title: Human Toll-like receptor 4 recognizes host-specific LPS modifications.
abstract: Lipopolysaccharide (LPS) is the principal proinflammatory component of the Gram-negative bacterial envelope and is recognized by the Toll-like receptor 4 (TLR4)-MD-2 receptor complex. Bacteria can alter the acylation state of their LPS in response to environmental changes. One opportunistic bacterium, Pseudomonas aeruginosa, synthesizes more highly acylated (hexa-acylated) LPS structures during adaptation to the cystic fibrosis airway. Here we show that human, but not murine, TLR4-MD-2 recognizes this adaptation and transmits robust proinflammatory signals in response to hexa-acylated but not penta-acylated LPS from P. aeruginosa. Whereas responses to lipidIVA and taxol are dependent on murine MD-2, discrimination of P. aeruginosa LPS structures is mediated by an 82-amino-acid region of human TLR4 that is hypervariable across species. Thus, in contrast to mice, humans use TLR4 to recognize a molecular signature of bacterial-host adaptation to modulate the innate immune response.
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Adeline M
authors.initials: AM
authors.lastname: Hajjar
authors.forename: Robert K
authors.initials: RK
authors.lastname: Ernst
authors.forename: Jeff H
authors.initials: JH
authors.lastname: Tsai
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Wilson
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Miller
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology*; D001665:Binding Sites; D002240:Carbohydrate Sequence; D002454:Cell Differentiation; D002460:Cell Line; D029721:Drosophila Proteins; D006801:Humans; D007223:Infant; D008050:Lipid A / Q000737:chemistry / Q000276:immunology*; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D011550:Pseudomonas aeruginosa / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D000954:Antigens, Surface; D029721:Drosophila Proteins; C495377:LY96 protein, human; D008050:Lipid A; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors