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Toll-like receptors and innate immunity

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Abstract

The innate immune system is an evolutionally conserved host defense mechanism against pathogens. Innate immune responses are initiated by pattern recognition receptors (PRRs), which recognize specific structures of microorganisms. Among them, Toll-like receptors (TLRs) are capable of sensing organisms ranging from bacteria to fungi, protozoa, and viruses, and play a major role in innate immunity. However, TLRs recognize pathogens either on the cell surface or in the lysosome/endosome compartment. Recently, cytoplasmic PRRs have been identified to detect pathogens that have invaded cytosols. In this review, we focus on the functions of PRRs in innate immunity and their downstream signaling cascades.

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References

  1. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA (1996) The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973–983

    PubMed  CAS  Google Scholar 

  2. Medzhitov R, Janeway CJ (1997) Innate immunity: the virtues of a nonclonal system of recognition. Cell 91:295–298

    PubMed  CAS  Google Scholar 

  3. Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801

    PubMed  CAS  Google Scholar 

  4. Strober W, Murray PJ, Kitani A, Watanabe T (2006) Signalling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol 6:9–20

    PubMed  CAS  Google Scholar 

  5. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S, Fujita T (2004) The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 5:730–737

    PubMed  CAS  Google Scholar 

  6. Kato H, Sato S, Yoneyama M, Yamamoto M, Uematsu S, Matsui K, Tsujimura T, Takeda K, Fujita T, Takeuchi O, Akira S (2005) Cell type-specific involvement of RIG-I in antiviral response. Immunity 23:19–28

    PubMed  CAS  Google Scholar 

  7. Shimazu R, Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake K, Kimoto M (1999) MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med 189:1777–1782

    PubMed  CAS  Google Scholar 

  8. Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev Immunol 21:335–376

    PubMed  CAS  Google Scholar 

  9. Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, Ogawa T, Takeda K, Akira S (1999) Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 11:443–451

    PubMed  CAS  Google Scholar 

  10. Netea MG, van Deuren M, Kullberg BJ, Cavaillon JM, Van der Meer JW (2002) Does the shape of lipid A determine the interaction of LPS with Toll-like receptors? Trends Immunol 23:135–139

    PubMed  CAS  Google Scholar 

  11. Hashimoto M, Asai Y, Ogawa T (2004) Separation and structural analysis of lipoprotein in a lipopolysaccharide preparation from Porphyromonas gingivalis. Int Immunol 16:1431–1437

    PubMed  CAS  Google Scholar 

  12. Akira S (2004) Toll receptor families: structure and function. Semin Immunol 16:1–2

    PubMed  CAS  Google Scholar 

  13. Takeuchi O, Kawai T, Muhlradt PF, Morr M, Radolf JD, Zychlinsky A, Takeda K, Akira S (2001) Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol 13:933–940

    PubMed  CAS  Google Scholar 

  14. Takeuchi O, Sato S, Horiuchi T, Hoshino K, Takeda K, Dong Z, Modlin RL, Akira S (2002) Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J Immunol 169:10–14

    PubMed  CAS  Google Scholar 

  15. Alexopoulou L, Thomas V, Schnare M, Lobet Y, Anguita J, Schoen RT, Medzhitov R, Fikrig E, Flavell RA (2002) Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice. Nat Med 8:878–884

    PubMed  CAS  Google Scholar 

  16. Hoebe K, Georgel P, Rutschmann S, Du X, Mudd S, Crozat K, Sovath S, Shamel L, Hartung T, Zahringer U, Beutler B (2005) CD36 is a sensor of diacylglycerides. Nature 433:523–527

    PubMed  CAS  Google Scholar 

  17. 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 

  18. 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 

  19. 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 

  20. Dunstan SJ, Hawn TR, Hue NT, Parry CP, Ho VA, Vinh H, Diep TS, House D, Wain J, Aderem A, Hien TT, Farrar JJ (2005) Host susceptibility and clinical outcomes in toll-like receptor 5-deficient patients with typhoid fever in Vietnam. J Infect Dis 191:1068–1071

    PubMed  CAS  Google Scholar 

  21. 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 USA 102:9247–9252

    PubMed  CAS  Google Scholar 

  22. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, Akira S (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408:740–745

    PubMed  CAS  Google Scholar 

  23. Zhang D, Zhang G, Hayden MS, Greenblatt MB, Bussey C, Flavell RA, Ghosh S (2004) A toll-like receptor that prevents infection by uropathogenic bacteria. Science 303:1522–1526

    PubMed  CAS  Google Scholar 

  24. Netea MG, Van der Graaf C, Van der Meer JW, Kullberg BJ (2004) Recognition of fungal pathogens by Toll-like receptors. Eur J Clin Microbiol Infect Dis 23:672–676

    PubMed  CAS  Google Scholar 

  25. Brown GD, Taylor PR, Reid DM, Willment JA, Williams DL, Martinez-Pomares L, Wong SY, Gordon S (2002) Dectin-1 is a major beta-glucan receptor on macrophages. J Exp Med 196:407–412

    PubMed  CAS  Google Scholar 

  26. Gantner BN, Simmons RM, Canavera SJ, Akira S, Underhill DM (2003) Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J Exp Med 197:1107–1117

    PubMed  CAS  Google Scholar 

  27. Rogers NC, Slack EC, Edwards AD, Nolte MA, Schulz O, Schweighoffer E, Williams DL, Gordon S, Tybulewicz VL, Brown GD, Reis ESC (2005) Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 22:507–517

    PubMed  CAS  Google Scholar 

  28. Underhill DM, Rossnagle E, Lowell CA, Simmons RM (2005) Dectin-1 activates Syk tyrosine kinase in a dynamic subset of macrophages for reactive oxygen production. Blood 106:2543–2550

    PubMed  CAS  Google Scholar 

  29. Gazzinelli RT, Ropert C, Campos MA (2004) Role of the Toll/interleukin-1 receptor signaling pathway in host resistance and pathogenesis during infection with protozoan parasites. Immunol Rev 201:9–25

    PubMed  CAS  Google Scholar 

  30. Yarovinsky F, Zhang D, Andersen JF, Bannenberg GL, Serhan CN, Hayden MS, Hieny S, Sutterwala FS, Flavell RA, Ghosh S, Sher A (2005) TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308(5728):1626–1629

    PubMed  CAS  Google Scholar 

  31. Coban C, Ishii KJ, Kawai T, Hemmi H, Sato S, Uematsu S, Yamamoto M, Takeuchi O, Itagaki S, Kumar N, Horii T, Akira S (2005) Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J Exp Med 201:19–25

    PubMed  CAS  Google Scholar 

  32. Kurt-Jones EA, Popova L, Kwinn L, Haynes LM, Jones LP, Tripp RA, Walsh EE, Freeman MW, Golenbock DT, Anderson LJ, Finberg RW (2000) Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol 1:398–401

    PubMed  CAS  Google Scholar 

  33. Haynes LM, Moore DD, Kurt-Jones EA, Finberg RW, Anderson LJ, Tripp RA (2001) Involvement of toll-like receptor 4 in innate immunity to respiratory syncytial virus. J Virol 75:10730–10737

    PubMed  CAS  Google Scholar 

  34. Rassa JC, Meyers JL, Zhang Y, Kudaravalli R, Ross SR (2002) Murine retroviruses activate B cells via interaction with toll-like receptor 4. Proc Natl Acad Sci USA 99:2281–2286

    PubMed  CAS  Google Scholar 

  35. Bieback K, Lien E, Klagge IM, Avota E, Schneider-Schaulies J, Duprex WP, Wagner H, Kirschning CJ, Ter Meulen V, Schneider-Schaulies S (2002) Hemagglutinin protein of wild-type measles virus activates toll-like receptor 2 signaling. J Virol 76:8729–8736

    PubMed  CAS  Google Scholar 

  36. Compton T, Kurt-Jones EA, Boehme KW, Belko J, Latz E, Golenbock DT, Finberg RW (2003) Human cytomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2. J Virol 77:4588–4596

    PubMed  CAS  Google Scholar 

  37. Kurt-Jones EA, Chan M, Zhou S, Wang J, Reed G, Bronson R, Arnold MM, Knipe DM, Finberg RW (2004) Herpes simplex virus 1 interaction with Toll-like receptor 2 contributes to lethal encephalitis. Proc Natl Acad Sci USA 101:1315–1320

    PubMed  CAS  Google Scholar 

  38. 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 

  39. Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, Takeuchi O, Sugiyama M, Okabe M, Takeda K, Akira S (2003) Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301:640–643

    PubMed  CAS  Google Scholar 

  40. Tabeta K, Georgel P, Janssen E, Du X, Hoebe K, Crozat K, Mudd S, Shamel L, Sovath S, Goode J, Alexopoulou L, Flavell RA, Beutler B (2004) Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc Natl Acad Sci USA 101:3516–3521

    PubMed  CAS  Google Scholar 

  41. Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RA (2004) Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat Med 10:1366–1373

    PubMed  CAS  Google Scholar 

  42. Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A (2003) Toll-like receptor 9-mediated recognition of herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med 198:513–520

    PubMed  CAS  Google Scholar 

  43. Krug A, French AR, Barchet W, Fischer JA, Dzionek A, Pingel JT, Orihuela MM, Akira S, Yokoyama WM, Colonna M (2004) TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Immunity 21:107–119

    PubMed  CAS  Google Scholar 

  44. Krug A, Luker GD, Barchet W, Leib DA, Akira S, Colonna M (2004) herpes simplex virus type 1 activates murine natural interferon-producing cells through toll-like receptor 9. Blood 103:1433–1437

    PubMed  CAS  Google Scholar 

  45. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K, Akira S (2002) Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 3:196–200

    PubMed  CAS  Google Scholar 

  46. Ito T, Amakawa R, Kaisho T, Hemmi H, Tajima K, Uehira K, Ozaki Y, Tomizawa H, Akira S, Fukuhara S (2002) Interferon-alpha and interleukin-12 are induced differentially by Toll-like receptor 7 ligands in human blood dendritic cell subsets. J Exp Med 195:1507–1512

    PubMed  CAS  Google Scholar 

  47. Akira S, Hemmi H (2003) Recognition of pathogen-associated molecular patterns by TLR family. Immunol Lett 85:85–95

    PubMed  CAS  Google Scholar 

  48. 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 

  49. 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 

  50. 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 

  51. Yamamoto M, Sato S, Hemmi H, Sanjo H, Uematsu S, Kaisho T, Hoshino K, Takeuchi O, Kobayashi M, Fujita T, Takeda K, Akira S (2002) Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420:324–329

    PubMed  CAS  Google Scholar 

  52. Kawai T, Adachi O, Ogawa T, Takeda K, Akira S (1999) Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11:115–122

    PubMed  CAS  Google Scholar 

  53. Yamamoto M, Sato S, Mori K, Hoshino K, Takeuchi O, Takeda K, Akira S (2002) Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J Immunol 169:6668–6672

    PubMed  CAS  Google Scholar 

  54. Oshiumi H, Matsumoto M, Funami K, Akazawa T, Seya T (2003) TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction. Nat Immunol 4:161–167

    PubMed  CAS  Google Scholar 

  55. Hoebe K, Du X, Georgel P, Janssen E, Tabeta K, Kim SO, Goode J, Lin P, Mann N, Mudd S, Crozat K, Sovath S, Han J, Beutler B (2003) Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424:743–748

    PubMed  CAS  Google Scholar 

  56. Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T, Takeuchi O, Takeda K, Akira S (2003) TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol 4:1144–1150

    PubMed  CAS  Google Scholar 

  57. Bin LH, Xu LG, Shu HB (2003) TIRP, a novel Toll/interleukin-1 receptor (TIR) domain-containing adapter protein involved in TIR signaling. J Biol Chem 278:24526–24532

    PubMed  CAS  Google Scholar 

  58. Oshiumi H, Sasai M, Shida K, Fujita T, Matsumoto M, Seya T (2003) TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to toll-like receptor 4 TICAM-1 that induces interferon-beta. J Biol Chem 278:49751–49762

    PubMed  CAS  Google Scholar 

  59. Sharma S, tenOever BR, Grandvaux N, Zhou GP, Lin R, Hiscott J (2003) Triggering the interferon antiviral response through an IKK-related pathway. Science 300:1148–1151

    PubMed  CAS  Google Scholar 

  60. Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, Coyle AJ, Liao SM, Maniatis T (2003) IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 4:491–496

    PubMed  CAS  Google Scholar 

  61. McWhirter SM, Fitzgerald KA, Rosains J, Rowe DC, Golenbock DT, Maniatis T (2004) IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts. Proc Natl Acad Sci USA 101:233–238

    PubMed  CAS  Google Scholar 

  62. Perry AK, Chow EK, Goodnough JB, Yeh WC, Cheng G (2004) Differential requirement for TANK-binding kinase-1 in type I interferon responses to toll-like receptor activation and viral infection. J Exp Med 199:1651–1658

    PubMed  CAS  Google Scholar 

  63. Hemmi H, Takeuchi O, Sato S, Yamamoto M, Kaisho T, Sanjo H, Kawai T, Hoshino K, Takeda K, Akira S (2004) The roles of two IkappaB Kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection. J Exp Med 199:1641–1650

    PubMed  CAS  Google Scholar 

  64. Sato S, Sugiyama M, Yamamoto M, Watanabe Y, Kawai T, Takeda K, Akira S (2003) Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling. J Immunol 171:4304–4310

    PubMed  CAS  Google Scholar 

  65. Kawai T, Takeuchi O, Fujita T, Inoue J, Muhlradt PF, Sato S, Hoshino K, Akira S (2001) Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J Immunol 167:5887–5894

    PubMed  CAS  Google Scholar 

  66. 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 

  67. Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F, Kelliher M, Tschopp J (2004) RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappaB activation. Nat Immunol 5:503–507

    PubMed  CAS  Google Scholar 

  68. Liu YJ (2005) IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol 23:275–306

    PubMed  CAS  Google Scholar 

  69. Hemmi H, Kaisho T, Takeda K, Akira S (2003) The roles of Toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets. J Immunol 170:3059–3064

    PubMed  CAS  Google Scholar 

  70. Kawai T, Sato S, Ishii KJ, Coban C, Hemmi H, Yamamoto M, Terai K, Matsuda M, Inoue J, Uematsu S, Takeuchi O, Akira S (2004) Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol 5:1061–1068

    PubMed  CAS  Google Scholar 

  71. Honda K, Yanai H, Mizutani T, Negishi H, Shimada N, Suzuki N, Ohba Y, Takaoka A, Yeh WC, Taniguchi T (2004) Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc Natl Acad Sci USA 101:15416–15421

    PubMed  CAS  Google Scholar 

  72. Yang K, Puel A, Zhang S, Eidenschenk C, Ku CL, Casrouge A, Picard C, von Bernuth H, Senechal B, Plancoulaine S, Al-Hajjar S, Al-Ghonaium A, Marodi L, Davidson D, Speert D, Roifman C, Garty BZ, Ozinsky A, Barrat FJ, Coffman RL, Miller RL, Li X, Lebon P, Rodriguez-Gallego C, Chapel H, Geissmann F, Jouanguy E, Casanova JL (2005) Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses. Immunity 23:465–478

    PubMed  CAS  Google Scholar 

  73. Uematsu S, Sato S, Yamamoto M, Hirotani T, Kato H, Takeshita F, Matsuda M, Coban C, Ishii KJ, Kawai T, Takeuchi O, Akira S (2005) Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction. J Exp Med 201:915–923

    PubMed  CAS  Google Scholar 

  74. Tsujimura H, Tamura T, Kong HJ, Nishiyama A, Ishii KJ, Klinman, DM, Ozato K (2004) Toll-like receptor 9 signaling activates NF-kappaB through IFN regulatory factor-8/IFN consensus sequence binding protein in dendritic cells. J Immunol 172:6820–6827

    PubMed  CAS  Google Scholar 

  75. Ting JP, Kastner DL, Hoffman HM (2006) CATERPILLERs, pyrin and hereditary immunological disorders. Nat Rev Immunol 6:183–195

    PubMed  CAS  Google Scholar 

  76. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nunez G, Cho JH (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411:603–606

    PubMed  CAS  Google Scholar 

  77. Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L, Ogura Y, Kawasaki A, Fukase K, Kusumoto S, Valvano MA, Foster SJ, Mak TW, Nunez G, Inohara N (2003) An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol 4:702–707

    PubMed  CAS  Google Scholar 

  78. 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 

  79. 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 

  80. Kobayashi K, Inohara, N, Hernandez LD, Galan JE, Nunez G, Janeway CA, Medzhitov R, Flavell RA (2002) RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 416:194–199

    PubMed  CAS  Google Scholar 

  81. Abbott DW, Wilkins A, Asara JM, Cantley LC (2004) The Crohn’s disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO. Curr Biol 14:2217–2227

    PubMed  CAS  Google Scholar 

  82. Zhou H, Wertz I, O’Rourke K, Ultsch M, Seshagiri S, Eby M, Xiao W, Dixit VM (2004) Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO. Nature 427:167–171

    PubMed  CAS  Google Scholar 

  83. 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 

  84. 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 

  85. 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 

  86. Stehlik C, Hayashi H, Pio F, Godzik A, Reed JC (2003) CARD6 is a modulator of NF-kappa B activation by Nod1- and Cardiak-mediated pathways. J Biol Chem 278:31941–31949

    PubMed  CAS  Google Scholar 

  87. 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 

  88. Petrilli V, Papin S, Tschopp J (2005) The inflammasome. Curr Biol 15:R581

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  90. 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 

  91. 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 

  92. 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 

  93. 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 

  94. 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 

  95. Miceli-Richard C, Lesage S, Rybojad M, Prieur AM, Manouvrier-Hanu S, Hafner R, Chamaillard M, Zouali H, Thomas G, Hugot JP (2001) CARD15 mutations in Blau syndrome. Nat Genet 29:19–20

    PubMed  CAS  Google Scholar 

  96. Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD (2001) Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nat Genet 29:301–305

    PubMed  CAS  Google Scholar 

  97. Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hofmann SR, Stein L, Russo R, Goldsmith D, Dent P, Rosenberg HF, Austin F, Remmers EF, Balow JE Jr, Rosenzweig S, Komarow H, Shoham NG, Wood G, Jones J, Mangra N, Carrero H, Adams BS, Moore TL, Schikler K, Hoffman H, Lovell DJ, Lipnick R, Barron K, O’Shea JJ, Kastner DL, Goldbach-Mansky R (2002) De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum 46:3340–3348

    PubMed  CAS  Google Scholar 

  98. Harton JA, Linhoff MW, Zhang J, Ting JP (2002) Cutting edge: CATERPILLER: a large family of mammalian genes containing CARD, pyrin, nucleotide-binding, and leucine-rich repeat domains. J Immunol 169:4088–4093

    PubMed  CAS  Google Scholar 

  99. Ting JP, Davis BK (2005) CATERPILLER: a novel gene family important in immunity, cell death, and diseases. Annu Rev Immunol 23:387–414

    PubMed  CAS  Google Scholar 

  100. Steimle V, Otten LA, Zufferey M, Mach B (1993) Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). Cell 75:135–146

    PubMed  CAS  Google Scholar 

  101. Kawai T, Akira S (2006) Innate immune recognition of viral infection. Nat Immunol 7:131–137

    PubMed  CAS  Google Scholar 

  102. Kang DC, Gopalkrishnan RV, Wu Q, Jankowsky E, Pyle AM, Fisher PB (2002) mda-5: An interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties. Proc Natl Acad Sci USA 99:637–642

    PubMed  CAS  Google Scholar 

  103. Kovacsovics M, Martinon F, Micheau O, Bodmer JL, Hofmann K, Tschopp J (2002) Overexpression of Helicard, a CARD-containing helicase cleaved during apoptosis, accelerates DNA degradation. Curr Biol 12:838–843

    PubMed  CAS  Google Scholar 

  104. Andrejeva J, Childs KS, Young DF, Carlos TS, Stock N, Goodbourn S, Randall RE (2004) The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter. Proc Natl Acad Sci USA 101:17264–17269

    PubMed  CAS  Google Scholar 

  105. Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M, Taira K, Foy E, Loo YM, Gale M Jr, Akira S, Yonehara S, Kato A, Fujita T (2005) Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol 175:2851–2858

    PubMed  CAS  Google Scholar 

  106. Rothenfusser S, Goutagny N, DiPerna G, Gong M, Monks BG, Schoenemeyer A, Yamamoto M, Akira S, Fitzgerald KA (2005) The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J Immunol 175:5260–5268

    PubMed  CAS  Google Scholar 

  107. Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, Ishii KJ, Takeuchi O, Akira S (2005) IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol 6:981–988

    PubMed  CAS  Google Scholar 

  108. Seth RB, Sun L, Ea CK, Chen ZJ (2005) Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122:669–682

    PubMed  CAS  Google Scholar 

  109. Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, Shu HB (2005) VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell 19:727–740

    PubMed  CAS  Google Scholar 

  110. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp J (2005) Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437:1167–1172

    PubMed  CAS  Google Scholar 

  111. Bowie A, Kiss-Toth E, Symons JA, Smith GL, Dower SK, O’Neill LA (2000) A46R and A52R from vaccinia virus are antagonists of host IL-1 and toll-like receptor signaling. Proc Natl Acad Sci USA 97:10162–10167

    PubMed  CAS  Google Scholar 

  112. Harte MT, Haga IR, Maloney G, Gray P, Reading PC, Bartlett NW, Smith GL, Bowie A, O’Neill LA (2003) The poxvirus protein A52R targets Toll-like receptor signaling complexes to suppress host defense. J Exp Med 197:343–351

    PubMed  CAS  Google Scholar 

  113. Stack J, Haga IR, Schroder M, Bartlett NW, Maloney G, Reading PC, Fitzgerald KA, Smith GL, Bowie AG (2005) Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence. J Exp Med 201:1007–1018

    PubMed  CAS  Google Scholar 

  114. Foy E, Li K, Sumpter R Jr, Loo YM, Johnson CL, Wang C, Fish PM, Yoneyama M, Fujita T, Lemon SM, Gale M Jr (2005) Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. Proc Natl Acad Sci USA 102:2986–2991

    PubMed  CAS  Google Scholar 

  115. Li XD, Sun L, Seth RB, Pineda G, Chen ZJ (2005) Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc Natl Acad Sci USA 102:17717–17722

    PubMed  CAS  Google Scholar 

  116. Kawane K, Fukuyama H, Yoshida H, Nagase H, Ohsawa Y, Uchiyama Y, Okada K, Iida T, Nagata S (2003) Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation. Nat Immunol 4:138–144

    PubMed  CAS  Google Scholar 

  117. Yoshida H, Okabe Y, Kawane K, Fukuyama H, Nagata S (2005) Lethal anemia caused by interferon-beta produced in mouse embryos carrying undigested DNA. Nat Immunol 6:49–56

    PubMed  CAS  Google Scholar 

  118. Suzuki K, Mori A, Ishii KJ, Saito J, Singer DS, Klinman DM, Krause PR, Kohn LD (1999) Activation of target-tissue immune-recognition molecules by double-stranded polynucleotides. Proc Natl Acad Sci USA 96:2285–2290

    PubMed  CAS  Google Scholar 

  119. Ishii KJ, Suzuki K, Coban C, Takeshita F, Itoh Y, Matoba H, Kohn LD, Klinman DM (2001) Genomic DNA released by dying cells induces the maturation of APCs. J Immunol 167:2602–2607

    PubMed  CAS  Google Scholar 

  120. Ishii KJ, Coban C, Kato H, Takahashi K, Torii Y, Takeshita F, Ludwig H, Sutter G, Suzuki K, Hemmi H, Sato S, Yamamoto M, Uematsu S, Kawai T, Takeuchi O, Akira S (2006) A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat Immunol 7:40–48

    PubMed  CAS  Google Scholar 

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Acknowledgements

We thank M. Hashimoto for secretarial assistance. This work was supported by grants from Special Coordination Funds, the Ministry of Education, Culture, Sports, Science and Technology, and the Japan Research Foundation for Clinical Pharmacology.

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Correspondence to Shizuo Akira.

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Uematsu, S., Akira, S. Toll-like receptors and innate immunity. J Mol Med 84, 712–725 (2006). https://doi.org/10.1007/s00109-006-0084-y

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