Fungal-Derived Immune Modulating Molecules

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 666)

Abstract

Invasive fungal infections are an increasing clinical problem for which new therapeutic approaches are needed. Understanding the initial interaction between fungi and the host offers potential for development of new drugs or vaccines. It has recendy been recognized that like other pathogens, fungi initially interact with the innate immune system via binding between fungus-specific chemical signatures (pattern-associated molecular patterns or PAMPs) and pattern recognition receptors (PRRs) on mononuclear phagocytes. Fungal PAMPs are restricted to complex carbohydrates in the cell wall, including mannoproteins, phospholipomannan, β-glucans and possibly chitin. These PAMPs bind specifically to two classes of PRR in phagocyte membranes, toll-like receptors and C-lectin-like receptors, through which they initiate signaling responses that culminate in release of pro- and anti-inflammatory cytokines, link the innate immune response with the adaptive immune response and initiate phagocytosis and intracellular killing. Isolated PAMPs have been used to dissect phagocyte responses in vitro and have revealed mechanisms by which host cells can tailor innate immune responses to individual pathogens. The interactions are complex and are yet to be translated into a clear understanding of the roles of the respective PAMPs and PRRs in vivo. Recent advances in this area in relation to the pathogenesis of fungal infections are summarized in this chapter.

Keywords

Polysaccharide Integrin Microbe Chitin Aspergillus 

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References

  1. 1.
    Willment JA, Brown GD, Willment JA et al. C-type lectin receptors in antifungal immunity. Trends Microbiol 2008; 16:27–32.CrossRefPubMedGoogle Scholar
  2. 2.
    Janeway CA Jr. The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol Today 1992; 13:11–16.CrossRefPubMedGoogle Scholar
  3. 3.
    Levitz SM. Interactions of toll-like receptors with fungi. Microbes and Infection 2004; 6:1351–1355.CrossRefPubMedGoogle Scholar
  4. 4.
    Bellocchio S, Montagnoli C, Bozza S et al. The contribution of the toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo. J Immunol 2004; 172:3059–3069.PubMedGoogle Scholar
  5. 5.
    Phadke AP, Mehrad B. Cytokines in host defense against Aspergillus: recent advances. Med Mycol 2005; 43(Suppl 1):S173–176.CrossRefGoogle Scholar
  6. 6.
    Akira S, Uematsu S, Takeuchi O et al. Pathogen recognition and innate immunity. Cell 2006; 124:783–801.CrossRefPubMedGoogle Scholar
  7. 7.
    Filler SG. Candida-host cell receptor-ligand interactions. Curr Opin Microbiol 2006; 9:333–339.CrossRefPubMedGoogle Scholar
  8. 8.
    Netea MG, Brown GD, Kullberg BJ et al. An integrated model of the recognition of Candida albicans by the innate immune system. Nat Revs Microbiol 2008; 6:67–78.CrossRefGoogle Scholar
  9. 9.
    Hocbc K, Janssen E, Beutler B et al. The interface between innate and adaptive immunity. Nat Immunol 2004; 5:971–974.CrossRefGoogle Scholar
  10. 10.
    Saville SP, Lazzell AL, Monteagudo C et al. Engineered control of cell morphology in vivo reveals distinct roles for yeast and filamentous forms of Candida albicans during infection. Eukaryot Cell 2003; 2:1053–1060.CrossRefPubMedGoogle Scholar
  11. 11.
    Schaffner A, Douglas H, Braude A. Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to Aspergillus. Observations on these two lines of defense in vivo and in vitro with human and mouse phagocytes. J Clin Invest 1982; 69:617–631.CrossRefPubMedGoogle Scholar
  12. 12.
    Steele C, Rapaka RR, Metz A et al. The beta-glucan receptor dectin-1 recognizes specific morphologies of Aspergillus fumigatus. PLoS Pathogens 2005; 1:e42.CrossRefGoogle Scholar
  13. 13.
    Nemecek JC, Wuthrich M, Klein BS et al. Global control of dimorphism and virulence in fungi. Science 2006; 312:583–588.CrossRefPubMedGoogle Scholar
  14. 14.
    Casadevall A, Perfect, JR. Cryptococcus neoformans. Washington DC: ASM Press, 1998.Google Scholar
  15. 15.
    Klis FM, de Groot P, Hellingwerf K. Molecular organization of the cell wall of Candida albicans. Med Mycol 2001; 39(Suppl 1):1–8.PubMedGoogle Scholar
  16. 16.
    Torosantucci A, Bromuro C, Chiani P et al. A novel glycoconjugate vaccine against fungal pathogens. J Exp Med 2005; 202:597–606.CrossRefPubMedGoogle Scholar
  17. 17.
    Gantner BN, Simmons RM, Underhill DM et al. Dectin-1 mediates macrophage recognition of Candida albicans yeast but not filaments. EMBO J 2005; 24:1277–1286.CrossRefPubMedGoogle Scholar
  18. 18.
    Netea MG, Van der Graaf C, Van der Meer JW et al. Recognition of fungal pathogens by Toll-like receptors. Eur J Clin Microbiol Infect Dis 2004; 23:672–676.CrossRefPubMedGoogle Scholar
  19. 19.
    Bernard M, Latge JP. Aspergillus fumigatus cell wall: composition and biosynthesis. Med Mycol 2001; 39(Suppl 1):9–17.PubMedGoogle Scholar
  20. 20.
    Latge JP, Kobayashi H, Debeaupuis JP et al. Chemical and immunological characterization of the extracellular galactomannan of Aspergillus fumigatus. Infect Immun 1994; 62:5424–5433.PubMedGoogle Scholar
  21. 21.
    Fontaine T, Simenel C, Dubreucq G et al. Molecular organization of the alkali-insoluble fraction of Aspergillus fumigatus cell wall. J Biol Chem 2000; 275:27594–27607.PubMedGoogle Scholar
  22. 22.
    Tronchin G, Bouchara JP, Ferron M et al. Cell surface properties of Aspergillus fumigatus conidia: correlation between adherence, agglutination and rearrangements of the cell wall. Can J Microbiol 1995; 41:714–721.CrossRefPubMedGoogle Scholar
  23. 23.
    Poulain D, Jouault T, Poulain D et al. Candida albicans cell wall glycans, host receptors and responses: elements for a decisive crosstalk. Curr Opin Microbiol 2004; 7:342–349.CrossRefPubMedGoogle Scholar
  24. 24.
    Gersuk GM, Underhill DM, Zhu L et al. Dectin-1 and TLRs permit macrophages to distinguish between different Aspergillus fumigatus cellular states. J Immunol 2006; 176:3717–3724.PubMedGoogle Scholar
  25. 25.
    Wheeler RT, Fink GR, et al. A drug-sensitive genetic network masks fungi from the immune system. PLoS Pathogens 2006; 2:e35.CrossRefGoogle Scholar
  26. 26.
    Shoham S, Huang C, Chen JM et al. Toll-like receptor 4 mediates intracellular signaling without TNF-α release in response to Cryptococcus neoformans polysaccharide capsule. J Immunol 2001; 166: 4620–4626.PubMedGoogle Scholar
  27. 27.
    Obayashi T, Yoshida M, Mori T et al. Plasma (l→3)-beta-D-glucan measurement in diagnosis of invasive deep mycosis and fungal febrile episodes. Lancet 1995; 345:17–20.CrossRefPubMedGoogle Scholar
  28. 28.
    Pirofski LA. Of mice and men, revisited: new insights into an ancient molecule from studies of complement activation by Cryptococcus neoformans. Infect Immun 2006; 74:3079–3084.CrossRefPubMedGoogle Scholar
  29. 29.
    Netea MG, Gow NA, Munro CA et al. 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.CrossRefPubMedGoogle Scholar
  30. 30.
    Trinel PA, Borg-von-Zepelin M, Lepage G et al. Isolation and preliminary characterization of the 14-to 18-kilodalton Candida albicans antigen as a phospholipomannan containing beta-l,2-linked oligomannosides. Infect Immun 1993; 61:4398–4405.PubMedGoogle Scholar
  31. 31.
    Jouault T, Fradin C, Trinel PA et al. Early signal transduction induced by Candida albicans in macrophages through shedding of a glycolipid. J Infect Dis 1998; 178:792–802.CrossRefPubMedGoogle Scholar
  32. 32.
    Monari C, Bistoni F, Casadevall A et al. Glucuronoxylomannan, a microbial compound, regulates expression of costimulatory molecules and production of cytokines in macrophages. J Infect Dis 2005; 191:127–137.CrossRefPubMedGoogle Scholar
  33. 33.
    Stahl PD, Rodman JS, Miller MJ et al. Evidence for receptor-mediated binding of glycoproteins, glycoconjugates and lysosomal glycosidases by alveolar macrophages. Proc Natl Acad Sci U S A 1978; 75.1399–1403.CrossRefPubMedGoogle Scholar
  34. 34.
    Linehan SA, Martinez-Pomares L, Gordon S. Macrophage lectins in host defence. Microbes Infect 2000; 2:279–288.CrossRefPubMedGoogle Scholar
  35. 35.
    McGreal EP, Rosas M, Brown GD et al. The carbohydrate-recognition domain of Dectin-2 is a C-type lectin with specificity for high mannose. Glycobiology 2006; 16:422–430.CrossRefPubMedGoogle Scholar
  36. 36.
    Kcry V, Krepinsky JJ, Warren CD et al. Ligand recognition by purified human mannose receptor. Arch Biochem Biophys 1992; 298:49–55.CrossRefGoogle Scholar
  37. 37.
    Palma AS, Feizi T, Zhang Y et al. Ligands for the beta-glucan receptor, Dectin-1, assigned using “designer” microarrays of oligosaccharide probes (neoglycolipids) generated from glucan polysaccharides. (erratum appears in J Biol Chem 2006 Aug 25; 281(34):24999). J Biol Chem 2006; 281:5771–5779.CrossRefPubMedGoogle Scholar
  38. 38.
    Brown GD, Brown GD. Dectin-1: a signalling nonTLR pattern-recognition receptor. Nature Revs Immunol 2006; 6:33–43.CrossRefGoogle Scholar
  39. 39.
    Herre J, Marshall AS, Caron E et al. Dectin-1 uses novel mechanisms for yeast phagocytosis in macrophages. Blood 2004; 104:4038–4045.CrossRefPubMedGoogle Scholar
  40. 40.
    Sato K, Yang XL, Yudate T et al. Dectin-2 is a pattern recognition receptor for fungi that couples with the Fc receptor gamma chain to induce innate immune responses. J Biol Chem 2006; 281:38854–38866.CrossRefPubMedGoogle Scholar
  41. 41.
    Feinberg H, Mitchell DA, Drickamer K et al. Structural basis for selective recognition of oligosaccharides by DC-SIGN and DC-SIGNR. Science 2001; 294:2163–2166.CrossRefPubMedGoogle Scholar
  42. 42.
    Mitchell DA, Fadden AJ, Drickamer K. A novel mechanism of carbohydrate recognition by the C-type lectins DC-SIGN and DC-SIGNR. Subunit organization and binding to multivalent ligands. J Biol Chem 2001; 276:28939–28945.CrossRefPubMedGoogle Scholar
  43. 43.
    Gringhuis SI, den Dunnen J, Litjens M et al. C-type lectin DC-SIGN modulates Toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NF-kappaB. Immunity 2007; 26:605–616.CrossRefPubMedGoogle Scholar
  44. 44.
    Fradin C, Poulain D, Jouault T. beta-l,2-linked oligomannosides from Candida albicans bind to a 32-kilodalton macrophage membrane protein homologous to the mammalian lectin galectin-3. Infect Immun 2000; 68:4391–4398.CrossRefPubMedGoogle Scholar
  45. 45.
    Kohatsu L, Hsu DK, Jegalian AG et al. Galectin-3 induces death of Candida species expressing specific beta-l,2-linked mannans. J Immunol 2006; 177:4718–4726.PubMedGoogle Scholar
  46. 46.
    Gantner BN, Simmons RM, Canavera SJ et al. Collaborative induction of inflammatory responses by Dectin-1 and Toll-like receptor 2. J Exp Med 2003; 197:1107–1117.CrossRefPubMedGoogle Scholar
  47. 47.
    Brown GD, Herre J, Williams DL et al. Dectin-1 mediates the biological effects of beta-glucans. J Exp Med 2003; 197:1119–1124.CrossRefPubMedGoogle Scholar
  48. 48.
    Jouault T, Ibata-Ombetta S, Takeuchi O et al. Candida albicans phospholipomannan is sensed through toll-like receptors. J Infect Dis 2003; 188:165–172.CrossRefPubMedGoogle Scholar
  49. 49.
    Tada H, Nemoto E, Shimauchi H et al. Saccharomyces cerevisiae-and Candida albicans-derived mannan induced production of tumor necrosis factor alpha by human monocytes in a CD 14-and Toll-like receptor 4-dependent manner. Microbiol Immunol 2002; 46:503–512.PubMedGoogle Scholar
  50. 50.
    Taylor PR, Reid DM, Heinsbroek SE et al. Dectin-2 is predominantly myeloid restricted and exhibits unique activation-dependent expression on maturing inflammatory monocytes elicited in vivo. Eur J Immunol 2005; 35:2163–2174.CrossRefPubMedGoogle Scholar
  51. 51.
    Carvalho APA, Pitzurra L, Romani L et al. Polymorphisms in toll-like receptor genes and susceptibility to pulmonary aspergillosis. J Infect Dis 2008; 197:618–621.CrossRefPubMedGoogle Scholar
  52. 52.
    Van der Graaf CA, Netea MG, Morre SA et al. Toll-like receptor 4 Asp299Gly/1hr399Ile polymorphisms are a risk factor for Candida bloodstream infection. Eur Cytokine Netw 2006; 17:29–34.PubMedGoogle Scholar
  53. 53.
    Morre SA, Murillo LS, Spaargaren J et al. Role of the toll-like receptor 4 Asp299Gly polymorphism in susceptibility to Candida albicans infection. J Infect Dis 2002; 186:1377–1379; vnauthor reply 1379.CrossRefPubMedGoogle Scholar
  54. 54.
    van der Graaf CA, Netea MG, Drenth IP et al. Candida-specific interferon-gamma deficiency and toll-like receptor polymorphisms in patients with chronic mucocutaneous candidiasis. Neth J Med 2003; 61:365–369.PubMedGoogle Scholar
  55. 55.
    Cambi A, Gijzen K, de Vries JM et al. The C-type lectin DC-SIGN (CD209) is an antigen-uptake receptor for Candida albicans on dendritic cells. Eur J Immunol 2003; 33:532–538.CrossRefPubMedGoogle Scholar
  56. 56.
    Steele C, Marrero L, Swain S et al. Alveolar macrophage-mediated killing of Pneumocystis carinii f. sp. muris involves molecular recognition by the Dectin-1 beta-glucan receptor. J Exp Med 2003; 198:1677–1688.CrossRefPubMedGoogle Scholar
  57. 57.
    Serrano-Gomez D, Leal JA, Corbi AL et al. DC-SIGN mediates the binding of Aspergillus fumigatus and keratinophylic fungi by human dendritic cells. Immunobiology 2005; 210:175–183.CrossRefPubMedGoogle Scholar
  58. 58.
    Serrano-Gomez D, Dominguez-Soto A, Ancochea J et al. Dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin mediates binding and internalization of Aspergillus fumigatus conidia by dendritic cells and macrophages. J Immunol 2004; 173:5635–5643.PubMedGoogle Scholar
  59. 59.
    Mambula SS, Sau K, Henneke P et al. Toll-like receptor (TLR) signaling in response to Aspergillus fumigatus. J Biol Chem 2002; 277:39320–39326.CrossRefPubMedGoogle Scholar
  60. 60.
    Viriyakosol S, Fierer J, Brown GD et al. Innate immunity to the pathogenic fungus Coccidioides posadasii is dependent on Toll-like receptor 2 and Dectin-1. Infect Immun 2005; 73:1553–1560.CrossRefPubMedGoogle Scholar
  61. 61.
    Garlanda C, Hirsch E, Bozza S et al. Nonredundant role of the long pentraxin PTX3 in antifungal innate immune response. Nature 2002; 420:182–186.CrossRefPubMedGoogle Scholar
  62. 62.
    Rappleye CA, Eissenberg LG, Goldman WE et al. Histoplasma capsulatum alpha-(l,3)-glucan blocks innate immune recognition by the beta-glucan receptor. Proc Natl Acad Sci USA 2007; 104:1366–1370.CrossRefPubMedGoogle Scholar
  63. 63.
    Nakamura KMA, Xiao G, Hatta M et al. Deoxynucleic acids from Cryptococcus neoformans activate myeloid dendritic cells via TLR9-dependent pathway. J Immunol 2008; 180:4067–4074.PubMedGoogle Scholar
  64. 64.
    Netea MG, Van Der Graaf CA, Vonk AG et al. The role of toll-like receptor (TLR) 2 and TLR4 in the host defense against disseminated candidiasis. J Infect Dis 2002; 185:1483–1489.CrossRefPubMedGoogle Scholar
  65. 65.
    Netea MG, Sutmuller R, Hermann C et al. Toll-like receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T-cells. J Immunol 2004; 172:3712–3718.PubMedGoogle Scholar
  66. 66.
    Villamon E, Gozalbo D, Roig P et al. Toll-like receptor-2 is essential in murine defenses against Candida albicans infections. Microbes Infect 2004; 6:1–7.CrossRefPubMedGoogle Scholar
  67. 67.
    Villamon E, Gozalbo D, Roig P et al. Myeloid differentiation factor 88 (MyD88) is required for murine resistance to Candida albicans and is critically involved in Candida-induced production of cytokines. Eur Cytokine Netw 2004; 15:263–271.PubMedGoogle Scholar
  68. 68.
    Netea MG, van de Veerdonk F, Verschueren I et al. Role of TLR1 and TLR6 in the host defense against disseminated candidiasis. FEMS Immunol Med Microbiol 2008; 52:118–123.CrossRefPubMedGoogle Scholar
  69. 69.
    Taylor PR, Tsoni SV, Willment JA et al. Dectin-1 is required for beta-glucan recognition and control of fungal infection. Nat Immunol 2007; 8:31–38.CrossRefPubMedGoogle Scholar
  70. 70.
    Saijo S, Fujikado N, Furuta T et al. Dectin-1 is required for host defense against Pneumocystis carinii but not against Candida albicans. Nat Immunol 2007; 8:39–46.CrossRefPubMedGoogle Scholar
  71. 71.
    Gross O, Gewies A, Finger K et al. Card9 controls a nonTLR signalling pathway for innate antifungal immunity. Nature 2006; 442:651–656.CrossRefPubMedGoogle Scholar
  72. 72.
    Huang W, Na L, Fidel PL et al. Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J Infect Dis 2004; 190:624–631.CrossRefPubMedGoogle Scholar
  73. 73.
    Dubourdeau M, Athman R, Bailoy V et al. Aspergillus fumigatus induces innate immune responses in alveolar macrophages through the MAPK pathway independently of TLR2 and TLR4. J Immunol 2006; 177:3994–4001.PubMedGoogle Scholar
  74. 74.
    Bretz C, Gersuk G, Knoblaugh S et al. MyD88 signaling contributes to early pulmonary responses to Aspergillus fumigatus. Infect Immun 2008; 76:952–958.CrossRefPubMedGoogle Scholar
  75. 75.
    Yauch LE, Mansour MK, Shoham S et al. Involvement of CD 14, toll-like receptors 2 and 4 and MyD88 in the host response to the fungal pathogen Cryptococcus neoformans in vivo. Infect Immun 2004; 72:5373–5382.CrossRefPubMedGoogle Scholar
  76. 76.
    Hoshino K, Takeuchi O, Kawai T et al. 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.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  1. 1.Centre for Infectious Diseases and Microbiology and Westmead Millennium InstituteUniversity of SydneySydneyAustralia
  2. 2.Department of Infectious DiseasesWestmead HospitalSydneyAustralia

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