Recognition of fungal pathogens by Toll-like receptors

  • M. G. NeteaEmail author
  • C. Van der Graaf
  • J. W. M. Van der Meer
  • B. J. Kullberg


Toll-like receptors (TLRs) have been identified as a major class of pattern-recognition receptors. Recognition of pathogen-associated molecular patterns by TLRs, either alone or in heterodimerization with other TLR or non-TLR receptors, induces signals responsible for the activation of the innate immune response. Recent studies have demonstrated a crucial involvement of TLRs in the recognition of fungal pathogens such as Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans. Through the study of fungal infection in knock-out mice deficient in either TLRs or TLR-associated adaptor molecules, it became apparent that specific TLRs such as TLR2 and TLR4 play differential roles in the activation of the various arms of the innate immune response. Recent data also suggest that TLRs offer escape mechanisms to certain pathogenic microorganisms, especially through TLR2-driven induction of anti-inflammatory cytokines. These new data have substantially increased our knowledge of the recognition of fungal pathogens, and the study of TLRs remains one of the most active areas of research in the field of fungal infections.


Fungal Pathogen Candidiasis Innate Immune Response Aspergillosis Invasive Aspergillosis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Lemaitre B, Nicolas E, Michaut L, Reichhart J-M, Hoffmann JA (1996) The dorsoventral regulatory gene cassette Spaetzle/Toll/Cactus controls the potent antifungal response in Drosophila adults. Cell 86:973–983CrossRefPubMedGoogle Scholar
  2. 2.
    Alarco A-M, Marcil A, Chen J, Suter B, Thomas D, Whiteway M (2004) Immune-deficient Drosophila melanogaster: a model for the innate immune response to human fungal pathogens. J Immunol 172:5622–5628PubMedGoogle Scholar
  3. 3.
    Rock FL, Hardiman G, Timans JC, Kastelein JA, Bazan JF (1998) A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci USA 95:588–593Google Scholar
  4. 4.
    Akira S, Hemmi H (2003) Recognition of pathogen-associated molecular patterns by TLR family. Immunol Lett 85:85–95CrossRefPubMedGoogle Scholar
  5. 5.
    Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev Immunol 21:335–376Google Scholar
  6. 6.
    Underhill DM, Ozinsky A (2002) Toll-like receptors: key mediators of microbe detection. Curr Opin Immunol 4:103–110CrossRefGoogle Scholar
  7. 7.
    Kopp E, Medzhitov R (2003) Recognition of microbial infection by Toll-like receptors. Curr Opin Immunol 15:396–401CrossRefPubMedGoogle Scholar
  8. 8.
    Underhill DM, Ozinski A, Hajjar AM, Stevens A, Wilson CB, Bassetti M, Aderem A (1999) The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 401:811–815CrossRefPubMedGoogle Scholar
  9. 9.
    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 USA 97:13766–13771Google Scholar
  10. 10.
    Klis FM, de Groot P, Hellingwerf K (2001) Molecular organization of the cell wall of Candida albicans. Med Mycol 39(Suppl 1):1–8Google Scholar
  11. 11.
    Netea MG, de Graaf C, Vonk A, Verschueren I, Van der Meer JWM, Kullberg BJ (2002) The role of Toll-like receptors in the defense against disseminated candidiasis. J Infect Dis 185:1483–1489CrossRefPubMedGoogle Scholar
  12. 12.
    Bellocchio S, Montagnoli C, Bozza S, Gaziano R, Rossi G, Mambula SS, Vecchi A, Mantovani A, Levitz SM, Romani L (2004) The contribution of Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo. J Immunol 172:3059–3069PubMedGoogle Scholar
  13. 13.
    Marr KA, Arunmozhi Balajee S, Hawn TR, Ozinsky A, Pham U, Akira S, Aderem A, Conrad Liles W (2003) Differential role of MyD88 in macrophage-mediated responses to opportunistic fungal pathogens. Infect Immun 71:5280–5286CrossRefPubMedGoogle Scholar
  14. 14.
    Brown GD, Herre J, Williams DL, Willment JA, Marshall AS, Gordon S (2003) Dectin-1 mediates the biological effects of beta-glucans. J Exp Med 197:1119–1124CrossRefPubMedGoogle Scholar
  15. 15.
    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 197:1107–1117CrossRefPubMedGoogle Scholar
  16. 16.
    Villamon E, Gozalbo D, Roig P, O’Connor JE, Fradelizi D, Gil ML (2004) Toll-like receptor-2 is essential in murine defenses against Candida albicans infections. Microbes Infect 6:1–7CrossRefPubMedGoogle Scholar
  17. 17.
    Netea MG, Sutmuller R, Hermann C, Van der Graaf CAA, Van der Meer JWM, Adema G, Kullberg BJ (2004) Toll-like receptor 2 inhibits cellular responses against Candida albicans through pathways mediated by IL-10 and CD4+CD25+regulatory T cells. J Immunol 172:3712–3718PubMedGoogle Scholar
  18. 18.
    Villamon E, Gozalbo D, Roig P, O’Connor JE, Ferrandiz ML, Fradelizi D, Gil ML (2004) Toll-like receptor 2 is dispensable for acquired host immune resistance to Candida albicans in a murine model of disseminated candidiasis. Microbes Infect 6:542–548PubMedGoogle Scholar
  19. 19.
    Beck-Sagué CM, Jarvis WR (1993) Secular trends in the epidemiology of nosocomial fungal infections in the United States, 1980–1990. J Infect Dis 167:1247–1251PubMedGoogle Scholar
  20. 20.
    Wang JE, Warris A, Ellingsen EA, Jorgensen PF, Flo TH, Espevik T, Solberg R, Verweij PE, Aasen AO (2001) Involvement of CD14 and Toll-like receptors in activation of human monocytes by Aspergillus fumigatus hyphae. Infect Immun 69:2402–2406CrossRefPubMedGoogle Scholar
  21. 21.
    Mambula SS, Sau K, Henneke P, Golenbock DT, Levitz SM (2002) Toll-like receptor (TLR) signaling in response to Aspergillus fumigatus. J Biol Chem 277:39320–39326CrossRefPubMedGoogle Scholar
  22. 22.
    Netea MG, Warris A, Van der Meer JWM, Fenton MJ, Jacobs L, Verver-Jansen T, Andressen T, Verweij P, Kullberg BJ (2003) Aspergillus fumigatus evades immune recognition during germination through loss of TLR4-mediated signal transduction. J Infect Dis 188:320–326CrossRefPubMedGoogle Scholar
  23. 23.
    Meier A, Kirschning CJ, Nikolaus T, Wagner H, Heesemann J, Ebel F (2003) Toll-like receptor (TLR) 2 and TLR4 are essential for Aspergillus-induced activation of murine macrophages. Cell Microbiol 5:561–570CrossRefPubMedGoogle Scholar
  24. 24.
    Braedel S, Radsak M, Einsele H, Latge J-P, Michan A, Loeffler J, Haddad Z, Grigoleit U, Schild H, Hebart H (2004) Aspergillus fumigatus antigens activate innate immune cells via Toll-like receptors 2 and 4. Br J Haematol 125:392–399PubMedGoogle Scholar
  25. 25.
    Shoham S, Huang C, Chen J-M, Golenbock DT, Levitz SM (2001) Toll-like receptor 4 mediates intracellular signaling without TNF release in response to Cryptococcus neoformans polysaccharide capsule. J Immunol 166:4620–4626PubMedGoogle Scholar
  26. 26.
    Jouault T, Ibata-Ombetta S, Takeuchi O, Trinel P-A, Sacchetti P, Lefebvre P, Akira S, Poulain D (2003) Candida albicans phospholipomannan is sensed through Toll-like receptors. J Infect Dis 188:165–172CrossRefPubMedGoogle Scholar
  27. 27.
    Tada H, Nemoto E, Shimauki H, Watanabe T, Mikami T, Matsumoto T, Ohna N, Tamura H, Shibata K, Akashi S, Miyake K, Sugawara S, Takada H (2002) S. cerevisiae- and Candida albicans-derived mannan induced production of tumor necrosis factor alpha by human monocytes in a CD14- and Toll-like receptor 4-dependent manner. Microbiol Immunol 46:503–512PubMedGoogle Scholar
  28. 28.
    Roeder A, Kirschning CJ, Rupec RA, Schaller M, Korting HC (2004) Toll-like receptors and innate antifungal responses. Trends Microbiol 12:44–49CrossRefPubMedGoogle Scholar
  29. 29.
    Romani L (2004) Immunity to fungal infections. Nat Rev Immunol 4:1–13CrossRefPubMedGoogle Scholar
  30. 30.
    Netea MG, Van der Graaf C, Van der Meer JWM, Kullberg BJ (2004) The role of Toll-like receptors in host defense: bringing specificity to the innate immune response. J Leuk Biol 75:749–755CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • M. G. Netea
    • 1
    • 2
    Email author
  • C. Van der Graaf
    • 1
    • 2
  • J. W. M. Van der Meer
    • 1
    • 2
  • B. J. Kullberg
    • 1
    • 2
  1. 1.Department of MedicineRadboud University Medical Center NijmegenNijmegenThe Netherlands
  2. 2.Nijmegen University Center for Infectious DiseasesNijmegenThe Netherlands

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