSB K-155, Box 357710, University of Washington, Seattle, WA 98195, USA. rkernst@u.washington.edu
authors.forename: Robert K
authors.initials: RK
authors.lastname: Ernst
authors.forename: Adeline M
authors.initials: AM
authors.lastname: Hajjar
authors.forename: Jeff H
authors.initials: JH
authors.lastname: Tsai
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Moskowitz
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Wilson
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Miller
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D003550:Cystic Fibrosis / Q000150:complications / Q000382:microbiology; D014644:Genetic Variation; D006801:Humans; D007668:Kidney / Q000166:cytology; D008050:Lipid A / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000737:chemistry / Q000276:immunology / Q000302:isolation & purification / Q000494:pharmacology*; D013058:Mass Spectrometry; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D008970:Molecular Weight; D011550:Pseudomonas aeruginosa / Q000737:chemistry* / Q000235:genetics / Q000254:growth & development / Q000302:isolation & purification; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection
chemical_list: D008050:Lipid A; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors