Skip to main content
SpringerLink
Log in

TLR5 and Ipaf: dual sensors of bacterial flagellin in the innate immune system

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

The innate immune system precisely modulates the intensity of immune activation in response to infection. Flagellin is a microbe-associated molecular pattern that is present on both pathogenic and nonpathogenic bacteria. Macrophages and dendritic cells are able to determine the virulence of flagellated bacteria by sensing whether flagellin remains outside the mammalian cell, or if it gains access to the cytosol. Extracellular flagellin is detected by TLR5, which induces expression of proinflammatory cytokines, while flagellin within the cytosol of macrophages is detected through the Nod-like receptor (NLR) Ipaf, which activates caspase-1. In macrophages infected with Salmonella typhimurium or Legionella pneumophila, Ipaf becomes activated in response to flagellin that appears to be delivered to the cytosol via specific virulence factor transport systems (the SPI1 type III secretion system (T3SS) and the Dot/Icm type IV secretion system (T4SS), respectively). Thus, TLR5 responds more generally to flagellated bacteria, while Ipaf responds to bacteria that express both flagellin and virulence factors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Acehan D, Jiang X, Morgan DG, Heuser JE, Wang X, Akey CW (2002) Three-dimensional structure of the apoptosome: implications for assembly, pro caspase -9 binding, and activation. Mol Cell 9:423–432

    PubMed  CAS  Google Scholar 

  2. Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J (2004) NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 20:319–325

    PubMed  CAS  Google Scholar 

  3. Aguero-Rosenfeld ME, Yang XH, Nachamkin I (1990) Infection of adult Syrian hamsters with flagellar variants of Campylobacter jejuni. Infect Immun 58:2214–2219

    PubMed  CAS  Google Scholar 

  4. Akamine M, Higa F, Haranaga S, Tateyama M, Mori N, Heuner K, Fujita J (2007) Interferon-gamma reverses the evasion of Birc1e/Naip5 gene mediated murine macrophage immunity by Legionella pneumophila mutant lacking flagellin. Microbiol Immunol 51:279–287

    PubMed  CAS  Google Scholar 

  5. Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511

    PubMed  CAS  Google Scholar 

  6. Alaniz RC, Cummings LA, Bergman MA, Rassoulian-Barrett SL, Cookson BT (2006) Salmonella typhimurium coordinately regulates FliC location and reduces dendritic cell activation and antigen presentation to CD4+ T cells. J Immunol 177:3983–3993

    PubMed  CAS  Google Scholar 

  7. Aldridge P, Hughes KT (2002) Regulation of flagellar assembly. Curr Opin Microbiol 5:160–165

    PubMed  CAS  Google Scholar 

  8. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413:732–738

    PubMed  CAS  Google Scholar 

  9. Amer A, Franchi L, Kanneganti TD, Body-Malapel M, Ozoren N, Brady G, Meshinchi S, Jagirdar R, Gewirtz A, Akira S, Nunez G (2006) Regulation of Legionella phagosome maturation and infection through flagellin and host IPAF. J Biol Chem 281(46):35217–35223

    PubMed  CAS  Google Scholar 

  10. Andersen-Nissen E, Smith KD, Strobe KL, Barrett SL, Cookson BT, Logan SM, Aderem A (2005) Evasion of Toll-like receptor 5 by flagellated bacteria. Proc Natl Acad Sci U S A 102:9247–9252

    PubMed  CAS  Google Scholar 

  11. Andersen-Nissen E, Hawn TR, Smith KD, Nachman A, Lampano AE, Uematsu S, Akira S, Aderem A (2007) Cutting edge: Tlr5−/− mice are more susceptible to Escherichia coli urinary tract infection. J Immunol 178:4717–4720

    PubMed  CAS  Google Scholar 

  12. Andersen-Nissen E, Smith KD, Bonneau R, Strong RK, Aderem A (2007) A conserved surface on Toll-like receptor 5 recognizes bacterial flagellin. J Exp Med 204:393–403

    PubMed  CAS  Google Scholar 

  13. Andrutis KA, Fox JG, Schauer DB, Marini RP, Li X, Yan L, Josenhans C, Suerbaum S (1997) Infection of the ferret stomach by isogenic flagellar mutant strains of Helicobacter mustelae. Infect Immun 65:1962–1966

    PubMed  CAS  Google Scholar 

  14. Bao Q, Shi Y (2007) Apoptosome: a platform for the activation of initiator caspases. Cell Death Differ 14:56–65

    PubMed  CAS  Google Scholar 

  15. Beatson SA, Minamino T, Pallen MJ (2006) Variation in bacterial flagellins: from sequence to structure. Trends Microbiol 14:151–155

    PubMed  CAS  Google Scholar 

  16. Belkhadir Y, Subramaniam R, Dangl JL (2004) Plant disease resistance protein signaling: NBS-LRR proteins and their partners. Curr Opin Plant Biol 7:391–399

    PubMed  CAS  Google Scholar 

  17. Bell JK, Mullen GE, Leifer CA, Mazzoni A, Davies DR, Segal DM (2003) Leucine-rich repeats and pathogen recognition in Toll-like receptors. Trends Immunol 24:528–533

    PubMed  CAS  Google Scholar 

  18. Berin MC, Darfeuille-Michaud A, Egan LJ, Miyamoto Y, Kagnoff MF (2002) Role of EHEC O157:H7 virulence factors in the activation of intestinal epithelial cell NF-kappaB and MAP kinase pathways and the upregulated expression of interleukin 8. Cell Microbiol 4:635–648

    PubMed  CAS  Google Scholar 

  19. Boyden ED, Dietrich WF (2006) Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet 38:240–244

    PubMed  CAS  Google Scholar 

  20. Brennan MA, Cookson BT (2000) Salmonella induces macrophage death by caspase-1-dependent necrosis. Mol Microbiol 38:31–40

    PubMed  CAS  Google Scholar 

  21. Brown A, Hormaeche CE (1989) The antibody response to salmonellae in mice and humans studied by immunoblots and ELISA. Microb Pathog 6:445–454

    PubMed  CAS  Google Scholar 

  22. Bruggemann H, Cazalet C, Buchrieser C (2006) Adaptation of Legionella pneumophila to the host environment: role of protein secretion, effectors and eukaryotic-like proteins. Curr Opin Microbiol 9:86–94

    PubMed  Google Scholar 

  23. Chen LM, Kaniga K, Galan JE (1996) Salmonella spp. are cytotoxic for cultured macrophages. Mol Microbiol 21:1101–1115

    PubMed  CAS  Google Scholar 

  24. Chen Y, Smith MR, Thirumalai K, Zychlinsky A (1996) A bacterial invasion induces macrophage apoptosis by binding directly to ICE. EMBO J 15:3853–3860

    PubMed  CAS  Google Scholar 

  25. Chilcott GS, Hughes KT (2000) Coupling of flagellar gene expression to flagellar assembly in Salmonella enterica serovar Typhimurium and Escherichia coli. Microbiol Mol Biol Rev 64:694–708

    PubMed  CAS  Google Scholar 

  26. Chinchilla D, Bauer Z, Regenass M, Boller T, Felix G (2006) The Arabidopsis receptor kinase FLS2 binds flg22 and determines the specificity of flagellin perception. Plant Cell 18:465–476

    PubMed  CAS  Google Scholar 

  27. Collazo CM, Galan JE (1997) The invasion-associated type III system of Salmonella typhimurium directs the translocation of Sip proteins into the host cell. Mol Microbiol 24:747–756

    PubMed  CAS  Google Scholar 

  28. Cookson BT, Bevan MJ (1997) Identification of a natural T cell epitope presented by Salmonella-infected macrophages and recognized by T cells from orally immunized mice. J Immunol 158:4310–4319

    PubMed  CAS  Google Scholar 

  29. Cookson BT, Brennan MA (2001) Pro-inflammatory programmed cell death. Trends Microbiol 9:113–114

    PubMed  CAS  Google Scholar 

  30. Damiano JS, Stehlik C, Pio F, Godzik A, Reed JC (2001) CLAN, a novel human CED-4-like gene. Genomics 75:77–83

    PubMed  CAS  Google Scholar 

  31. Damiano JS, Newman RM, Reed JC (2004) Multiple roles of CLAN (caspase-associated recruitment domain, leucine-rich repeat, and NAIP CIIA HET-E, and TP1-containing protein) in the mammalian innate immune response. J Immunol 173:6338–6345

    PubMed  CAS  Google Scholar 

  32. Damiano JS, Oliveira V, Welsh K, Reed JC (2004) Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses. Biochem J 381:213–219

    PubMed  CAS  Google Scholar 

  33. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529–1531

    PubMed  CAS  Google Scholar 

  34. Diez E, Lee SH, Gauthier S, Yaraghi Z, Tremblay M, Vidal S, Gros P (2003) Birc1e is the gene within the Lgn1 locus associated with resistance to Legionella pneumophila. Nat Genet 33:55–60

    PubMed  CAS  Google Scholar 

  35. Diker KS, Hascelik G, Diker S (1992) Colonization of infant mice with flagellar variants of Campylobacter jejuni. Acta Microbiol Hung 39:133–136

    PubMed  CAS  Google Scholar 

  36. Dinarello CA (1998) Interleukin-1 beta, interleukin-18, and the interleukin-1 beta converting enzyme. Ann N Y Acad Sci 856:1–11

    PubMed  CAS  Google Scholar 

  37. Ding Z, Christie PJ (2003) Agrobacterium tumefaciens twin-arginine-dependent translocation is important for virulence, flagellation, and chemotaxis but not type IV secretion. J Bacteriol 185:760–771

    PubMed  CAS  Google Scholar 

  38. Donnelly MA, Steiner TS (2002) Two nonadjacent regions in enteroaggregative Escherichia coli flagellin are required for activation of toll-like receptor 5. J Biol Chem 277:40456–40461

    PubMed  CAS  Google Scholar 

  39. Druilhe A, Srinivasula SM, Razmara M, Ahmad M, Alnemri ES (2001) Regulation of IL-1beta generation by Pseudo-ICE and ICEBERG, two dominant negative caspase recruitment domain proteins. Cell Death Differ 8:649–657

    PubMed  CAS  Google Scholar 

  40. Eaton KA, Morgan DR, Krakowka S (1989) Campylobacter pylori virulence factors in gnotobiotic piglets. Infect Immun 57:1119-1125

    PubMed  CAS  Google Scholar 

  41. Eaton KA, Suerbaum S, Josenhans C, Krakowka S (1996) Colonization of gnotobiotic piglets by Helicobacter pylori deficient in two flagellin genes. Infect Immun 64:2445–2448

    PubMed  CAS  Google Scholar 

  42. Eaves-Pyles T, Murthy K, Liaudet L, Virag L, Ross G, Soriano FG, Szabo C, Salzman AL (2001) Flagellin, a novel mediator of Salmonella-induced epithelial activation and systemic inflammation: I kappa B alpha degradation, induction of nitric oxide synthase, induction of proinflammatory mediators, and cardiovascular dysfunction. J Immunol 166:1248–1260

    PubMed  CAS  Google Scholar 

  43. Eaves-Pyles TD, Wong HR, Odoms K, Pyles RB (2001) Salmonella flagellin-dependent proinflammatory responses are localized to the conserved amino and carboxyl regions of the protein. J Immunol 167:7009–7016

    PubMed  CAS  Google Scholar 

  44. Eckmann L, Kagnoff MF (2001) Cytokines in host defense against Salmonella. Microbes Infect 3:1191–1200

    PubMed  CAS  Google Scholar 

  45. Ehrbar K, Mirold S, Friebel A, Stender S, Hardt WD (2002) Characterization of effector proteins translocated via the SPI1 type III secretion system of Salmonella typhimurium. Int J Med Microbiol 291:479–485

    PubMed  CAS  Google Scholar 

  46. Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E, Bailly-Maitre B, Volkmann N, Hanein D, Rouiller I, Reed JC (2007) Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol Cell 25:713–724

    PubMed  CAS  Google Scholar 

  47. Feuillet V, Medjane S, Mondor I, Demaria O, Pagni PP, Galan JE, Flavell RA, Alexopoulou L (2006) Involvement of Toll-like receptor 5 in the recognition of flagellated bacteria. Proc Natl Acad Sci U S A 103:12487–12492

    PubMed  CAS  Google Scholar 

  48. Fierer J (2001) Polymorphonuclear leukocytes and innate immunity to Salmonella infections in mice. Microbes Infect 3:1233–1237

    PubMed  CAS  Google Scholar 

  49. Fink SL, Cookson BT (2005) Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect Immun 73:1907–1916

    PubMed  CAS  Google Scholar 

  50. Fink SL, Cookson BT (2006) Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages. Cell Microbiol 8:1812–1825

    PubMed  CAS  Google Scholar 

  51. Fitzgerald KA, Palsson-McDermott EM, Bowie AG, Jefferies CA, Mansell AS, Brady G, Brint E, Dunne A, Gray P, Harte MT, McMurray D, Smith DE, Sims JE, Bird TA, O’Neill LA (2001) Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413:78–83

    PubMed  CAS  Google Scholar 

  52. Flo TH, Smith KD, Sato S, Rodriguez DJ, Holmes MA, Strong RK, Akira S, Aderem A (2004) Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432:917–921

    PubMed  CAS  Google Scholar 

  53. Fortier A, de Chastellier C, Balor S, Gros P (2007) Birc1e/Naip5 rapidly antagonizes modulation of phagosome maturation by Legionella pneumophila. Cell Microbiol 9:910–923

    PubMed  CAS  Google Scholar 

  54. Franchi L, Amer A, Body-Malapel M, Kanneganti TD, Ozoren N, Jagirdar R, Inohara N, Vandenabeele P, Bertin J, Coyle A, Grant EP, Nunez G (2006) Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages. Nat Immunol 7:576–582

    PubMed  CAS  Google Scholar 

  55. Frankel G, Newton SM, Schoolnik GK, Stocker BA (1989) Intragenic recombination in a flagellin gene: characterization of the H1-j gene of Salmonella typhi. EMBO J 8:3149–3152

    PubMed  CAS  Google Scholar 

  56. Fujita T, Onoguchi K, Onomoto K, Hirai R, Yoneyama M (2007) Triggering antiviral response by RIG-I-related RNA helicases. Biochimie (in press)

  57. Geddes BJ, Wang L, Huang WJ, Lavellee M, Manji GA, Brown M, Jurman M, Cao J, Morgenstern J, Merriam S, Glucksmann MA, DiStefano PS, Bertin J (2001) Human CARD12 is a novel CED4/Apaf-1 family member that induces apoptosis. Biochem Biophys Res Commun 284:77–82

    PubMed  CAS  Google Scholar 

  58. Gewirtz AT, Navas TA, Lyons S, Godowski PJ, Madara JL (2001) Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J Immunol 167:1882–1885

    PubMed  CAS  Google Scholar 

  59. Gewirtz AT, Yu Y, Krishna US, Israel DA, Lyons SL, Peek RM Jr (2004) Helicobacter pylori flagellin evades toll-like receptor 5-mediated innate immunity. J Infect Dis 189:1914–1920

    PubMed  CAS  Google Scholar 

  60. Gewirtz AT (2006) Flag in the crossroads: flagellin modulates innate and adaptive immunity. Curr Opin Gastroenterol 22:8–12

    PubMed  CAS  Google Scholar 

  61. Ghayur T, Banerjee S, Hugunin M, Butler D, Herzog L, Carter A, Quintal L, Sekut L, Talanian R, Paskind M, Wong W, Kamen R, Tracey D, Allen H (1997) caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature 386:619–623

    PubMed  CAS  Google Scholar 

  62. Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, Philpott DJ, Sansonetti PJ (2003) Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 278:8869–8872

    PubMed  CAS  Google Scholar 

  63. Gohda J, Matsumura T, Inoue J (2004) Cutting edge: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent pathway in TLR signaling. J Immunol 173:2913–2917

    PubMed  CAS  Google Scholar 

  64. Gomez-Gomez L, Boller T (2000) FLS2: an LRR receptor-like kinase involved in the perception of the bacterial elicitor flagellin in Arabidopsis. Mol Cell 5:1003–1011

    PubMed  CAS  Google Scholar 

  65. Gomez-Gomez L, Boller T (2002) Flagellin perception: a paradigm for innate immunity. Trends Plant Sci 7:251–256

    PubMed  CAS  Google Scholar 

  66. Gracie JA, Robertson SE, McInnes IB (2003) Interleukin-18. J Leukoc Biol 73:213–224

    PubMed  CAS  Google Scholar 

  67. Gu Y, Kuida K, Tsutsui H, Ku G, Hsiao K, Fleming MA, Hayashi N, Higashino K, Okamura H, Nakanishi K, Kurimoto M, Tanimoto T, Flavell RA, Sato V, Harding MW, Livingston DJ, Su MS (1997) Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme. Science 275:206–209

    PubMed  CAS  Google Scholar 

  68. Gutierrez O, Pipaon C, Fernandez-Luna JL (2004) Ipaf is upregulated by tumor necrosis factor-alpha in human leukemia cells. FEBS Lett 568:79–82

    PubMed  CAS  Google Scholar 

  69. Hawn TR, Verbon A, Lettinga KD, Zhao LP, Li SS, Laws RJ, Skerrett SJ, Beutler B, Schroeder L, Nachman A, Ozinsky A, Smith KD, Aderem A (2003) A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires’ disease. J Exp Med 198:1563–1572

    PubMed  CAS  Google Scholar 

  70. Hawn TR, Smith KD, Aderem A, Skerrett SJ (2006) Myeloid differentiation primary response gene (88)- and toll-like receptor 2-deficient mice are susceptible to infection with aerosolized Legionella pneumophila. J Infect Dis 193:1693–1702

    PubMed  CAS  Google Scholar 

  71. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A (2001) The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410:1099–1103

    PubMed  CAS  Google Scholar 

  72. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S (2004) Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303:1526–1529

    PubMed  CAS  Google Scholar 

  73. Hernandez LD, Pypaert M, Flavell RA, Galan JE (2003) A Salmonella protein causes macrophage cell death by inducing autophagy. J Cell Biol 163:1123–1131

    PubMed  CAS  Google Scholar 

  74. Hersh D, Monack DM, Smith MR, Ghori N, Falkow S, Zychlinsky A (1999) The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1. Proc Natl Acad Sci U S A 96:2396–2401

    PubMed  CAS  Google Scholar 

  75. Horng T, Barton GM, Flavell RA, Medzhitov R (2002) The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature 420:329–333

    PubMed  CAS  Google Scholar 

  76. Hueck CJ (1998) Type III protein secretion systems in bacterial pathogens of animals and plants. Microbiol Mol Biol Rev 62:379–433

    PubMed  CAS  Google Scholar 

  77. Hueffer K, Galan JE (2004) Salmonella-induced macrophage death: multiple mechanisms, different outcomes. Cell Microbiol 6:1019–1025

    PubMed  CAS  Google Scholar 

  78. Hughes KT, Gillen KL, Semon MJ, Karlinsey JE (1993) Sensing structural intermediates in bacterial flagellar assembly by export of a negative regulator. Science 262:1277–1280

    PubMed  CAS  Google Scholar 

  79. Humke EW, Shriver SK, Starovasnik MA, Fairbrother WJ, Dixit VM (2000) ICEBERG: a novel inhibitor of interleukin-1beta generation. Cell 103:99–111

    PubMed  CAS  Google Scholar 

  80. Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, Fukase K, Inamura S, Kusumoto S, Hashimoto M, Foster SJ, Moran AP, Fernandez-Luna JL, Nunez G (2003) Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn’s disease. J Biol Chem 278:5509–5512

    PubMed  CAS  Google Scholar 

  81. Ivison SM, Khan MA, Graham NR, Bernales CQ, Kaleem A, Tirling CO, Cherkasov A, Steiner TS (2007) A phosphorylation site in the Toll-like receptor 5 TIR domain is required for inflammatory signalling in response to flagellin. Biochem Biophys Res Commun 352:936–941

    PubMed  CAS  Google Scholar 

  82. Jones JD, Dangl JL (2006) The plant immune system. Nature 444:323–329

    PubMed  CAS  Google Scholar 

  83. Kanneganti TD, Body-Malapel M, Amer A, Park JH, Whitfield J, Taraporewala ZF, Miller D, Patton JT, Inohara N, Nunez G (2006) Critical role for cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J Biol Chem 281:36560–36568

    PubMed  CAS  Google Scholar 

  84. Kanneganti TD, Ozoren N, Body-Malapel M, Amer A, Park JH, Franchi L, Whitfield J, Barchet W, Colonna M, Vandenabeele P, Bertin J, Coyle A, Grant EP, Akira S, Nunez G (2006) Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440:233–236

    PubMed  CAS  Google Scholar 

  85. Kavermann H, Burns BP, Angermuller K, Odenbreit S, Fischer W, Melchers K, Haas R (2003) Identification and characterization of Helicobacter pylori genes essential for gastric colonization. J Exp Med 197:813–822

    PubMed  CAS  Google Scholar 

  86. Khan MA, Kang J, Steiner TS (2004) Enteroaggregative Escherichia coli flagellin-induced interleukin-8 secretion requires Toll-like receptor 5-dependent p38 MAP kinase activation. Immunology 112:651–660

    PubMed  CAS  Google Scholar 

  87. Kimbrough TG, Miller SI (2002) Assembly of the type III secretion needle complex of Salmonella typhimurium. Microbes Infect 4:75–82

    PubMed  CAS  Google Scholar 

  88. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, Flavell RA (2005) Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307:731–734

    PubMed  CAS  Google Scholar 

  89. Kuida K, Lippke JA, Ku G, Harding MW, Livingston DJ, Su MS, Flavell RA (1995) Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. Science 267:2000–2003

    PubMed  CAS  Google Scholar 

  90. Lamkanfi M, Denecker G, Kalai M, D’Hondt K, Meeus A, Declercq W, Saelens X, Vandenabeele P (2004) INCA, a novel human caspase recruitment domain protein that inhibits interleukin-1beta generation. J Biol Chem 279:51729–51738

    PubMed  CAS  Google Scholar 

  91. Lara-Tejero M, Sutterwala FS, Ogura Y, Grant EP, Bertin J, Coyle AJ, Flavell RA, Galan JE (2006) Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis. J Exp Med 203:1407–1412

    PubMed  CAS  Google Scholar 

  92. Lee SH, Galan JE (2004) Salmonella type III secretion-associated chaperones confer secretion-pathway specificity. Mol Microbiol 51:483–495

    PubMed  CAS  Google Scholar 

  93. Li P, Allen H, Banerjee S, Franklin S, Herzog L, Johnston C, McDowell J, Paskind M, Rodman L, Salfeld J et al (1995) Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. Cell 80:401–411

    PubMed  CAS  Google Scholar 

  94. Lu C, Wang A, Wang L, Dorsch M, Ocain TD, Xu Y (2005) Nucleotide binding to CARD12 and its role in CARD12-mediated caspase-1 activation. Biochem Biophys Res Commun 331:1114–1119

    PubMed  CAS  Google Scholar 

  95. Lund JM, Alexopoulou L, Sato A, Karow M, Adams NC, Gale NW, Iwasaki A, Flavell RA (2004) Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc Natl Acad Sci U S A 101:5598–5603

    PubMed  CAS  Google Scholar 

  96. Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, Roose-Girma M, Erickson S, Dixit VM (2004) Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430:213–218

    PubMed  CAS  Google Scholar 

  97. Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monack DM, Dixit VM (2006) Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440:228–232

    PubMed  CAS  Google Scholar 

  98. Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10:417–426

    PubMed  CAS  Google Scholar 

  99. Martinon F, Agostini L, Meylan E, Tschopp J (2004) Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome. Curr Biol 14:1929–1934

    PubMed  CAS  Google Scholar 

  100. Martinon F, Tschopp J (2004) Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 117:561–574

    PubMed  CAS  Google Scholar 

  101. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J (2006) Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237–241

    PubMed  CAS  Google Scholar 

  102. Martinon F, Tschopp J (2006) Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death Differ 14(1):10–22

    PubMed  Google Scholar 

  103. Masumoto J, Dowds TA, Schaner P, Chen FF, Ogura Y, Li M, Zhu L, Katsuyama T, Sagara J, Taniguchi S, Gumucio DL, Nunez G, Inohara N (2003) ASC is an activating adaptor for NF-kappa B and caspase-8-dependent apoptosis. Biochem Biophys Res Commun 303:69–73

    PubMed  CAS  Google Scholar 

  104. McDermott PF, Ciacci-Woolwine F, Snipes JA, Mizel SB (2000) High-affinity interaction between gram-negative flagellin and a cell surface polypeptide results in human monocyte activation. Infect Immun 68:5525–5529

    PubMed  CAS  Google Scholar 

  105. Means TK, Hayashi F, Smith KD, Aderem A, Luster AD (2003) The Toll-like receptor 5 stimulus bacterial flagellin induces maturation and chemokine production in human dendritic cells. J Immunol 170:5165–5175

    PubMed  CAS  Google Scholar 

  106. Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW, Miller SI, Aderem A (2006) Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol 7:569–575

    PubMed  CAS  Google Scholar 

  107. Miggin SM, Palsson-McDermott E, Dunne A, Jefferies C, Pinteaux E, Banahan K, Murphy C, Moynagh P, Yamamoto M, Akira S, Rothwell N, Golenbock D, Fitzgerald KA, O’Neill LA (2007) NF-kappaB activation by the Toll-IL-1 receptor domain protein MyD88 adapter-like is regulated by caspase-1. Proc Natl Acad Sci U S A 104:3372–3377

    PubMed  CAS  Google Scholar 

  108. Molofsky AB, Shetron-Rama LM, Swanson MS (2005) Components of the Legionella pneumophila flagellar regulon contribute to multiple virulence traits, including lysosome avoidance and macrophage death. Infect Immun 73:5720–5734

    PubMed  CAS  Google Scholar 

  109. Molofsky AB, Byrne BG, Whitfield NN, Madigan CA, Fuse ET, Tateda K, Swanson MS (2006) Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection. J Exp Med 203:1093–1104

    PubMed  CAS  Google Scholar 

  110. Moors MA, Li L, Mizel SB (2001) Activation of interleukin-1 receptor-associated kinase by gram-negative flagellin. Infect Immun 69:4424–4429

    PubMed  CAS  Google Scholar 

  111. Murthy KG, Deb A, Goonesekera S, Szabo C, Salzman AL (2004) Identification of conserved domains in Salmonella muenchen flagellin that are essential for its ability to activate TLR5 and to induce an inflammatory response in vitro. J Biol Chem 279:5667–5675

    PubMed  CAS  Google Scholar 

  112. Ozoren N, Masumoto J, Franchi L, Kanneganti TD, Body-Malapel M, Erturk I, Jagirdar R, Zhu L, Inohara N, Bertin J, Coyle A, Grant EP, Nunez G (2006) Distinct roles of TLR2 and the adaptor ASC in IL-1beta/IL-18 secretion in response to Listeria monocytogenes. J Immunol 176:4337–4342

    PubMed  Google Scholar 

  113. Pan Q, Mathison J, Fearns C, Kravchenko VV, Correia JD, Hoffman HM, Kobayashi KS, Bertin J, Grant EP, Coyle AJ, Sutterwala FS, Ogura Y, Flavell RA, Ulevitch RJ (2007) MDP-induced interleukin-1{beta} processing requires Nod2 and CIAS1/NALP3. J Leukoc Biol (in press)

  114. Park HH, Logette E, Raunser S, Cuenin S, Walz T, Tschopp J, Wu H (2007) Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex. Cell 128:533–546

    PubMed  CAS  Google Scholar 

  115. Patel JC, Galan JE (2005) Manipulation of the host actin cytoskeleton by Salmonella—all in the name of entry. Curr Opin Microbiol 8:10–15

    PubMed  CAS  Google Scholar 

  116. Pavlovskis OR, Rollins DM, Haberberger RL Jr, Green AE, Habash L, Strocko S, Walker RI (1991) Significance of flagella in colonization resistance of rabbits immunized with Campylobacter spp. Infect Immun 59:2259–2264

    PubMed  CAS  Google Scholar 

  117. Picard C, Puel A, Bonnet M, Ku CL, Bustamante J, Yang K, Soudais C, Dupuis S, Feinberg J, Fieschi C, Elbim C, Hitchcock R, Lammas D, Davies G, Al-Ghonaium A, Al-Rayes H, Al-Jumaah S, Al-Hajjar S, Al-Mohsen IZ, Frayha HH, Rucker R, Hawn TR, Aderem A, Tufenkeji H, Haraguchi S, Day NK, Good RA, Gougerot-Pocidalo MA, Ozinsky A, Casanova JL (2003) Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299:2076–2079

    PubMed  CAS  Google Scholar 

  118. Poyet JL, Srinivasula SM, Tnani M, Razmara M, Fernandes-Alnemri T, Alnemri ES (2001) Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1. J Biol Chem 276:28309–28313

    PubMed  CAS  Google Scholar 

  119. Ramos HC, Rumbo M, Sirard JC (2004) Bacterial flagellins: mediators of pathogenicity and host immune responses in mucosa. Trends Microbiol 12:509–517

    PubMed  CAS  Google Scholar 

  120. Ren T, Zamboni DS, Roy CR, Dietrich WF, Vance RE (2006) Flagellin-deficient Legionella mutants evade caspase-1- and Naip5-mediated macrophage immunity. PLoS Pathog 2:e18

    PubMed  Google Scholar 

  121. Rhee SH, Kim H, Moyer MP, Pothoulakis C (2006) Role of MyD88 in phosphatidylinositol 3-kinase activation by flagellin/toll-like receptor 5 engagement in colonic epithelial cells. J Biol Chem 281:18560–18568

    PubMed  CAS  Google Scholar 

  122. Saleh M, Mathison JC, Wolinski MK, Bensinger SJ, Fitzgerald P, Droin N, Ulevitch RJ, Green DR, Nicholson DW (2006) Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice. Nature 440:1064–1068

    PubMed  CAS  Google Scholar 

  123. Samatey FA, Imada K, Nagashima S, Vonderviszt F, Kumasaka T, Yamamoto M, Namba K (2001) Structure of the bacterial flagellar protofilament and implications for a switch for supercoiling. Nature 410:331–337

    PubMed  CAS  Google Scholar 

  124. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, Gorman DM, Bazan JF, Kastelein RA (2005) IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23:479–490

    PubMed  CAS  Google Scholar 

  125. Segal G, Feldman M, Zusman T (2005) The Icm/Dot type-IV secretion systems of Legionella pneumophila and Coxiella burnetii. FEMS Microbiol Rev 29:65–81

    PubMed  CAS  Google Scholar 

  126. Shi Y (2002) Mechanisms of caspase activation and inhibition during apoptosis. Mol Cell 9:459–470

    PubMed  CAS  Google Scholar 

  127. Smith KD, Andersen-Nissen E, Hayashi F, Strobe K, Bergman MA, Barrett SL, Cookson BT, Aderem A (2003) Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility. Nat Immunol 4:1247–1253

    PubMed  CAS  Google Scholar 

  128. Srinivasula SM, Poyet JL, Razmara M, Datta P, Zhang Z, Alnemri ES (2002) The PYRIN-CARD protein ASC is an activating adaptor for caspase-1. J Biol Chem 277:21119–21122

    PubMed  CAS  Google Scholar 

  129. Steiner TS (2007) How flagellin and toll-like receptor 5 contribute to enteric infection. Infect Immun 75:545–552

    PubMed  CAS  Google Scholar 

  130. Sutterwala FS, Ogura Y, Szczepanik M, Lara-Tejero M, Lichtenberger GS, Grant EP, Bertin J, Coyle AJ, Galan JE, Askenase PW, Flavell RA (2006) Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 24:317–327

    PubMed  CAS  Google Scholar 

  131. Takeda K, Tsutsui H, Yoshimoto T, Adachi O, Yoshida N, Kishimoto T, Okamura H, Nakanishi K, Akira S (1998) Defective NK cell activity and Th1 response in IL-18-deficient mice. Immunity 8:383–390

    PubMed  CAS  Google Scholar 

  132. Tateda K, Moore TA, Newstead MW, Tsai WC, Zeng X, Deng JC, Chen G, Reddy R, Yamaguchi K, Standiford TJ (2001) Chemokine-dependent neutrophil recruitment in a murine model of Legionella pneumonia: potential role of neutrophils as immunoregulatory cells. Infect Immun 69:2017–2024

    PubMed  CAS  Google Scholar 

  133. Thakar J, Schleinkofer K, Borner C, Dandekar T (2006) RIP death domain structural interactions implicated in TNF-mediated proliferation and survival. Proteins 63:413–423

    PubMed  CAS  Google Scholar 

  134. Uematsu S, Jang MH, Chevrier N, Guo Z, Kumagai Y, Yamamoto M, Kato H, Sougawa N, Matsui H, Kuwata H, Hemmi H, Coban C, Kawai T, Ishii KJ, Takeuchi O, Miyasaka M, Takeda K, Akira S (2006) Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c+ lamina propria cells. Nat Immunol 7:868–874

    PubMed  CAS  Google Scholar 

  135. van der Woude MW, Baumler AJ (2004) Phase and antigenic variation in bacteria. Clin Microbiol Rev 17:581–611

    PubMed  Google Scholar 

  136. Verma A, Arora SK, Kuravi SK, Ramphal R (2005) Roles of specific amino acids in the N terminus of Pseudomonas aeruginosa flagellin and of flagellin glycosylation in the innate immune response. Infect Immun 73:8237–8246

    PubMed  CAS  Google Scholar 

  137. Vonderviszt F, Kanto S, Aizawa S, Namba K (1989) Terminal regions of flagellin are disordered in solution. J Mol Biol 209:127–133

    PubMed  CAS  Google Scholar 

  138. Weber CH, Vincenz C (2001) A docking model of key components of the DISC complex: death domain superfamily interactions redefined. FEBS Lett 492:171–176

    PubMed  CAS  Google Scholar 

  139. Weber CH, Vincenz C (2001) The death domain superfamily: a tale of two interfaces? Trends Biochem Sci 26:475–481

    PubMed  CAS  Google Scholar 

  140. Wright EK, Goodart SA, Growney JD, Hadinoto V, Endrizzi MG, Long EM, Sadigh K, Abney AL, Bernstein-Hanley I, Dietrich WF (2003) Naip5 affects host susceptibility to the intracellular pathogen Legionella pneumophila. Curr Biol 13:27–36

    PubMed  CAS  Google Scholar 

  141. Yonekura K, Maki-Yonekura S, Namba K (2002) Growth mechanism of the bacterial flagellar filament. Res Microbiol 153:191–197

    PubMed  CAS  Google Scholar 

  142. Yonekura K, Maki-Yonekura S, Namba K (2003) Complete atomic model of the bacterial flagellar filament by electron cryomicroscopy. Nature 424:643–650

    PubMed  CAS  Google Scholar 

  143. Yu X, Acehan D, Menetret JF, Booth CR, Ludtke SJ, Riedl SJ, Shi Y, Wang X, Akey CW (2005) A structure of the human apoptosome at 12.8 A resolution provides insights into this cell death platform. Structure 13:1725–1735

    PubMed  CAS  Google Scholar 

  144. Yu Y, Nagai S, Wu H, Neish AS, Koyasu S, Gewirtz AT (2006) TLR5-mediated phosphoinositide 3-kinase activation negatively regulates flagellin-induced proinflammatory gene expression. J Immunol 176:6194–6201

    PubMed  CAS  Google Scholar 

  145. Zamboni DS, Kobayashi KS, Kohlsdorf T, Ogura Y, Long EM, Vance RE, Kuida K, Mariathasan S, Dixit VM, Flavell RA, Dietrich WF, Roy CR (2006) The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nat Immunol 7:318–325

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute for Systems Biology, 1441 N 34th St, Seattle, WA, 98103, USA

    Edward A. Miao, Erica Andersen-Nissen, Sarah E. Warren & Alan Aderem

  2. Department of Immunology, University of Washington, Seattle, WA, 98195, USA

    Erica Andersen-Nissen & Sarah E. Warren

Authors
  1. Edward A. Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Erica Andersen-Nissen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sarah E. Warren
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alan Aderem
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alan Aderem.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Miao, E.A., Andersen-Nissen, E., Warren, S.E. et al. TLR5 and Ipaf: dual sensors of bacterial flagellin in the innate immune system. Semin Immunopathol 29, 275–288 (2007). https://doi.org/10.1007/s00281-007-0078-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-007-0078-z

Keywords

Search

Navigation