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Vol. 92, No. 3, 2007
Issue release date: September 2007
Neonatology 2007;92:145–157

Innate Immunity: Toll-Like Receptors and Some More

A Brief History, Basic Organization and Relevance for the Human Newborn

Fleer A. · Krediet T.G.
aEijkman-Winkler Institute for Microbiology, Infectious Diseases and Inflammation, and bDepartment of Neonatology, Wilhelmina Children’s Hospital, University Medical Center, Utrecht, The Netherlands

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The discovery of Toll-like receptors (TLRs) as essential components of the innate immune system has greatly advanced our knowledge and understanding of immune responses to infection and how these are regulated. Innate immunity in general and TLRs in particular play a crucial role in the front line of host defenses against microbes, but also are a key element in the proper functioning of the immune system at large in vertebrate animals. The innate immune system has been identified as a collection of factors, both cell-associated and cell-free, that comprises an impressively effective and well-organized system that is capable of immediate recognition of a whole array of microbes and microbial components. The cell-bound TLRs fulfill a central role in the process from pathogen recognition to activation of adaptive immunity. From the cell-free factors the plasma protein mannose-binding lectin (MBL) has been studied most extensively. Associations have already been documented between TLR polymorphisms in man and TLR deficiency in animals and an increased susceptibility to infection. The effect of MBL on infectious disease susceptibility only seems to emerge when host defenses are compromised by a severe underlying condition. The functional state of the various components of innate immunity at birth is largely unknown and only recently a number of studies have assessed this feature of the innate immune system. In addition, for the human newborn the innate immune systemmay have a broader significance; it may well be the key system determining the course of inflammatory events associated with premature birth, a notion that is emphasized by the recently described association between TLR polymorphisms and prematurity. However, there are still many open questions, particularly about the exact relation between individual TLRs and infectious disease susceptibility and how TLRs cooperate in resistance to infection and in initiating adaptive immune responses. With regard to the human newborn, the most relevant question that needs to be resolved is the precise role of innate immunity in the pathogenesis of prematurity.

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  1. Germain RN: An innately interesting decade of research in immunology. Nat Med 2004;10:1307–1320.
  2. Beutler B, Rietschel E Th: Innate immune sensing and its roots: the story of endotoxin. Nat Rev Immunol 2003;3:169–176.
  3. Janeway CA Jr: Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 1989;1:1–13.
  4. Belvin MP, Anderson KV: A conserved signaling pathway: the Drosophila Toll-dorsal pathway. Annu Rev Cell Dev Biol 1996;12:393–416.
  5. Lemaitre B, Nicolas E, Michaut L, Reichhart J-M, Hoffmann JA: The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996;86:973–983.
  6. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr: A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 1997;388:394–397.
  7. Poltorak A, He X, Smirnova I, Liu M, van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B: Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998;282:2085–2088.
  8. Takeda K, Kaisho T, Akira S: Toll-like receptors. Annu Rev Immunol 2003;21:335–276.
  9. Takeda K, Akira S: Toll receptors and pathogen resistance. Cell Microbiol 2003;5:143–153.
  10. Ozinsky A, Underhill DM, Fontenot JD, Hajjar AM, Smith KD, Wilson CB, Schroeder L, Aderem A: The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors. Proc Natl Acad Sci USA 2000;10:13766–13771.

    External Resources

  11. Bell JK, Mullen GED, Leifer CA, Mazzoni A, Davies DR, Segal DM: Leucine-rich repeats and pathogen recognition in Toll-like receptors. Trends Immunol 2003;24:528–533.
  12. Choe J, Kelker MS, Wilson IA: Crystal structure of human Toll-like receptor 3 (TLR3) ectodomain. Science 2005;309:581–585.
  13. Bell JK, Botos I, Hall PR, Askins J, Shiloach J, Segal DM, Davies DR: The molecular structure of the Toll-like receptor 3 ligand-binding domain. PNAS 2005;102:10976–10980.
  14. Kirk P, Bazan JF: Pathogen recognition: TLRs throw us a curve. Immunity 2005;23:347–350.
  15. Akira S, Takeda K: Toll-like receptor signalling. Nat Rev Immunol 2004;4:499–511.
  16. Kawai T, Akira S: Pathogen recognition with Toll-like receptors. Curr Opin Immunol 2005;17:338–344.
  17. O’Neill LAJ: How Toll-like receptors signal: what we know and what we don’t know. Curr Opin Immunol 2006;18:3–9.
  18. Okusawa T, Fujita M, Nakamura J, Into T, Yasuda M, Yoshimura A, Hara Y, Hasebe A, Golenbock DT, Morita M, Kuroki Y, Ogawa T, Shibata K: Relationship between structures and biological activities of mycoplasmal diacylated lipopeptides and their recognition by Toll-like receptors 2 and 6. Infect Immun 2004;72:1657–1665.
  19. Beutler B, Jiang Z, Georgel P, Crozat K, Croker B, Rutschmann S, Du X, Hoebe K: Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. Annu Rev Immunol 2006;24:353–389.
  20. Netea MG, Gow NAR, Munro CA, Bates S, Collins C, Ferwerda G, Hobson RP, Bertram G, Hughes HB, Jansen T, Jacobs L, Buurman ET, Gijzen K, Williams DL, Torensma R, McKinnon A, MacCallum DM, Odds FC, van der Meer JWM, Brown AJP, Kullberg BJ: Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors. J Clin Invest 2006;116:1642–1650.
  21. Netea MG, van der Graaf C, van der Meer JWM, Kullberg BJ: Recogniton of fungal pathogens by Toll-like receptors. Eur J Clin Microbiol Infect Dis 2004;23:672–676.
  22. Netea MG, van der Meer JWM, Kullberg BJ: Toll-like receptors as an escape mechanism from the host defense. Trends Microbiol 2004;12:484–488.
  23. Netea MG, van der Meer JWM, Kullberg BJ: Role of the dual interaction of fungal pathogens with pattern recognition receptors in the activation and modulation of host defence. Clin Microbiol Infect 2006;12:404–409.
  24. van der Graaf CAA, Netea MG, Verschueren I, van der Meer JWM, Kullberg BJ: Differential cytokine production and Toll-like receptor signaling pathways by Candida albicans blastoconidia and hyphae. Infect Immun 2005;73:7458–7464.
  25. Gantner BN, Simmons RM, Underhill DM: Dectin-1 mediates macrophage recognition of Candida albicans yeast but not filaments. EMBO J 2005;24:1277–1286.
  26. Hallman M, Rämet M, Ezekowitz RA: Toll-like receptors as sensors of pathogens. Pediatr Res 2001;50:315–321.
  27. Zarember KA, Godowski PJ: Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol 2002;168:554–561.
  28. Iwasaki A, Medzhitov R: Toll-like receptor control of the adaptive immune responses. Nat Immunol 2004;5:987–995.
  29. Muzio M, Polentarutti N, Bosisio D, Prahladan MKP, Mantovani A: Toll-like receptors: a growing family of immune receptors that are differentially expressed and regulated by different leukocytes. J Leukoc Biol 2000;67:450–456.
  30. Abreu MT, Fukata M, Arditi M: TLR signaling in the gut in health and disease. J Immunol 2005;174:4453–4460.
  31. Philpott DJ, Girardin SE: The role of Toll-like receptors and NOD proteins in bacterial infection. Mol Immunol 2004;41:1099–1108.
  32. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh M, Edberg S, Medzhitov R: Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 2004;118:229–241.
  33. Martinon F, Tschopp J: NLRs join TLRs as innate sensors of pathogens. Trends Immunol 2005;26:447–454.
  34. Strober W, Murray PJ, Kitani A, Watanabe T: Signalling pathways and molecular interactions of NOD1 and NOD2. Nature Rev Immunol 2006;6:9–20.
  35. Brown GD: Dectin-1: a signalling non-TLR pattern-recognition receptor. Nature Rev Immunol 2006;6:33–43.
  36. Fujita T: Evolution of the lectin-complement pathway and its role in innate immunity. Nat Rev Immunol 2002;2:346–343.
  37. Ezekowitz RA: Role of mannose-binding lectin in innate immunity. J Infect Dis 2003;187:S335–S339.
  38. Turner MW: The role of mannose-binding lectin in health and disease. Mol Immunol 2003;40:423–429.
  39. Van de Wetering JK, Van Golde L, Batenburg J: Collectins: players of the innate immune system. Eur J Biochem 2004;271:1229–1249.
  40. Lillie BN, Brooks AS, Keirstead ND, Hayes MA: Comparative genetics and innate immune function of collagenous lectins in animals. Vet Immunol Immunopathol 2005;108:97–110.
  41. Aittoniemi J, Miettinen A, Laippala P, Isolauri E, Viikari J, Ruuska T, Soppi E: Age-dependent variation in the serum concentration of mannan-binding protein. Acta Paediatr 1996;85:906–909.
  42. Whitsett JA: Surfactant proteins in innate host defense of the lung. Biol Neonate 2005;88:175–180.
  43. Kishore U, Greenhough TJ, Waters P, Shrive AK, Kamran MF, Bernal AL, Reid KBM, Madan T, Chakraborty T: Surfactant proteins SP-A and SP-D: structure, function and receptors. Mol Immunol 2006;43:1293–1315.
  44. Hawlisch H, Köhl J: Complement and Toll-like receptors: key regulators of adaptive immune responses. Mol Immunol 2006;43:13–21.
  45. Schröder NWJ, Schumann RR: Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis 2005;5:156–164.
  46. Lasker MV, Nair SK: Intracellular TLR signalling: a structural perspective on human disease. J Immunol 2006;177:11–16.
  47. Lorenz E, Mira JP, Frees KL, Schwartz DA: Relevance of mutations in the TLR4 receptor in patients with Gram-negative septic shock. Arch Intern Med 2002;162:1028–1032.
  48. Agnese DM, Calvano JE, Hahm SJ, Coyle SM, Corbett SA, Calvano SE, Lowry SF: Human Toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of Gram-negative infections. J Infect Dis 2002;186:1522–1525.
  49. Read RC, Pullin J, Gregory S, Borrow R, Kaczmarski EB, di Giovine FS, Dower SK, Cannings C, Wilson AG: A functional polymorphism of Toll-like receptor 4 is not associated with likelihood or severity of meningococcal disease. J Infect Dis 2001;184:640–642.
  50. Smirnova I, Mann N, Dols A, Derkx HH, Hibberd ML, Levin M, Beutler B: Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc Natl Acad Sci USA 2003;100:6075–6080.
  51. Allen A, Obaro S, Bojarg K, Awomoyi AA, Greenwood BM, Whittle HF, Sirugo G, Newport MJ: Pediatr Infect Dis J 2003;22:1018–1019.
  52. Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, Takeda K, Akira S: Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 1999;162:3749–3752.
  53. O’Brien AD, Rosenstreich DL, Scher I, Campbell GH, MacDermott P, Formal SB: Genetic control of susceptibility to Salmonella typhimurium in mice: role of the LPS gene. J Immunol 1980;124:20–24.
  54. Bernheiden M, Heinrich JM, Minigo G, Schütt C, Stelter F, Freeman M, Golenbock D, Jack RS: LBP, CD14, TLR4 and the murine innate immune response to a peritoneal Salmonella infection. J Endotox Res 2001;7:447–450.
  55. Leveque G, Forgetta V, Morroll S, Smith AL, Bumstead N, Barrow P, Loredo-Osti JC, Morgan K, Malo D: Allelic variation in TLR4 islinked to susceptibility to Salmonella enterica serovar typhimurium infection in chickens. Infect Immunol 2003;71:1116–1124.
  56. Takeuchi O, Hoshino K, Akira S: Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J Immunol 2000;165:5392–5396.
  57. Echchannaoui H, Frei K, Schnell C, Leib SL, Zimmerli W, Landmann R: Toll-like receptor 2-deficient mice are highly susceptible to Streptococcus pneumoniae meningitis because of reduced bacterial clearing and enhanced inflammation. J Infect Dis 2002;186:798–806.
  58. Koedel U, Angele B, Rupprecht T, Wagner H, Roggenkamp A, Pfister H-W, Kirschning CJ: Toll-like receptor 2 participates in mediation of immune response in experimental pneumococcal meningitis. J Immunol 2003;170:438–444.
  59. Knapp S, Wieland CW, van ‘t Veer C, Takeuchi O, Akira S, Florquin S, van der Poll T: Toll-like receptor 2 plays a role in the early inflammatory response to murine pneumococcal pneumonia but does not contribute to antibacterial defense. J Immunol 2004;172:3132–3138.
  60. Malley R, Henneke P, Morse SC, Cieslewicz MJ, Lipsitch M, Thompson CM, Kurt-Jones E, Paton JC, Wessels MR, Golenbock DT: Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection. Proc Natl Acad Sci USA 2003;100:1966–1971.
  61. Kang T, Chae G: Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients. FEMS Immunol Med Microbiol 2001;31:53–58.
  62. Ben-Ali M, Barbouche M, Bousnina S, Chabbou A, Dellagi K: Toll-like receptor 2 Arg677Trp polymorphism is associated with susceptibility to tuberculosis in Tunisian patients. Clin Diagn Lab Immunol 2004;11:625–626.
  63. Ogus AC, Yoldas B, Ozdemir T, Uguz A, Olcen S, Keser I, Coskun M, Cilli A, Yegin O: The Arg753Gln polymorphism of the Toll-like receptor 2 gene in tuberculosis disease. Eur Respir J 2004;23:219–223.
  64. Moore CE, Segal S, Berendt AR, Hill AV, Day NP: Lack of association between Toll-like receptor 2 polymorphisms and susceptibility to severe disease caused by Staphylococcus aureus. Clin Diagn Lab Immunol 2004;11:1194–1197.
  65. Schröder NWJ, Diterich I, Zinke A, Eckert J, Draing C, v Baehr V, Hassler D, Priem S, Hahn K, Michelsen KS, Hartung T, Burmester GR, Göbel UB, Hermann C, Schumann RR: Heterozygous Arg753Gln polymorphism of human TLR-2 impairs immune activation by Borrelia burgdorferi and protects from late stage Lyme disease. J Immunol 2005;175:2534–2540.
  66. Netea MG, Sutmuller R, Hermann C, van der Graaf CAA, van der Meer JWM, van Krieken JH, Hartung T, Adema G, Kullberg BJ: Toll-like receptor 2 suppresses immunity against Candida albicans through induction of Il-10 and regulatory T cells. J Immunol 2004;172:3712–3718.
  67. Hibberd ML, Sumiya M, Summerfield JA, Booy R, Levin M: Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease. Lancet 1999;353:1049–1053.
  68. Garred P, Michaelsen TE, Bjune G, Thiel S, Svejgaard A: A low serum concentration of mannan-binding protein is not associated with serogroup B or C meningococcal disease. Scand J Immunol 1993;37:468–470.
  69. Bax WA, Cluysenaer OJJ, Bartelink AKM, Aerts PC, Ezekowitz RAB, van Dijk H: Association of familial deficiency of mannose-binding lectin and meningococcal disease. Lancet 1999;354:1094–1095.
  70. Kronborg G, Weis N, Madsen HO, Pederson SS, Wesje C, Nielsen H, Skinhøj, Garred P: Variant mannose-binding lectin alleles are not associated with susceptibility to or outcome of invasive pneumococcal infection in randomly included patients. J Infect Dis 2002;185:1517–1520.
  71. Roy S, Knox K, Segal S, Griffiths D, Moore CE, Welsh KI, Smarason A, Day NP, McPheat WL, Crook DW, Hill AVS: MBL genotype and risk of invasive pneumococcal disease: a case control study. Lancet 2002;359:1569–1573.
  72. Garred P, Pressler T, Madsen HO, Frederiksen B, Svejgaard A, Høiby N, Schwartz M, Koch C: Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis. J Clin Invest 1999;104:431–437.
  73. Peterslund NA, Koch C, Jensenius J, Thiel S: Association between deficiency of mannose-binding lectin and severe infections after chemotherapy. Lancet 2001;358:637–638.
  74. Mullighan CG, Heatly S, Doherty K, Scabo F, Grigg A, Hughes TP, Schwarer AP, Szer J, Tait BD, Bik To L, Bardy PG: Mannose-binding lectin gene polymorphisms are associated with major infection following hemopoietic stem cell transplantation. Blood 2002;99:3524–3529.
  75. Dickinson AM, Middleton PG, Rocha V, Gluckman E, Holler E: Genetic polymorphisms predicting the outcome of bone marrow transplants. British J Haematol 2004;127:479–490.
  76. Fidler KJ, Wilson P, Davies JC, Turner MW, Peters MJ, Klein NJ: Increased incidence and severity of the systemic inflammatory response syndrome in patients deficient in mannose-binding lectin. Intensive Care Med 2004;30:1438–1445.
  77. Carcillo JA: Mannose-binding lectin deficiency provides a genetic basis for the use of SIRS/sepsis definitions in critically ill patients. Intensive Care Med 2004;30:1263–1265.
  78. Levy O, Zarember KA, Roy RM, Cywes C, Godowski PJ, Wessels MR: Selective impairment of TLR-mediated innate immunity in human newborns: neonatal blood plasma reduces monocyte TNF-α induction by bacterial lipopeptides, lipopolysaccharide, and imiquimod, but preserves the response to R-848. J Immunol 2004;173:4627–4634.
  79. Viemann D, Dubbel G, Schleifenbaum S, Harms E, Sorg C, Roth J: Expression of Toll-like receptors in neonatal sepsis. Pediatr Res 2005;58:654–659.
  80. Yan SR, Qing G, Byers DM, Stadnyk AW, Al-Hertani W, Bortolussi R: Role of MyD88 in diminished tumor necrosis factor alpha production by newborn mononuclear cells in response to lipopolysaccharide. Infect Immun 2004;72;1223–1229.
  81. Förster-Waldi E, Sadeghi K, Tamandl D, Gerhold B, Hallwirth U, Rohrmeister K, Hayde M, Prusa AR, Herkner K, Boltz-Nitulescu G, Pollak A, Spittler A: Monocyte Toll-like receptor 4 expression and LPS-induced cytokine production increase during gestational aging. Pediatr Res 2005;58:121–124.
  82. Angelone DF, Wessels MR, Coughlin M, Suter EE, Valentini P, Kalish LA, Levy O: Innate immunity of the human newborn is polarized toward a high ratio of IL-6/TNF-α production in vitro and in vivo. Pediatr Res 2006;60:206–210.

    External Resources

  83. Fusunyan RD, Nanthakumar NN, Baldeon ME, Walker WA: Evidence for an innate immune response in the immature human intestine: Toll-like receptors on fetal enterocytes. Pediatr Res 2001;49:589–593.
  84. Ahrens P, Kattner E, Köhler B, Härtel C, Seidenberg J, Segerer H, Möller J, Göpel W: Mutations of genes involved in the innate immune system as predictors of sepsis in very low birth weight infants. Pediatr Res 2004;55:652–656.
  85. Marodi L: Neonatal innate immunity to infectious agents. Infect Immun 2006;74:1999–2006.
  86. Marodi L: Innate cellular immune responses in newborns. Clin Immunol 2006;118:137–144.
  87. Lorenz E, Hallman M, Marttila R, Haataja R, Schwartz DA: Association between the Asp299Gly Polymorphisms in the Toll-like receptor 4 and premature births in the Finnish population. Pediatr Res 2002;52:373–376.
  88. Wiertsema SP, Vossers MJ, Krediet TG, Hoeks SBEA, Fleer A, Ruven HJT, Rijkers GT: Association of Toll-like receptor-2 polymorphisms with premature birth among infants admitted to a neonatal intensive care unit. Program and Abstracts of the Pediatr Acad Soc 2006 Ann Meeting, San Francisco, Calif., USA, abstr 2610.6.
  89. Crider KS, Whitehead N, Buus RM: Genetic variation associated with preterm birth: a HuGe review. Genet Med 2005;7:593–604.
  90. Mulherin Engel SA, Erichsen HC, Savitz DA, Thorp J, Chanock SJ, Olshan AF: Risk of spontaneous preterm birth is associated with common proinflammatory cytokine polymorphisms. Epidemiology 2005;16:469–477.
  91. Mulherin Engel SA, Olshan AF, Savitz DA, Thorp J, Erichsen HC, Chanock SJ: Risk of small-for-gestational age is associated with common anti-inflammatory cytokine polymorphisms. Epidemiology 2005;16:478–486.
  92. Szekeres-Bartho J: Immunological relationship between the mother and the fetus. Int Rev Immunol 2002;21:471–495.
  93. Wegmann TG, Lin H, Guilbert L, Mosmann TR: Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a Th2 phenomenon? Immunol Today;1993:14:353–356.
  94. Varner MW, Esplin MS. Current understanding of genetic factors in preterm birth. BJOG 2005;112(suppl 1):28–31.

    External Resources

  95. Goldenberg RL, Hauth JC, Andrews WW: Intrauterine infection and preterm delivery. N Engl J Med 2000;342:1500–1507.
  96. Romero R, Espinoza J, Chaiworapongsa T, Kalache K: Infection and prematurity and the role of preventive strategies. Semin Neonatol 2002;7:259–274.

    External Resources

  97. Dammann O, Leviton A: Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn. Pediatr Res 1997;42:1–8.
  98. Dammann O, Leviton A: Inflammatory brain damage in preterm newborns- dry numbers, wet lab, and causal inferences. Early Hum Dev 2004;79:1–15.
  99. Bracci R, Buonocore G: Chorioamnionitis: a risk factor for fetal and neonatal morbidity. Biol Neonate 2003;83:85–96.
  100. O’Neill LAJ: After the Toll rush. Science 2004;303:1481–1482.

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