title: The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5.
abstract: The innate immune system recognizes pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, but not on the host. Toll-like receptors (TLRs) recognize PAMPs and mediate the production of cytokines necessary for the development of effective immunity. Flagellin, a principal component of bacterial flagella, is a virulence factor that is recognized by the innate immune system in organisms as diverse as flies, plants and mammals. Here we report that mammalian TLR5 recognizes bacterial flagellin from both Gram-positive and Gram-negative bacteria, and that activation of the receptor mobilizes the nuclear factor NF-kappaB and stimulates tumour necrosis factor-alpha production. TLR5-stimulating activity was purified from Listeria monocytogenes culture supernatants and identified as flagellin by tandem mass spectrometry. Expression of L. monocytogenes flagellin in non-flagellated Escherichia coli conferred on the bacterium the ability to activate TLR5, whereas deletion of the flagellin genes from Salmonella typhimurium abrogated TLR5-stimulating activity. All known TLRs signal through the adaptor protein MyD88. Mice challenged with bacterial flagellin rapidly produced systemic interleukin-6, whereas MyD88-null mice did not respond to flagellin. Our data suggest that TLR5, a member of the evolutionarily conserved Toll-like receptor family, has evolved to permit mammals specifically to detect flagellated bacterial pathogens.
authors.affiliation: Department of Immunology, University of Washington, Seattle 98195, USA.
authors.forename: F
authors.initials: F
authors.lastname: Hayashi
authors.forename: K D
authors.initials: KD
authors.lastname: Smith
authors.forename: A
authors.initials: A
authors.lastname: Ozinsky
authors.forename: T R
authors.initials: TR
authors.lastname: Hawn
authors.forename: E C
authors.initials: EC
authors.lastname: Yi
authors.forename: D R
authors.initials: DR
authors.lastname: Goodlett
authors.forename: J K
authors.initials: JK
authors.lastname: Eng
authors.forename: S
authors.initials: S
authors.lastname: Akira
authors.forename: D M
authors.initials: DM
authors.lastname: Underhill
authors.forename: A
authors.initials: A
authors.lastname: Aderem
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D029721:Drosophila Proteins; D004926:Escherichia coli; D005408:Flagellin / Q000235:genetics / Q000276:immunology*; D006090:Gram-Negative Bacteria / Q000276:immunology; D006094:Gram-Positive Bacteria / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D008089:Listeria monocytogenes / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology* / Q000378:metabolism; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism; D051198:Toll-Like Receptor 5; D051193:Toll-Like Receptors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D029721:Drosophila Proteins; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D051193:Toll-Like Receptors; D005408:Flagellin