Encyclopedia of Signaling Molecules

2012 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-1-4419-0461-4_639



An infected host can quickly recognize an invading pathogen via germ-line-encoded pattern recognition receptors (PRRs) that detect microbe-associated molecular patterns (MAMPs) commonly expressed by many pathogens. Recognition of MAMPs by their corresponding receptor allows the host to initiate a rapid inflammatory response that can limit initial pathogen replication (Janeway and Medzhitov 2002). At least four different groups of PRRs have been described with varying cellular location and ligand specificity. Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) are membrane-associated, while RIG-I-like receptors (RLRs) and NOD-like receptors (NLRs) are found in the cytosol. Among the 13 known TLRs, only TLR5 and TLR11 exclusively recognize protein microbial ligands (Kawai and Akira 2010). TLR5 detects flagellin, a...

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


  1. Andersen-Nissen E, Smith KD, Bonneau R, Strong RK, Aderem A. A conserved surface on toll-like receptor 5 recognizes bacterial flagellin. J Exp Med. 2007;204(2):393–403. Epub 2007/02/07.PubMedGoogle Scholar
  2. Bogunovic M, Dave SH, Tilstra JS, Chang DT, Harpaz N, Xiong H, et al. Enteroendocrine cells express functional toll-like receptors. Am J Physiol Gastrointest Liver Physiol. 2007;292(6):G1770–83. Epub 2007/03/31.PubMedGoogle Scholar
  3. Choi YJ, Im E, Pothoulakis C, Rhee SH. TRIF modulates TLR5-dependent responses by inducing proteolytic degradation of TLR5. J Biol Chem. 2010;285(28):21382–90. Epub 2010/05/11.PubMedGoogle Scholar
  4. Didierlaurent A, Ferrero I, Otten LA, Dubois B, Reinhardt M, Carlsen H, et al. Flagellin promotes myeloid differentiation factor 88-dependent development of Th2-type response. J Immunol. 2004;172(11):6922–30. Epub 2004/05/22.PubMedGoogle Scholar
  5. Dunstan SJ, Hawn TR, Hue NT, Parry CP, Ho VA, Vinh H, et al. Host susceptibility and clinical outcomes in toll-like receptor 5-deficient patients with typhoid fever in Vietnam. J Infect Dis. 2005;191(7):1068–71. Epub 2005/03/05.PubMedGoogle Scholar
  6. Gewirtz AT, Navas TA, Lyons S, Godowski PJ, Madara JL. Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J Immunol. 2001;167(4):1882–5. Epub 2001/08/08.PubMedGoogle Scholar
  7. Hawn TR, Verbon A, Lettinga KD, Zhao LP, Li SS, Laws RJ, et al. A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires’ disease. J Exp Med. 2003;198(10):1563–72. Epub 2003/11/19.PubMedGoogle Scholar
  8. Hawn TR, Wu H, Grossman JM, Hahn BH, Tsao BP, Aderem A. A stop codon polymorphism of toll-like receptor 5 is associated with resistance to systemic lupus erythematosus. Proc Natl Acad Sci USA. 2005;102(30):10593–7. Epub 2005/07/20.PubMedGoogle Scholar
  9. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, et al. The innate immune response to bacterial flagellin is mediated by toll-like receptor 5. Nature. 2001;410(6832):1099–103. Epub 2001/04/27.PubMedGoogle Scholar
  10. Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol. 2004;5(10):987–95. Epub 2004/09/30.PubMedGoogle Scholar
  11. Janeway Jr CA, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002;20:197–216. Epub 2002/02/28.PubMedGoogle Scholar
  12. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat Immunol. 2010;11(5):373–84. Epub 2010/04/21.PubMedGoogle Scholar
  13. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011;34(5):637–50. Epub 2011/05/28.PubMedGoogle Scholar
  14. Letran SE, Lee SJ, Atif SM, Uematsu S, Akira S, McSorley SJ. TLR5 functions as an endocytic receptor to enhance flagellin-specific adaptive immunity. Eur J Immunol. 2011a;41(1):29–38. Epub 2010/12/25.PubMedGoogle Scholar
  15. Letran SE, Lee SJ, Atif SM, Flores-Langarica A, Uematsu S, Akira S, et al. TLR5-deficient mice lack basal inflammatory and metabolic defects but exhibit impaired CD4 T cell responses to a flagellated pathogen. J Immunol. 2011b;186(9):5406–12. Epub 2011/04/01.PubMedGoogle Scholar
  16. Liaudet L, Deb A, Pacher P, Mabley JG, Murthy KG, Salzman AL, et al. The Flagellin-TLR5 axis: therapeutic opportunities. Drug News Perspect. 2002;15(7):397–409. Epub 2003/04/05.PubMedGoogle Scholar
  17. Lin SC, Lo YC, Wu H. Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signaling. Nature. 2010;465(7300):885–90. Epub 2010/05/21.PubMedGoogle Scholar
  18. Lodes MJ, Cong Y, Elson CO, Mohamath R, Landers CJ, Targan SR, et al. Bacterial flagellin is a dominant antigen in Crohn disease. J Clin Invest. 2004;113(9):1296–306. Epub 2004/05/05.PubMedGoogle Scholar
  19. McGettrick AF, O’Neill LA. The expanding family of MyD88-like adaptors in toll-like receptor signal transduction. Mol Immunol. 2004;41(6–7):577–82. Epub 2004/06/29.PubMedGoogle Scholar
  20. McSorley SJ, Ehst BD, Yu Y, Gewirtz AT. Bacterial flagellin is an effective adjuvant for CD4+ T cells in vivo. J Immunol. 2002;169(7):3914–9. Epub 2002/09/24.PubMedGoogle Scholar
  21. Means TK, Hayashi F, Smith KD, Aderem A, Luster AD. The toll-like receptor 5 stimulus bacterial flagellin induces maturation and chemokine production in human dendritic cells. J Immunol. 2003;170(10):5165–75. Epub 2003/05/08.PubMedGoogle Scholar
  22. Mizel SB, Honko AN, Moors MA, Smith PS, West AP. Induction of macrophage nitric oxide production by Gram-negative flagellin involves signaling via heteromeric toll-like receptor 5/toll-like receptor 4 complexes. J Immunol. 2003;170(12):6217–23. Epub 2003/06/10.PubMedGoogle Scholar
  23. Moors MA, Li L, Mizel SB. Activation of interleukin-1 receptor-associated kinase by gram-negative flagellin. Infect Immun. 2001;69(7):4424–9. Epub 2001/06/13.PubMedGoogle Scholar
  24. Munoz N, Van Maele L, Marques JM, Rial A, Sirard JC, Chabalgoity JA. Mucosal administration of flagellin protects mice from Streptococcus pneumoniae lung infection. Infect Immun. 2010;78(10):4226–33. Epub 2010/07/21.PubMedGoogle Scholar
  25. Nishimura M, Naito S. Tissue-specific mRNA expression profiles of human toll-like receptors and related genes. Biol Pharm Bull. 2005;28(5):886–92. Epub 2005/05/03.PubMedGoogle Scholar
  26. Ochiel DO, Ghosh M, Fahey JV, Guyre PM, Wira CR. Human uterine epithelial cell secretions regulate dendritic cell differentiation and responses to TLR ligands. J Leukoc Biol. 2010;88(3):435–44. Epub 2010/04/14.PubMedGoogle Scholar
  27. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004;118(2):229–41. Epub 2004/07/21.PubMedGoogle Scholar
  28. Rock FL, Hardiman G, Timans JC, Kastelein RA, Bazan JF. A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci USA. 1998;95(2):588–93. Epub 1998/01/22.PubMedGoogle Scholar
  29. Salazar-Gonzalez RM, McSorley SJ. Salmonella flagellin, a microbial target of the innate and adaptive immune system. Immunol Lett. 2005;101(2):117–22. Epub 2005/06/25.PubMedGoogle Scholar
  30. Salazar-Gonzalez RM, Srinivasan A, Griffin A, Muralimohan G, Ertelt JM, Ravindran R, et al. Salmonella flagellin induces bystander activation of splenic dendritic cells and hinders bacterial replication in vivo. J Immunol. 2007;179(9):6169–75. Epub 2007/10/20.PubMedGoogle Scholar
  31. Santaolalla R, Fukata M, Abreu MT. Innate immunity in the small intestine. Curr Opin Gastroenterol. 2011;27(2):125–31. Epub 2011/01/21.PubMedGoogle Scholar
  32. Sebastiani G, Leveque G, Lariviere L, Laroche L, Skamene E, Gros P, et al. Cloning and characterization of the murine toll-like receptor 5 (Tlr5) gene: sequence and mRNA expression studies in Salmonella-susceptible MOLF/Ei mice. Genomics. 2000;64(3):230–40. Epub 2000/04/11.PubMedGoogle Scholar
  33. Smith KD, Andersen-Nissen E, Hayashi F, Strobe K, Bergman MA, Barrett SL, et al. Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility. Nat Immunol. 2003;4(12):1247–53. Epub 2003/11/20.PubMedGoogle Scholar
  34. Subramanian N, Qadri A. Lysophospholipid sensing triggers secretion of flagellin from pathogenic salmonella. Nat Immunol. 2006;7(6):583–9. Epub 2006/05/02.PubMedGoogle Scholar
  35. Uematsu S, Akira S. Immune responses of TLR5(+) lamina propria dendritic cells in enterobacterial infection. J Gastroenterol. 2009;44(8):803–11. Epub 2009/06/24.PubMedGoogle Scholar
  36. Vijay-Kumar M, Aitken JD, Gewirtz AT. Toll like receptor-5: protecting the gut from enteric microbes. Semin Immunopathol. 2008;30(1):11–21. Epub 2007/12/11.PubMedGoogle Scholar
  37. Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, et al. Metabolic syndrome and altered gut microbiota in mice lacking toll-like receptor 5. Science. 2010;328(5975):228–31. Epub 2010/03/06.PubMedGoogle Scholar
  38. Werling D, Jann OC, Offord V, Glass EJ, Coffey TJ. Variation matters: TLR structure and species-specific pathogen recognition. Trends Immunol. 2009;30(3):124–30. Epub 2009/02/13.PubMedGoogle Scholar
  39. Zhang Z, Louboutin JP, Weiner DJ, Goldberg JB, Wilson JM. Human airway epithelial cells sense Pseudomonas aeruginosa infection via recognition of flagellin by toll-like receptor 5. Infect Immun. 2005;73(11):7151–60. Epub 2005/10/22.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Center for Comparative MedicineUniversity of California DavisDavisUSA