Skip to main content
SpringerLink
Log in

Toll like receptor-5: protecting the gut from enteric microbes

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

Abstract

The intestine is normally colonized by a large and diverse commensal microbiota and is occasionally exposed to a variety of potential pathogens. In recent years, there has been substantial progress made in identifying molecular mechanisms that normally serve to protect the intestine from such enteric bacteria and which may go awry in chronic idiopathic inflammatory diseases of the gut. One specific molecular interaction that appears to play a key role in governing bacterial–intestinal interactions is that of the bacterial protein flagellin with toll-like receptor 5. This article reviews studies performed in vitro, in mice, and in humans that indicate an important role for the flagellin-TLR5 interaction in regulating both the innate and adaptive immune responses in the intestine.

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. 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

    Article  PubMed  CAS  Google Scholar 

  2. Barthel M, Hapfelmeier S, Quintanilla-Martinez L, Kremer M, Rohde M, Hogardt M, Pfeffer K, Russmann H, Hardt WD (2003) Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis model that allows analysis of both pathogen and host. Infect Immun 71:2839–2858

    Article  PubMed  CAS  Google Scholar 

  3. 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 

  4. Darfeuille-Michaud A (2002) Adherent-invasive Escherichia coli: a putative new E. coli pathotype associated with Crohn’s disease. Int J Med Microbiol 292:185–193

    Article  PubMed  CAS  Google Scholar 

  5. Didierlaurent A, Ferrero I, Otten LA, Dubois B, Reinhardt M, Carlsen H, Blomhoff R, Akira S, Kraehenbuhl JP, Sirard JC (2004) Flagellin promotes myeloid differentiation factor 88-dependent development of Th2-type response. J Immunol 172:6922–6930

    PubMed  CAS  Google Scholar 

  6. Duck LW, Walter MR, Novak J, Kelly D, Tomasi M, Cong Y, Elson CO (2007) Isolation of flagellated bacteria implicated in Crohn’s disease. Inflamm Bowel Dis 13:1191–1201

    Article  PubMed  Google Scholar 

  7. 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

    Article  PubMed  CAS  Google Scholar 

  8. 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

    Article  PubMed  CAS  Google Scholar 

  9. 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

    Article  PubMed  CAS  Google Scholar 

  10. Franchi L, Kanneganti TD, Dubyak GR, Nunez G (2007) Differential requirement of P2X7 receptor and intracellular K+ for caspase-1 activation induced by intracellular and extracellular bacteria. J Biol Chem 282:18810–18818

    Article  PubMed  CAS  Google Scholar 

  11. Geis G, Suerbaum S, Forsthoff B, Leying H, Opferkuch W (1993) Ultrastructure and biochemical studies of the flagellar sheath of Helicobacter pylori. J Med Microbiol 38:371–377

    Article  PubMed  CAS  Google Scholar 

  12. 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 

  13. 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 

  14. Gewirtz AT, Simon PO Jr, Schmitt CK, Taylor LJ, Hagedorn CH, O'Brien AD, Neish AS, Madara JL (2001) Salmonella typhimurium translocates flagellin across intestinal epithelia, inducing a proinflammatory response. J Clin Invest 107:99–109

    PubMed  CAS  Google Scholar 

  15. Gewirtz AT, Liu Y, Sitaraman SV, Madara JL (2002) Intestinal epithelial pathobiology: past, present and future. Best Pract Res Clin Gastroenterol 16:851–867

    Article  PubMed  CAS  Google Scholar 

  16. Gewirtz AT (2003) Intestinal epithelial toll-like receptors: to protect. And serve? Curr Pharm Des 9:1–5

    Article  PubMed  CAS  Google Scholar 

  17. 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

    Article  PubMed  CAS  Google Scholar 

  18. Gewirtz AT, Vijay-Kumar M, Brant SR, Duerr RH, Nicolae DL, Cho JH (2006) Dominant-negative TLR5 polymorphism reduces adaptive immune response to flagellin and negatively associates with Crohn’s disease. Am J Physiol Gastrointest Liver Physiol 290:G1157–G1163

    Article  PubMed  CAS  Google Scholar 

  19. Gewirtz AT (2007) TLRs in the Gut. III. Immune responses to flagellin in Crohn’s disease: good, bad, or irrelevant? Am J Physiol Gastrointest Liver Physiol 292:G706–G710

    Article  PubMed  CAS  Google Scholar 

  20. 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

    Article  PubMed  CAS  Google Scholar 

  21. Hawn TR, Wu H, Grossman JM, Hahn BH, Tsao BP, Aderem A (2005) A stop codon polymorphism of Toll-like receptor 5 is associated with resistance to systemic lupus erythematosus. Proc Natl Acad Sci U S A 102:10593–10597

    Article  PubMed  CAS  Google Scholar 

  22. 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

    Article  PubMed  CAS  Google Scholar 

  23. Hollander D (1992) The intestinal permeability barrier. A hypothesis as to its regulation and involvement in Crohn’s disease. Scand J Gastroenterol 27:721–726

    Article  PubMed  CAS  Google Scholar 

  24. Konrad A, Cong Y, Duck W, Borlaza R, Elson CO (2006) Tight mucosal compartmentation of the murine immune response to antigens of the enteric microbiota. Gastroenterology 130:2050–2059

    Article  PubMed  CAS  Google Scholar 

  25. Lee SK, Stack A, Katzowitsch E, Aizawa SI, Suerbaum S, Josenhans C (2003) Helicobacter pylori flagellins have very low intrinsic activity to stimulate human gastric epithelial cells via TLR5. Microbes Infect 5:1345–1356

    Article  PubMed  CAS  Google Scholar 

  26. Ley RE, Knight R, Gordon JI (2007) The human microbiome: eliminating the biomedical/environmental dichotomy in microbial ecology. Environ Microbiol 9:3–4

    Article  PubMed  Google Scholar 

  27. Lodes MJ, Cong Y, Elson CO, Mohamath R, Landers CJ, Targan SR, Fort M, Hershberg RM (2004) Bacterial flagellin is a dominant antigen in Crohn disease. J Clin Invest 113:1296–1306

    Article  PubMed  CAS  Google Scholar 

  28. Lu W, Hisatsune A, Koga T, Kato K, Kuwahara I, Lillehoj EP, Chen W, Cross AS, Gendler SJ, Gewirtz AT, Kim KC (2006) Cutting edge: enhanced pulmonary clearance of Pseudomonas aeruginosa by Muc1 knockout mice. J Immunol 176:3890–3894

    PubMed  CAS  Google Scholar 

  29. Lyons S, Wang L, Casanova JE, Sitaraman SV, Merlin D, Gewirtz AT (2004) Salmonella typhimurium transcytoses flagellin via an SPI2-mediated vesicular transport pathway. J Cell Sci 117:5771–5780

    Article  PubMed  CAS  Google Scholar 

  30. Macnab RM (2003) How bacteria assemble flagella. Annu Rev Microbiol 57:77–100

    Article  PubMed  CAS  Google Scholar 

  31. Manson MD, Armitage JP, Hoch JA, Macnab RM (1998) Bacterial locomotion and signal transduction. J Bacteriol 180:1009–1022

    PubMed  CAS  Google Scholar 

  32. McDonald WF, Huleatt JW, Foellmer HG, Hewitt D, Tang J, Desai P, Price A, Jacobs A, Takahashi VN, Huang Y, Nakaar V, Alexopoulou L, Fikrig E, Powell TJ (2007) A West Nile virus recombinant protein vaccine that coactivates innate and adaptive immunity. J Infect Dis 195:1607–1617

    Article  PubMed  CAS  Google Scholar 

  33. McSorley SJ, Cookson BT, Jenkins MK (2000) Characterization of CD4+ T cell responses during natural infection with Salmonella typhimurium. J Immunol 164:986–993

    PubMed  CAS  Google Scholar 

  34. McSorley SJ, Ehst BD, Yu Y, Gewirtz AT (2002) Bacterial flagellin is an effective adjuvant for CD4+ T cells in vivo. J Immunol 169:3914–3919

    PubMed  CAS  Google Scholar 

  35. 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 

  36. 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

    Article  PubMed  CAS  Google Scholar 

  37. Miao EA, Andersen-Nissen E, Warren SE, Aderem A (2007) TLR5 and Ipaf: dual sensors of bacterial flagellin in the innate immune system. Semin Immunopathol (in press)

  38. Mizel SB, West AP, Hantgan RR (2003) Identification of a sequence in human toll-like receptor 5 required for the binding of Gram-negative flagellin. J Biol Chem 278:23624–23629

    Article  PubMed  CAS  Google Scholar 

  39. 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

    Article  PubMed  CAS  Google Scholar 

  40. Ozinsky A, Underhill DM, Fontenot JD, Hajjar AM, Smith KD, Wilson CB, Schroeder L, Aderem A (2000) The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Natl Acad Sci U S A 97:13766–13771

    Article  PubMed  CAS  Google Scholar 

  41. Reed KA, Hobert ME, Kolenda CE, Sands KA, Rathman M, O’Connor M, Lyons S, Gewirtz AT, Sansonetti PJ, Madara JL (2002) The Salmonella typhimurium flagellar basal body protein FliE is required for flagellin production and to induce a proinflammatory response in epithelial cells. J Biol Chem 277:13346–13353

    Article  PubMed  CAS  Google Scholar 

  42. 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

    Article  PubMed  CAS  Google Scholar 

  43. Rhee SH, Im E, Riegler M, Kokkotou E, O'Brien M, Pothoulakis C (2005) Pathophysiological role of Toll-like receptor 5 engagement by bacterial flagellin in colonic inflammation. Proc Natl Acad Sci U S A 102:13610–13615

    Article  PubMed  CAS  Google Scholar 

  44. Sanders CJ, Yu Y, Moore DA 3rd, Williams IR, Gewirtz AT (2006) Humoral immune response to flagellin requires T cells and activation of innate immunity. J Immunol 177:2810–2818

    PubMed  CAS  Google Scholar 

  45. Sitaraman SV, Klapproth JM, Moore DA 3rd, Landers C, Targan S, Williams IR, Gewirtz AT (2005) Elevated flagellin-specific immunoglobulins in Crohn’s disease. Am J Physiol Gastrointest Liver Physiol 288:G403–G406

    Article  PubMed  CAS  Google Scholar 

  46. 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

    Article  PubMed  CAS  Google Scholar 

  47. Strober W, Fuss I, Mannon P (2007) The fundamental basis of inflammatory bowel disease. J Clin Invest 117:514–521

    Article  PubMed  CAS  Google Scholar 

  48. Subramanian N, Qadri A (2006) Lysophospholipid sensing triggers secretion of flagellin from pathogenic Salmonella. Nat Immunol 7:583–589

    Article  PubMed  CAS  Google Scholar 

  49. Swidsinski A, Ladhoff A, Pernthaler A, Swidsinski S, Loening-Baucke V, Ortner M, Weber J, Hoffmann U, Schreiber S, Dietel M, Lochs H (2002) Mucosal flora in inflammatory bowel disease. Gastroenterology 122:44–54

    Article  PubMed  Google Scholar 

  50. 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

    Article  PubMed  CAS  Google Scholar 

  51. Vijay-Kumar M, Wu H, Jones R, Grant G, Babbin B, King TP, Kelly D, Gewirtz AT, Neish AS (2006) Flagellin suppresses epithelial apoptosis and limits disease during enteric infection. Am J Pathol 169:1686–1700

    Article  PubMed  CAS  Google Scholar 

  52. Vijay-Kumar M, Sanders CJ, Akira S, Neish AS, Williams IR, Uematsu S, Gewirtz AT (2007) Mice lacking TLR5 develop spontaneous colitis. J Clin Invest (in press)

  53. Watson RO, Galan JE (2005) Signal transduction in Campylobacter jejuni-induced cytokine production. Cell Microbiol 7:655–665

    Article  PubMed  CAS  Google Scholar 

  54. Yu Y, Zeng H, Lyons S, Carlson A, Merlin D, Neish AS, Gewirtz AT (2003) TLR5-mediated activation of p38 MAPK regulates epithelial IL-8 expression via posttranscriptional mechanism. Am J Physiol Gastrointest Liver Physiol 285:G282–G290

    PubMed  CAS  Google Scholar 

  55. Yu Y, Zeng H, Vijay-Kumar M, Neish AS, Merlin D, Sitaraman SV, Gewirtz AT (2004) STAT signaling underlies difference between flagellin-induced and tumor necrosis factor-alpha-induced epithelial gene expression. J Biol Chem 279:35210–35218

    Article  PubMed  CAS  Google Scholar 

  56. 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 

  57. Zeng H, Carlson AQ, Guo Y, Yu Y, Collier-Hyams LS, Madara JL, Gewirtz AT, Neish AS (2003) Flagellin is the major proinflammatory determinant of enteropathogenic Salmonella. J Immunol 171:3668–3674

    PubMed  CAS  Google Scholar 

  58. Zeng H, Wu H, Sloane V, Jones R, Yu Y, Lin P, Gewirtz AT, Neish AS (2006) Flagellin/TLR5 responses in epithelia reveal intertwined activation of inflammatory and apoptotic pathways. Am J Physiol Gastrointest Liver Physiol 290:G96–G108

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, Emory University, Atlanta, GA, USA

    Matam Vijay-Kumar, Jesse D. Aitken & Andrew T. Gewirtz

Authors
  1. Matam Vijay-Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jesse D. Aitken
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew T. Gewirtz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrew T. Gewirtz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vijay-Kumar, M., Aitken, J.D. & Gewirtz, A.T. Toll like receptor-5: protecting the gut from enteric microbes. Semin Immunopathol 30, 11–21 (2008). https://doi.org/10.1007/s00281-007-0100-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-007-0100-5

Keywords

Search

Navigation