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  • Review Article
  • Published:

An integrated model of the recognition of Candida albicans by the innate immune system

Nature Reviews Microbiology volume 6, pages 67–78 (2008)Cite this article

Key Points

  • Recognition of fungi by the innate immune system depends on 'tasting' several pathogen-associated molecular patterns (PAMPs) in the fungal cell wall. Specific receptor systems have evolved for the recognition of the major polysaccharide cell wall components, such as the mannose receptor (MR) and DC-SIGN for recognition of branched N-linked mannan, Toll-like receptor 4 (TLR4) for linear O-linked mannan, galectin 3 for β-mannosides, complement receptor 3 (CR3) for β-(1,6)-glucan, and dectin 1 and TLR2 for β-glucan and phospholipomannan.

  • Despite overlapping and sometimes redundant functions, each ligand–receptor system activates specific intracellular pathways, and this has distinct consequences for the activation of the various arms of the immune response.

  • Differential expression of the various pattern-recognition receptors (PRRs) is an important mechanism for the cell-type-specific response to fungal pathogens.

  • The fully integrated response to a specific pathogen depends on the mosaic of PRRs and receptor complexes that is engaged.

  • The recognition pathways might operate singly or, more likely, in combination. Co-stimulation via multiple PAMP–PRR combinations might increase both the sensitivity and the specificity of the immune recognition process.

  • Although described here for Candida albicans, these principles of innate immune recognition can be considered as a blueprint for pattern recognition of all pathogenic microorganisms by the innate immune response.

Abstract

The innate immune response was once considered to be a limited set of responses that aimed to contain an infection by primitive 'ingest and kill' mechanisms, giving the host time to mount a specific humoral and cellular immune response. In the mid-1990s, however, the discovery of Toll-like receptors heralded a revolution in our understanding of how microorganisms are recognized by the innate immune system, and how this system is activated. Several major classes of pathogen-recognition receptors have now been described, each with specific abilities to recognize conserved bacterial structures. The challenge ahead is to understand the level of complexity that underlies the response that is triggered by pathogen recognition. In this Review, we use the fungal pathogen Candida albicans as a model for the complex interaction that exists between the host pattern-recognition systems and invading microbial pathogens.

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Figure 1: The structure of the Candida albicans cell wall.
Figure 2: Cell populations and pattern-recognition receptors involved in Candida albicans recognition.
Figure 3: Recognition of Candida albicans at the membrane level.
Figure 4: Candida albicans mechanisms to escape the innate response using pattern-recognition receptors.

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References

  1. Edmond, M. B. et al. Nosocomial bloodstream infections in United States hospitals: a three-year analysis. Clin. Infect. Dis. 29, 239–244 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Enoch, D. A., Ludlam, H. A. & Brown, N. M. Invasive fungal infections: a review of epidemiology and management options. J. Med. Microbiol. 55, 809–818 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Wisplinghoff, H. et al. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin. Infect. Dis. 39, 309–317 (2004).

    PubMed  Google Scholar 

  4. Gudlaugsson, O. et al. Attributable mortality of nosocomial candidemia, revisited. Clin. Infect. Dis. 37, 1172–1177 (2003).

    Article  PubMed  Google Scholar 

  5. Stevens, D. A. Combination immunotherapy and antifungal chemotherapy. Clin. Infect. Dis. 26, 1266–1269 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Mitchison, A. Will we survive? Sci. Am. 269, 136–144 (1993).

    Article  CAS  PubMed  Google Scholar 

  7. Hoebe, K., Janssen, E. & Beutler, B. The interface between innate and adaptive immunity. Nature Immunol. 5, 971–974 (2004).

    Article  CAS  Google Scholar 

  8. Ernst, J. F. & Prill, S. K. O-glycosylation. Med. Mycol. 39 1, 67–74 (2001).

    Article  Google Scholar 

  9. Cutler, J. E. N-glycosylation of yeast, with emphasis on Candida albicans. Med. Mycol. 39, 75–86 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Klis, F. M., Boorsma, A. & De Groot, P. W. Cell wall construction in Saccharomyces cerevisiae. Yeast 23, 185–202 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Gantner, B. N., Simmons, R. M. & Underhill, D. M. Dectin-1 mediates macrophage recognition of Candida albicans yeasts but not filaments. EMBO J. 24, 1277–1286 (2005). Describes the differential recognition of C. albicans yeast and hyphae by dectin 1 as a major escape mechanism.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Suzuki, A. in Candida and Candidosis (ed. Calderone, R. A.) 29–36 (ASM Press, Washington, 2002).

    Google Scholar 

  13. Vecchiarelli, A., Puliti, M., Torosantucci, A., Cassone, A. & Bistoni, F. In vitro production of tumor necrosis factor by murine splenic macrophages stimulated with mannoprotein constituents of Candida albicans cell wall. Cell. Immunol. 134, 65–76 (1991).

    Article  CAS  PubMed  Google Scholar 

  14. Garner, R. E., Rubanowice, K., Sawyer, R. T. & Hudson, J. A. Secretion of TNF-α by alveolar macrophages in response to Candida albicans mannan. J. Leuk. Biol. 55, 161–168 (1994).

    Article  CAS  Google Scholar 

  15. Pietrella, D., Bistoni, G., Corbucci, C., Perito, S. & Vecchiarelli, A. Candida albicans mannoprotein influences the biological function of dendritic cells. Cell. Microbiol. 8, 602–612 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Gomez, M. J. et al. Purification and biochemical characterization of a 65-kilodalton mannoprotein (MP65), a main target of anti-Candida cell-mediated immune responses in humans. Infect. Immun. 64, 2577–2584 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Gomez, M. J. et al. Biochemical and immunological characterization of MP65, a major mannoprotein antigen of the opportunistic human pathogen Candida albicans. Infect. Immun. 68, 694–701 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mencacci, A. et al. A mannoprotein constituent of Candida albicans that elicits different levels of delayed-type hypersensitivity, cytokine production, and anticandidal protection in mice. Infect. Immun. 62, 5353–5360 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Wileman, T. E., Lennartz, M. R. & Stahl, P. D. Identification of the macrophage mannose receptor as a 175-kDa membrane protein. Proc. Natl Acad. Sci. USA 83, 2501–2505 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Stephenson, J. D. & Shepherd, V. L. Purification of the human alveolar macrophage mannose receptor. Biochem. Biophys. Res. Commun. 148, 883–889 (1987).

    Article  CAS  PubMed  Google Scholar 

  21. Stahl, P. D., Rodman, J. S., Miller, M. J. & Schlesinger, P. H. Evidence for receptor-mediated binding of glycoproteins, glycoconjugates, and lysosomal glycosidases by alveolar macrophages. Proc. Natl Acad. Sci. USA 75, 1399–1403 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Linehan, S. A., Martinez-Pomares, L. & Gordon, S. Macrophage lectins in host defence. Microbes Infect. 2, 279–288 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Kery, V., Krepinsky, J. J., Warren, C. D., Capek, P. & Stahl, P. D. Ligand recognition by purified human mannose receptor. Arch. Biochem. Biophys. 298, 49–55 (1992).

    Article  CAS  PubMed  Google Scholar 

  24. Netea, M. G. et al. Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors. J. Clin. Invest. 116, 1642–1650 (2006). Proposed, for the first time, an integrated model of fungal recognition.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tada, H. et al. Saccharomyces cerevisiae- and Candida albicans-derived mannan induced production of tumor necrosis factor α by human monocytes in a CD14- and Toll-like receptor 4-dependent manner. Microbiol. Immunol. 2002, 503–512 (2002).

    Article  Google Scholar 

  26. van der Graaf, C. A. A., Netea, M. G., Verschueren, I., van der Meer, J. W. M. & Kullberg, B. J. Differential cytokine production and Toll-like receptor signaling pathways by Candida albicans blastoconidia and hyphae. Infect. Immun. 73, 7458–7464 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cambi, A. et al. The C-type lectin DC-SIGN (CD209) is an antigen-uptake receptor for Candida albicans on dendritic cells. Eur. J. Immunol. 33, 532–538 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Jouault, T. et al. Candida albicans phospholipomannan is sensed through Toll-like receptors. J. Infect. Dis. 188, 165–172 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Jouault, T. et al. Specific recognition of Candida albicans by macrophages requires galectin-3 to discriminate Saccharomyces cerevisiae and needs association with TLR2 for signaling. J. Immunol. 177, 4679–4687 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Ariizumi, K. et al. Cloning of a second dendritic cell-associated C-type lectin (dectin-2) and its alternatively spliced isoforms. J. Biol. Chem. 275, 11957–11963 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Taylor, P. R. et al. Dectin-2 is predominantly myeloid restricted and exhibits unique activation-dependent expression on maturing inflammatory monocytes elicited in vivo. Eur. J. Immunol. 35, 2163–2174 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Sato, K. et al. Dectin-2 is a pattern recognition receptor for fungi that couples with the Fc receptor γ chain to induce innate immune responses. J. Biol. Chem. 281, 38854–38866 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. McGreal, E. P. et al. The carbohydrate-recognition domain of Dectin-2 is a C-type lectin with specificity for high mannose. Glycobiology 16, 422–430 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Klis, F. M., de Groot, P. & Hellingwerf, K. Molecular organization of the cell wall of Candida albicans. Med. Mycol. 39, 1–8 (2001). A model of the C. albicans cell wall.

    Article  CAS  PubMed  Google Scholar 

  35. Torosantucci, A. et al. A novel glyco-conjugate vaccine against fungal pathogens. J. Exp. Med. 202, 597–606 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Brown, G. D. & Gordon, S. Immune recognition of fungal β-glucans. Cell. Microbiol. 7, 471–479 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Obayashi, T. et al. Plasma (1,3)-β-D-glucan measurement in diagnosis of invasive deep mycosis and fungal febrile episodes. Lancet 345, 17–20 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Thornton, B. P., Vetvicka, V., Pitman, M., Goldman, R. C. & Ross, G. D. Analysis of the sugar specificity and molecular location of the β-glucan-binding lectin site of complement receptor type 3 (CD11b/CD18). J. Immunol. 156, 1235–1246 (1996).

    CAS  PubMed  Google Scholar 

  39. Diamond, M. S., Garcia-Aguilar, J., Bickford, J. K., Corbi, A. L. & Springer, T. A. The I domain is a major recognition site on the leukocyte integrin Mac-1 (CD11b/CD18) for four distinct adhesion ligands. J. Cell Biol. 120, 1031–1043 (1993).

    Article  CAS  PubMed  Google Scholar 

  40. Forsyth, C. B. & Mathews, H. L. Lymphocyte adhesion to Candida albicans. Infect. Immun. 70, 517–527 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Forsyth, C. B., Plow, E. F. & Zhang, L. Interaction of the fungal pathogen Candida albicans with integrin CD11b/CD18: recognition by the I domain is modulated by the lectin-like domain and the CD18 subunit. J. Immunol. 161, 6198–6205 (1998).

    CAS  PubMed  Google Scholar 

  42. Wright, S. D. & Silverstein, S. C. Receptors for C3b and C3bi promote phagocytosis but not the release of toxic oxygen from human phagocytes. J. Exp. Med. 158, 2016–2023 (1983).

    Article  CAS  PubMed  Google Scholar 

  43. Brandhorst, T. T., Wuthrich, M., Finkel-Jimenez, B., Warner, T. & Klein, B. S. Exploiting type 3 complement receptor for TNF-α suppression, immune evasion, and progressive pulmonary fungal infection. J. Immunol. 173, 7444–7453 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Wright, S. D. & Silverstein, S. C. Tumor-promoting phorbol esters stimulate C3b and C3b′ receptor-mediated phagocytosis in cultured human monocytes. J. Exp. Med. 156, 1149–1164 (1982).

    Article  CAS  PubMed  Google Scholar 

  45. Brown, G. D. & Gordon, S. Fungal β-glucans and mammalian immunity. Immunity 19, 311–315 (2003). A review that describes the role of β-glucan recognition in host defence.

    Article  CAS  PubMed  Google Scholar 

  46. Rogers, N. C. et al. SYK-dependent cytokine induction by dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 22, 507–517 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Gow, N. A. R. et al. Recognition of Candida albicans β-glucan by dectin-1 induces cytokines and has non-redundant effects on the activation of innate immunity. J. Infect. Dis. (in the press).

  48. Leibundgut-Landmann, S. et al. SYK- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nature Immunol. 8, 630–638 (2007). This study demonstrates the specific activation of T H 17 cells by dectin 1.

    Article  CAS  Google Scholar 

  49. Brown, G. D. et al. Dectin-1 mediates the biological effects of β-glucans. J. Exp. Med. 197, 1119–1124 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Gantner, B. N., Simmons, R. M., Canavera, S. J., Akira, S. & Underhill, D. M. Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J. Exp. Med. 197, 1107–1117 (2003). References 49 and 50 show for the first time the collaboration between TLRs (TLR2) and LRs (dectin 1).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Rubin-Bejerano, I., Abeijon, C., Magnelli, P., Grisafi, P. & Fink, G. R. Phagocytosis by human neutrophils is stimulated by a unique fungal cell wall component. Cell Host Microbe 2, 55–67 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Minke, R. & Blackwell, J. The structure of α-chitin. J. Mol. Biol. 120, 167–181 (1978).

    Article  CAS  PubMed  Google Scholar 

  53. van der Graaf, C. A. et al. Nucleotide oligomerization domain 2 (Nod2) is not involved in the pattern recognition of Candida albicans. Clin. Vaccine Immunol. 13, 423–425 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wagner, H. Toll meets bacterial CpG-DNA. Immunity 14, 499–502 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Bellocchio, S. et al. The contribution of Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo. J. Immunol. 172, 3059–3069 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Kozel, T. R. Activation of the complement system by pathogenic fungi. Clin. Microbiol. Rev. 9, 34–46 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kozel, T. R., Weinhold, L. C. & Lupan, D. M. Distinct characteristics of initiation of the classical and alternative complement pathways by Candida albicans. Infect. Immun. 64, 3360–3368 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Herre, J. et al. Dectin-1 uses novel mechanisms for yeast phagocytosis in macrophages. Blood 104, 4038–4045 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Ezekowitz, R. A. B. et al. Restoration of phagocyte function by interferon-γ in X-linked chronic granulomatous disease occurs at the level of a progenitor cell. Blood 76, 2443–2448 (1990).

    CAS  PubMed  Google Scholar 

  60. Romani, L. et al. The exploitation of distinct recognition receptors in dendritic cells determines the full range of host immune relationships with Candida albicans. Int. Immunol. 16, 149–161 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Le Cabec, V., Emorine, L. J., Toesca, I., Cougoule, C. & Maridonneau-Parini, I. The human macrophage mannose receptor is not a professional phagocytic receptor. J. Leuk. Biol. 77, 934–943 (2005).

    Article  CAS  Google Scholar 

  62. Blander, J. M. & Medzhitov, R. Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature 440, 808–812 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Romani, L. Immunity to fungal infections. Nature Rev. Immunol. 4, 1–13 (2004).

    Article  CAS  Google Scholar 

  64. Kennedy, A. D. et al. Dectin-1 promotes fungicidal activity of human neutrophils. Eur. J. Immunol. 37, 467–478 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Aratani, Y. et al. Severe impairment in early host defense against Candida albicans in mice deficient in myeloperoxidase. Infect. Immun. 67, 1828–1836 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Mansour, M. K. & Levitz, S. M. Interactions of fungi with phagocytes. Curr. Opin. Microbiol. 5, 359–365 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Reeves, E. P. et al. Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature 416, 291–297 (2002).

    Article  CAS  PubMed  Google Scholar 

  68. Kohatsu, L., Hsu, D. K., Jegalian, A. G., Liu, F. T. & Baum, L. G. Galectin-3 induces death of Candida species expressing specific β-1, 2-linked mannans. J. Immunol. 177, 4718–4726 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Akira, S. & Hemmi, H. Recognition of pathogen-associated molecular patterns by TLR family. Immunol. Letters 85, 85–95 (2003).

    Article  CAS  Google Scholar 

  70. Toshchakov, V. et al. TLR4, but not TLR2, mediates IFNβ-induced STAT I α/β-dependent gene expression in macrophages. Nature Immunol. 3, 392–398 (2002).

    Article  CAS  Google Scholar 

  71. Netea, M. G. et al. The role of Toll-like receptors in the defense against disseminated candidiasis. J. Infect. Dis. 185, 1483–1489 (2002). Demonstrates, for the first time, the role of TLRs in C. albicans recognition.

    Article  CAS  PubMed  Google Scholar 

  72. Hirschfeld, M. et al. Signaling by Toll-like receptor 2 and 4 agonists results in differential gene expression in murine macrophages. Infect. Immun. 69, 1477–1482 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Re, F. & Strominger, J. L. Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells. J. Biol. Chem. 276, 37692–37699 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Agrawal, S. et al. Different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos. J. Immunol. 171, 4984–4989 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Dillon, S. et al. Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance. J. Clin. Invest. 116, 916–928 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Pulendran, B. et al. Lipopolysaccharides from distinct pathogens induce different classes of immune responses in vivo. J. Immunol. 167, 5067–5076 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Netea, M. G. et al. 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, 3712–3718 (2004). Demonstrates, for the first time, induction of T Reg cells through TLR2 signals.

    Article  CAS  PubMed  Google Scholar 

  78. Sutmuller, R. P. et al. Toll-like receptor 2 controls expansion and function of regulatory T cells. J. Clin. Invest. 116, 485–494 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Van der Kleij, D. et al. A novel host-parasite lipid cross-talk: schistosomal lyso-phosphatidylserine activates Toll-like receptor 2 and affects immune polarization. J. Biol. Chem. 277, 48122–48129 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Diterich, I., Rauter, C., Kirschning, C. J. & Hartung, T. Borrelia burgdorferi-induced tolerance as a model of persistence via immunosuppression. Infect. Immun. 71, 3979–3985 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Underhill, D. M. et al. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminate between pathogens. Nature 401, 811–815 (1999). One of the first studies to demonstrate the discrimination of pathogens by TLRs.

    Article  CAS  PubMed  Google Scholar 

  82. Netea, M. G., van de Veerdonk, F., Verschueren, I., van der Meer, J. W. & Kullberg, B. J. Role of TLR1 and TLR6 in the host defense against disseminated candidiasis. FEMS Immnol. Med. Microbiol. (in the press).

  83. Brown, G. R., Silva, M. D., Thompson, P. A. & Beutler, B. Lymphoid hyperplasia, CD45RBhigh to CD45RBlow T-cell imbalance, and suppression of type I diabetes mellitus result from TNF blockade in NOD–NOD–scid adoptive T cell transfer. Diabetologia 41, 1502–1510 (1998).

    Article  CAS  PubMed  Google Scholar 

  84. Steele, C. et al. The β-glucan receptor dectin-1 recognizes specific morphologies of Aspergillus fumigatus. PLoS Pathog. 4, 323–334 (2005).

    Google Scholar 

  85. Steele, C. et al. Alveolar macrophage-mediated killing of Pneumocystis carinii f. sp. muris involves molecular recognition by the Dectin-1 β-glucan receptor. J. Exp. Med. 198, 1677–1688 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Viriyakosol, S., Fierer, J., Brown, G. D. & Kirkland, T. N. Innate immunity to the pathogenic fungus Coccidioides posadasii is dependent on Toll-like receptor 2 and dectin-1. Infect. Immun. 73, 1553–1560 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Slack, E. C. et al. Syk-dependent ERK activation regulates IL-2 and IL-10 production by DC stimulated with zymosan. Eur. J. Immunol. 37, 1600–1612 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Meyer-Wentrup, F. et al. Dectin-1 interaction with tetraspanin CD37 inhibits IL-6 production. J. Immunol. 178, 154–162 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Gross, O. et al. Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 442, 651–656 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Acosta-Rodriguez, E. V. et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nature Immunol. 8, 639–646 (2007).

    Article  CAS  Google Scholar 

  91. Huang, W., Na, L., Fidel, P. L. & Schwarzenberger, P. Requirement for interleukin-17A for systemic anti-Candida albicans host defense in mice. J. Infect. Dis. 190, 524–631 (2004).

    Article  Google Scholar 

  92. Zelante, T. et al. IL-23 and the TH17 pathway promote inflammation and impair antifungal immune resistance. Eur. J. Immunol. 37, 2695–2706 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Hsu, Y. M. et al. The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens. Nature Immunol. 8, 198–205 (2007).

    Article  CAS  Google Scholar 

  94. Hara, H. et al. The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors. Nature Immunol. 8, 619–629 (2007).

    Article  CAS  Google Scholar 

  95. De Luca, A. et al. Functional yet balanced reactivity to Candida albicans requires TRIF, MyD88, and IDO-dependent inhibition of Rorc. J. Immunol. 179, 5999–6008 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Weindl, G. et al. Human epithelial cells establish direct antifungal defense through TLR4-mediated signaling. J. Clin. Invest. (in the press).

  97. Schaller, M. et al. Polymorphonuclear leukocytes (PMNs) induce protective Th1-type cytokine epithelial responses in an in vitro model of oral candidosis. Microbiology 150, 2807–2813 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Fidel, P. L. Jr. History and update on host defense against vaginal candidiasis. Am. J. Reprod. Immunol. 57, 2–12 (2007).

    Article  PubMed  Google Scholar 

  99. Pivarcsi, A. et al. Microbial compounds induce the expression of pro-inflammatory cytokines, chemokines and human β-defensin-2 in vaginal epithelial cells. Microbes Infect. 7, 1117–1127 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. Gozalbo, D., Roig, P., Villamon, E. & Gil, M. L. Candida and candidiasis: the cell wall as a potential molecular target for antifungal therapy. Curr. Drug Targets Infect. Disord. 4, 117–135 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Marr, K. A. et al. Differential role of MyD88 in macrophage-mediated responses to opportunistic fungal pathogens. Infect. Immun. 71, 5280–5286 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Villamon, E. et al. Toll-like receptor-2 is essential in murine defenses against Candida albicans infections. Microbes Infect. 6, 1–7 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. Blasi, E. et al. Biological importance of the two Toll-like receptors, TLR2 and TLR4, in macrophage response to infection with Candida albicans. FEMS Immunol. Med. Microbiol. 44, 69–79 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Murciano, C. et al. Toll-like receptor 4 defective mice carrying point or null mutations do not show increased susceptibility to Candida albicans in a model of hematogenously disseminated infection. Med. Mycol. 44, 149–157 (2006).

    Article  CAS  PubMed  Google Scholar 

  105. Taylor, P. R. et al. Dectin-1 is required for β-glucan recognition and control of fungal infection. Nature Immunol. 8, 31–38 (2007).

    Article  CAS  Google Scholar 

  106. Saijo, S. et al. Dectin-1 is required for host defense against Pneumocystis carinii but not against Candida albicans. Nature Immunol. 8, 39–46 (2007). References 105 and 106 are the first reports of in vivo fungal infections in dectin 1 knockout mice.

    Article  CAS  Google Scholar 

  107. Lee, S. J., Zheng, N. Y., Clavijo, M. & Nussenzweig, M. C. Normal host defense during systemic candidiasis in mannose receptor-deficient mice. Infect. Immun. 71, 437–445 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Vonk, A. G., Netea, M. G., van Krieken, J. H., Van der Meer, J. W. M. & Kullberg, B. J. Delayed clearance of intraabdominal abcesses caused by Candida albicans in tumor necrosis factor-α and lymphotoxin-α deficient mice. J. Infect. Dis. 186, 1815–1822 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. Gottar, M. et al. Dual detection of fungal infections in Drosophila via recognition of glucans and sensing of virulence factors. Cell 127, 1425–1437 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Geijtenbeek, T. B. et al. Mycobacteria target DC-SIGN to suppress dendritic cell function. J. Exp. Med. 197, 7–17 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. van Kooyk, Y., Engering, A., Lekkerkerker, A. N., Ludwig, I. S. & Geijtenbeek, T. B. Pathogens use carbohydrates to escape immunity induced by dendritic cells. Curr. Opin. Immunol. 16, 488–493 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Taylor, P. R., Brown, G. D., Geldhof, A. B., Martinez-Pomares, L. & Gordon, S. Pattern recognition receptors and differentiation antigens define murine myeloid cell heterogeneity ex vivo. Eur. J. Immunol. 33, 2090–2097 (2003).

    Article  CAS  PubMed  Google Scholar 

  113. d'Ostiani, C. F. et al. Dendritic cells discriminate between yeasts and hyphae of the fungus Candida albicans. Implications for initiation of T helper cell immunity in vitro and in vivo. J. Exp. Med. 191, 1661–1674 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Wheeler, R. T. & Fink, G. R. A drug-sensitive genetic network masks fungi from the immune system. PLoS Pathog. 2, 328–339 (2006).

    Article  CAS  Google Scholar 

  115. Rappleye, C. A., Eissenberg, L. G. & Goldman, W. E. Histoplasma capsulatum α-(1,3)-glucan blocks innate immune recognition by the β-glucan receptor. Proc. Natl Acad. Sci. USA 104, 1366–1370 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Mangeney, M., Fischer, A., Le Deist, F., Latge, J. P. & Durandy, A. Direct activation of human B lymphocytes by Candida albicans-derived mannan antigen. Cell. Immunol. 122, 329–337 (1989).

    Article  CAS  PubMed  Google Scholar 

  117. Lillegard, J. B., Sim, R. B., Thorkildson, P., Gates, M. A. & Kozel, T. R. Recognition of Candida albicans by mannan-binding lectin in vitro and in vivo. J. Infect. Dis. 193, 1589–1597 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Sheng, K. C. et al. Mannan derivatives induce phenotypic and functional maturation of mouse dendritic cells. Immunology 118, 372–383 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Van der Graaf, C. A. et al. Toll-like receptor 4 Asp299Gly/Thr399Ile polymorphisms are a risk factor for Candida bloodstream infection. Eur. Cytokine Netw. 17, 29–34 (2006).

    CAS  PubMed  Google Scholar 

  120. Cassone, A. & Torosantucci, A. Opportunistic fungi and fungal infections: the challenge of a single, general antifungal vaccine. Expert Rev. Vaccines 5, 859–867 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Dillon, S. et al. Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance. J. Clin. Invest. 116, 916–928 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Reese, T. A. et al. Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature 447, 92–96 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by a Vidi Grant from Netherlands Organization for Scientific Research to M.G.N., and by the Wellcome Trust to N.A.R.G. and G.D.B.

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Authors and Affiliations

  1. Department of Medicine and Nijmegen University Centre for Infectious Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Mihai G. Netea & Bart Jan Kullberg

  2. Division of Immunology, Institute of Infectious Diseases and Molecular Medicine, CLS, University of Cape Town, Rondebosch, 7925, South Africa

    Gordon D. Brown

  3. School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, AB25 2ZD, Aberdeen, UK

    Neil A. R. Gow

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  1. Mihai G. Netea
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  2. Gordon D. Brown
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  4. Neil A. R. Gow
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Corresponding authors

Correspondence to Mihai G. Netea or Neil A. R. Gow.

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DATABASES

Entrez Genome project

Borrelia burgdorferi

Candida albicans

Saccharomyces cerevisiae

Schistosoma mansoni

Glossary

Innate immune system

The suite of host responses to microbial invaders that results in rapid defence without requiring prior stimulation.

Dendritic cells

'Professional' antigen-presenting cells that are found in the T-cell areas of lymphoid tissues and as minor cellular components in most tissues. They have a branched or dendritic morphology and are important stimulators of T-cell responses.

Cytokines

Biologically active molecules that are released by cells and that affect the function of other cells.

Fcγ receptor

A surface molecule on various cells that binds to the Fc regions of immunoglobulins, thereby initiating effector functions.

T helper 1

An immune response that is characterized by a subset of helper T-cells that secrete a particular set of cytokines, including interleukin 2, interferon-γ and TNFα, the main function of which is to stimulate phagocytosis-mediated defences against intracellular pathogens.

C-type lectin

C-type lectins are largely calcium-dependent animal lectins that are carbohydrate-binding proteins. The binding activity of C-type lectins is based on the structure of the carbohydrate-recognition domain, which is highly conserved in this family.

Chemokines

Small, inducibly secreted proteins that induce the activation and migration of lymphocytes.

Complement

A part of the innate immune system that comprises serum proteins that can protect against infection.

Type I interferons

Interferons that are rapidly induced by virus replication, as well as by some bacterial and fungal infections.

TH2

A type of activated T helper cell that participates in phagocytosis-independent responses and that downregulates pro-inflammatory responses that are induced by TH1 cells. TH2 cells secrete interleukin 4 (IL-4), IL-5, IL-6 and IL-10.

Regulatory T-cell

A small population of CD4+ T-cells that expresses the transcription factor forkhead box P3 and that has suppressor activity towards other T-cells either by cell–cell contact or cytokine release.

Zymosan

Particulate preparation of S. cerevisiae cell walls that is rich in β-glucans and mannan and that can be used to activate the innate immune system.

Tetraspanin

A family of transmembrane proteins that have four transmembrane domains and two extracellular domains of different sizes. The function of tetraspanins is unclear, but they seem to interact with many other transmembrane proteins and form large multimeric protein networks.

TH17 response

The TH17 subpopulation are T-cells that release mainly IL-17, which has both neutrophil chemotactic activity and the potential to promote autoimmunity.

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Netea, M., Brown, G., Kullberg, B. et al. An integrated model of the recognition of Candida albicans by the innate immune system. Nat Rev Microbiol 6, 67–78 (2008). https://doi.org/10.1038/nrmicro1815

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