Review Article | Published:

Candida albicans morphogenesis and host defence: discriminating invasion from colonization

Nature Reviews Microbiology volume 10, pages 112122 (2012) | Download Citation


Candida albicans is a common fungal pathogen of humans that colonizes the skin and mucosal surfaces of most healthy individuals. Until recently, little was known about the mechanisms by which mucosal antifungal defences tolerate colonizing C. albicans but react strongly when hyphae of the same microorganism attempt to invade tissue. In this Review, we describe the properties of yeast cells and hyphae that are relevant to their interaction with the host, and the immunological mechanisms that differentially recognize colonizing versus invading C. albicans.

Key points

  • Candida albicans is the most common fungal pathogen of humans, and also colonizes the skin and mucosal surfaces of most healthy individuals. Little was known about the mechanisms by which the mucosal immune response tolerates colonizing C. albicans yeast cells but reacts strongly when hyphae invade tissue.

  • C. albicans yeast cells and hyphae differ in their morphological properties, and this has important consequences for their recognition by mucosal immune cells.

  • Different mechanisms, in epithelial cells on the one hand and in immune cells on the other, are important for recognizing fungal invasion of the mucosa.

  • The germination of hyphae and increased fungal loads are recognized by epithelial cells, which then release pro-inflammatory cytokines and chemokines though specific kinase-dependent pathways.

  • Tissue macrophages recognize C. albicans hyphae through inflammasome activation mediated by a dectin 1-dependent pathway. In turn, this results in processing of pro-interleukin-1β and induction of T helper 17-type responses.

  • These mechanisms provide a conceptual framework for our understanding of tolerance to colonization versus immune defence against invasion by C. albicans and probably also by other microorganisms.

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  1. 1.

    & Dimorphism and virulence in fungi. Curr. Opin. Microbiol. 10, 314–319 (2007).

  2. 2.

    , & Adaptation of Candida albicans to the host environment: the role of morphogenesis in virulence and survival in mammalian hosts. Curr. Opin. Microbiol. 6, 338–343 (2003).

  3. 3.

    , & Fungal morphogenesis and host invasion. Curr. Opin. Microbiol. 5, 366–371 (2002).

  4. 4.

    , , & Engineered control of cell morphology in vivo reveals distinct roles for yeast and filamentous forms of Candida albicans during infection. Eukaryot. Cell 2, 1053–1060 (2003).

  5. 5.

    , , , & From attachment to damage: defined genes of Candida albicans mediate adhesion, invasion and damage during interaction with oral epithelial cells. PLoS ONE 6, e17046 (2011).

  6. 6.

    & The damage-response framework of microbial pathogenesis. Nature Rev. Microbiol. 1, 17–24 (2003).

  7. 7.

    , & Nosocomial fungal infections: epidemiology, diagnosis, and treatment. Med. Mycol. 45, 321–346 (2007).

  8. 8.

    Chronic mucocutaneous candidiasis. J. Am. Acad. Dermatol. 31, S14–S17 (1994).

  9. 9.

    et al. Anti-glycan antibodies establish an unexpected link between C. albicans and Crohn disease. Med. Sci. 25, 473–481 (2009).

  10. 10.

    , , & An integrated model of the recognition of Candida albicans by the innate immune system. Nature Rev. Microbiol. 6, 67–78 (2008). This article is the first to propose an integrated model of C. albicans immune recognition.

  11. 11.

    Immunity to fungal infections. Nature Rev. Immunol. 11, 275–288 (2011). An excellent review on fungal pattern recognition and antifungal host defence.

  12. 12.

    , , , & The Candida albicans HYR1 gene, which is activated in response to hyphal development, belongs to a gene family encoding yeast cell wall proteins. J. Bacteriol. 178, 5353–5360 (1996).

  13. 13.

    , , , & Candida albicans ALS3 and insights into the nature of the ALS gene family. Curr. Genet. 33, 451–459 (1998).

  14. 14.

    , & Developmental expression of a tandemly repeated, proline-and glutamine-rich amino acid motif on hyphal surfaces on Candida albicans. J. Biol. Chem. 271, 6298–6305 (1996).

  15. 15.

    et al. Genome-wide analysis of Candida albicans gene expression patterns during infection of the mammalian kidney. Fungal Genet. Biol. 46, 210–219 (2009).

  16. 16.

    et al. Structure and regulation of the HSP90 gene from the pathogenic fungus Candida albicans. Infect. Immun. 63, 4506–4514 (1995).

  17. 17.

    et al. Glycolytic enzymes of Candida albicans are nonubiquitous immunogens during candidiasis. Infect. Immun. 61, 4263–4271 (1993).

  18. 18.

    et al. Candida albicans Hyr1p confers resistance to neutrophil killing and is a potential vaccine target. J. Infect. Dis. 201, 1718–1728 (2010).

  19. 19.

    & Candida albicans Als3, a multifunctional adhesin and invasin. Eukaryot. Cell 10, 168–173 (2011).

  20. 20.

    , , & Chemical structure of the cell-wall mannan of Candida albicans serotype A and its difference in yeast and hyphal forms. Biochem. J. 404, 365–372 (2007).

  21. 21.

    et al. Stimulation of chitin synthesis rescues Candida albicans from echinocandins. PLoS Pathog. 4, e1000040 (2008).

  22. 22.

    & Generating cell surface diversity in Candida albicans and other fungal pathogens. FEMS Microbiol. Lett. 285, 137–145 (2008).

  23. 23.

    & Chitin and yeast budding. Localization of chitin in yeast bud scars. J. Biol. Chem. 246, 152–159 (1971).

  24. 24.

    et al. Recognition and blocking of innate immunity cells by Candida albicans chitin. Infect. Immun. 79, 1961–1970 (2011).

  25. 25.

    , & Dectin-1 mediates macrophage recognition of Candida albicans yeast but not filaments. EMBO J. 24, 1277–1286 (2005).

  26. 26.

    et al. Nonfilamentous C. albicans mutants are avirulent. Cell 90, 939–949 (1997).

  27. 27.

    & Hgc1, a novel hypha-specific G1 cyclin-related protein regulates Candida albicans hyphal morphogenesis. EMBO J. 23, 1845–1856 (2004).

  28. 28.

    et al. Bacterial peptidoglycan triggers Candida albicans hyphal growth by directly activating the adenylyl cyclase Cyr1p. Cell Host Microbe 4, 28–39 (2008).

  29. 29.

    et al. CO2 acts as a signalling molecule in populations of the fungal pathogen Candida albicans. PLoS Pathog. 6, e1001193 (2010).

  30. 30.

    , , & Ras signaling is required for serum-induced hyphal differentiation in Candida albicans. J. Bacteriol. 181, 6339–6346 (1999).

  31. 31.

    et al. Identification of the dialysable serum inducer of germ-tube formation in Candida albicans. Microbiology 150, 3041–3049 (2004).

  32. 32.

    et al. The G protein-coupled receptor Gpr1 and the Gα protein Gpa2 act through the cAMP-protein kinase A pathway to induce morphogenesis in Candida albicans. Mol. Biol. Cell 16, 1971–1986 (2005).

  33. 33.

    et al. Hsp90 orchestrates temperature-dependent Candida albicans morphogenesis via Ras1-PKA signaling. Curr. Biol. 19, 621–629 (2009).

  34. 34.

    , , & Farnesol induces hydrogen peroxide resistance in Candida albicans yeast by inhibiting the Ras-cyclic AMP signaling pathway. Eukaryot. Cell 9, 569–577 (2010).

  35. 35.

    & A potential phosphorylation site for an A-type kinase in the Efg1 regulator protein contributes to hyphal morphogenesis of Candida albicans. Genetics 157, 1523–1530 (2001).

  36. 36.

    , , & EFG1 is a major regulator of cell wall dynamics in Candida albicans as revealed by DNA microarrays. Mol. Microbiol. 47, 89–102 (2003).

  37. 37.

    et al. Cyclin-dependent kinases control septin phosphorylation in Candida albicans hyphal development. Dev. Cell 13, 421–432 (2007).

  38. 38.

    et al. Hyphal growth in Candida albicans requires the phosphorylation of Sec2 by the Cdc28-Ccn1/Hgc1 kinase. EMBO J. 29, 2930–2942 (2010).

  39. 39.

    , & A conserved mitogen-activated protein kinase pathway is required for mating in Candida albicans. Mol. Microbiol. 46, 1335–1344 (2002).

  40. 40.

    et al. The Cek1 and Hog1 mitogen-activated protein kinases play complementary roles in cell wall biogenesis and chlamydospore formation in the fungal pathogen Candida albicans. Eukaryot. Cell 5, 347–358 (2006).

  41. 41.

    , & Evidence for novel pH-dependent regulation of Candida albicans Rim101, a direct transcriptional repressor of the cell wall β-glycosidase Phr2. Eukaryot. Cell 5, 1550–1559 (2006).

  42. 42.

    , , , & RBR1, a novel pH-regulated cell wall gene of Candida albicans, is repressed by RIM101 and activated by NRG1. Eukaryot. Cell 3, 776–784 (2004).

  43. 43.

    et al. Sch9 kinase integrates hypoxia and CO2 sensing to suppress hyphal morphogenesis in Candida albicans. Eukaryot. Cell 10, 502–511 (2011).

  44. 44.

    & Hypoxic adaptation by Efg1 regulates biofilm formation by Candida albicans. Appl. Environ. Microbiol. 75, 3663–3672 (2009).

  45. 45.

    , , , & Critical role of DNA checkpoints in mediating genotoxic-stress-induced filamentous growth in Candida albicans. Mol. Biol. Cell 18, 815–826 (2007).

  46. 46.

    , & Depletion of a polo-like kinase in Candida albicans activates cyclase-dependent hyphal-like growth. Mol. Biol. Cell 14, 2163–2180 (2003).

  47. 47.

    , & Rad6p represses yeast-hypha morphogenesis in the human fungal pathogen Candida albicans. Mol. Microbiol. 35, 1264–1275 (2000).

  48. 48.

    et al. Thioredoxin regulates multiple hydrogen peroxide-induced signaling pathways in Candida albicans. Mol. Cell. Biol. 30, 4550–4563 (2010).

  49. 49.

    Microbe sensing, positive feedback loops, and the pathogenesis of inflammatory diseases. Immunol. Rev. 227, 248–263 (2009).

  50. 50.

    , , , & Host innate immune receptors and beyond: making sense of microbial infections. Cell Host Microbe 3, 352–363 (2008).

  51. 51.

    , , , & Host–microbe interactions: innate pattern recognition of fungal pathogens. Curr. Opin. Microbiol. 11, 305–312 (2008).

  52. 52.

    , , & Dynamic, morphotype-specific Candida albicans β-glucan exposure during infection and drug treatment. PLoS Pathog. 4, e1000227 (2008).

  53. 53.

    et al. 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, 13766–13771 (2000).

  54. 54.

    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).

  55. 55.

    , , & Both viable and killed Candida albicans cells induce in vitro production of TNF-α and IFN-γ in murine cells through a TLR2-dependent signalling. Eur. Cytokine Netw. 18, 38–43 (2007).

  56. 56.

    et al. The role of toll-like receptor (TLR) 2 and TLR4 in the host defense against disseminated candidiasis. J. Infect. Dis. 185, 1483–1489 (2002).

  57. 57.

    et al. Redundant role of TLR9 for anti-Candida host defense. Immunobiology 213, 613–620 (2008).

  58. 58.

    et al. Absence of functional TLR4 impairs response of macrophages after Candida albicans infection. Med. Mycol. 48, 1009–1017 (2010).

  59. 59.

    , , , & Role of TLR1 and TLR6 in the host defense against disseminated candidiasis. FEMS Immunol. Med. Microbiol. 52, 118–123 (2008).

  60. 60.

    Dectin-1: a signalling non-TLR pattern-recognition receptor. Nature Rev. Immunol. 6, 33–43 (2006).

  61. 61.

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

  62. 62.

    et al. Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-κB activation through Raf-1 and Syk. Nature Immunol. 10, 203–213 (2009).

  63. 63.

    , , , & Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J. Exp. Med. 197, 1107–1117 (2003).

  64. 64.

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

  65. 65.

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

  66. 66.

    et al. Dectin-1 is required for host defense against Pneumocystis carinii but not against Candida albicans. Nature Immunol. 8, 39–46 (2007).

  67. 67.

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

  68. 68.

    et al. Human dectin-1 deficiency and mucocutaneous fungal infections. N. Engl. J. Med. 361, 1760–1767 (2009).

  69. 69.

    et al. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N. Engl. J. Med. 361, 1727–1735 (2009).

  70. 70.

    & The mannose receptor is a pattern recognition receptor involved in host defense. Curr. Opin. Immunol. 10, 50–55 (1998).

  71. 71.

    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).

  72. 72.

    , , , & The human macrophage mannose receptor is not a professional phagocytic receptor. J. Leukoc. Biol. 77, 934–943 (2005).

  73. 73.

    et al. Stage-specific sampling by pattern recognition receptors during Candida albicans phagocytosis. PLoS Pathog. 4, e1000218 (2008).

  74. 74.

    et al. The macrophage mannose receptor induces IL-17 in response to Candida albicans. Cell Host Microbe 5, 329–340 (2009). This study is the first to demonstrate the importance of mannose-containing structures in driving TH17 cell responses.

  75. 75.

    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).

  76. 76.

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

  77. 77.

    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).

  78. 78.

    et al. Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection. J. Exp. Med. 206, 2037–2051 (2009).

  79. 79.

    , , & Distinct functions of DC-SIGN and its homologues L-SIGN (DC-SIGNR) and mSIGNR1 in pathogen recognition and immune regulation. Cell. Microbiol. 7, 157–165 (2005).

  80. 80.

    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).

  81. 81.

    et al. Dendritic cell interaction with Candida albicans critically depends on N-linked mannan. J. Biol. Chem. 283, 20590–20599 (2008).

  82. 82.

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

  83. 83.

    et al. The macrophage-inducible C-type lectin, Mincle, is an essential component of the innate immune response to Candida albicans. J. Immunol. 180, 7404–7413 (2008).

  84. 84.

    et al. Evolutionarily conserved recognition and innate immunity to fungal pathogens by the scavenger receptors SCARF1 and CD36. J. Exp. Med. 206, 637–653 (2009).

  85. 85.

    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).

  86. 86.

    et al. Colonization of mice by Candida albicans is promoted by chemically induced colitis and augments inflammatory responses through galectin-3. J. Infect. Dis. 197, 972–980 (2008).

  87. 87.

    & Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 117, 561–574 (2004).

  88. 88.

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

  89. 89.

    et al. Endogenous interleukin (IL)–1α and IL-1β are crucial for host defense against disseminated candidiasis. J. Infect. Dis. 193, 1419–1426 (2006).

  90. 90.

    et al. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 459, 433–436 (2009).

  91. 91.

    et al. Involvement of the NLRP3 inflammasome in innate and humoral adaptive immune responses to fungal β-glucan. J. Immunol. 183, 8061–8067 (2009). This study finds that there is differential activation of the inflammasome by C. albicans yeast cells and hyphae.

  92. 92.

    et al. The inflammasome drives protective Th1 and Th17 cellular responses in disseminated candidiasis. Eur. J. Immunol. 41, 2260–2268 (2011). This investigation demonstrates the importance of the inflammasome in driving protective TH1-type and TH17-type responses during fungal infection.

  93. 93.

    et al. An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans. Cell Host Microbe 5, 487–497 (2009).

  94. 94.

    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).

  95. 95.

    , , , & Differential cytokine production and Toll-like receptor signaling pathways by Candida albicans blastoconidia and hyphae. Infect. Immun. 73, 7458–7464 (2005).

  96. 96.

    et al. The dectin-1/inflammasome pathway is responsible for the induction of protective T-helper 17 responses that discriminate between yeasts and hyphae of Candida albicans. J. Leukoc. Biol. 90, 357–366 (2011). This article describes the inflammasome–IL-1β–TH17 cell axis as an important mechanism that is capable of discriminating C. albicans colonization from invasion at the mucosal level.

  97. 97.

    et al. CARD9 mediates dectin-2-induced IκBα kinase ubiquitination leading to activation of NF-κB in response to stimulation by the hyphal form of Candida albicans. J. Biol. Chem. 285, 25969–25977 (2010).

  98. 98.

    , , , & C. albicans increases cell wall mannoprotein, but not mannan, in response to blood, serum and cultivation at physiological temperature. Glycobiology 21, 1173–1180 (2011).

  99. 99.

    Ultrastructure of human cutaneous candidosis. J. Invest. Dermatol. 78, 200–205 (1982).

  100. 100.

    & Scanning electron microscopy of epidermal adherence and cavitation in murine candidiasis: a role for Candida acid proteinase. Infect. Immun. 56, 1942–1949 (1988).

  101. 101.

    & Alternative Candida albicans lifestyles: growth on surfaces. Annu. Rev. Microbiol. 59, 113–133 (2005).

  102. 102.

    et al. A biphasic innate immune MAPK response discriminates between the yeast and hyphal forms of Candida albicans in epithelial cells. Cell Host Microbe 8, 225–235 (2010). A seminal study describing the mechanisms through which epithelial cells can discriminate between colonizing yeast cells and invading hyphae.

  103. 103.

    & Epithelial GM-CSF induction by Candida glabrata. J. Dent. Res. 88, 746–751 (2009).

  104. 104.

    et al. Human epithelial cells establish direct antifungal defense through TLR4-mediated signaling. J. Clin. Invest. 117, 3664–3672 (2007).

  105. 105.

    et al. Candida albicans internalization by host cells is mediated by a clathrin-dependent mechanism. Cell. Microbiol. 11, 1179–1189 (2009).

  106. 106.

    , , , & Host-pathogen interactions and virulence-associated genes during Candida albicans oral infections. Int. J. Med. Microbiol. 301, 417–422 (2011).

  107. 107.

    et al. Cellular interactions of Candida albicans with human oral epithelial cells and enterocytes. Cell. Microbiol. 12, 248–271 (2010).

  108. 108.

    et al. Role of the fungal Ras-protein kinase A pathway in governing epithelial cell interactions during oropharyngeal candidiasis. Cell. Microbiol. 7, 499–510 (2005).

  109. 109.

    et al. An internal polarity landmark is important for externally induced hyphal behaviors in Candida albicans. Eukaryot. Cell 7, 712–720 (2008).

  110. 110.

    et al. Disruption of each of the secreted aspartyl proteinase genes SAP1, SAP2, and SAP3 of Candida albicans attenuates virulence. Infect. Immun. 65, 3529–3538 (1997).

  111. 111.

    , & Candida albicans secreted aspartyl proteinases in virulence and pathogenesis. Microbiol. Mol. Biol. Rev. 67, 400–428 (2003).

  112. 112.

    et al. Evidence implicating phospholipase as a virulence factor of Candida albicans. Infect. Immun. 63, 1993–1998 (1995).

  113. 113.

    , & Interaction of the mucosal barrier with accessory immune cells during fungal infection. Int. J. Med. Microbiol. 301, 431–435 (2011).

  114. 114.

    et al. Patients with chronic mucocutaneous candidiasis exhibit reduced production of Th17-associated cytokines IL-17 and IL-22. J. Invest. Dermatol. 128, 2640–2645 (2008).

  115. 115.

    et al. Impaired TH17 responses in patients with chronic mucocutaneous candidiasis with and without autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy. J. Allergy Clin. Immunol. 126, 1006–1015. e4 (2010).

  116. 116.

    et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N. Engl. J. Med. 365, 54–61 (2011).

  117. 117.

    et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J. Exp. Med. 208, 1635–1648 (2011).

  118. 118.

    et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 332, 65–68 (2011).

  119. 119.

    et al. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J. Exp. Med. 207, 291–297 (2010). This paper describes the link between STAT3 mutations and defective TH17 cell differentiation.

  120. 120.

    et al. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J. Exp. Med. 207, 299–30 8 (2010).

  121. 121.

    et al. Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452, 773–776 (2008).

  122. 122.

    et al. Mutations in STAT3 and IL12RB1 impair the development of human IL-17–producing T cells. J. Exp. Med. 205, 1543–1550 (2008).

  123. 123.

    et al. Milder clinical hyperimmunoglobulin E syndrome phenotype is associated with partial interleukin-17 deficiency. Clin. Exp. Immunol. 159, 57–64 (2010).

  124. 124.

    et al. Early stop polymorphism in human DECTIN-1 is associated with increased Candida colonization in hematopoietic stem cell transplant recipients. Clin. Infect. Dis. 49, 724–732 (2009).

  125. 125.

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

  126. 126.

    , , & Epithelial cell-derived S100 calcium-binding proteins as key mediators in the hallmark acute neutrophil response during Candida vaginitis. Infect. Immun. 78, 5126–5137 (2010).

  127. 127.

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

  128. 128.

    , , & Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17-producing human T helper cells. Nature Immunol. 8, 942–949 (2007).

  129. 129.

    et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

  130. 130.

    & Th17 cell differentiation: the long and winding road. Immunity 28, 445–453 (2008).

  131. 131.

    et al. Cutting edge: Candida albicans hyphae formation triggers activation of the Nlrp3 inflammasome. J. Immunol. 183, 3578–3581 (2009).

  132. 132.

    et al. Candida albicans dampens host defense by downregulating IL-17 production. J. Immunol. 185, 2450–2457 (2010).

  133. 133.

    et al. Bypassing pathogen-induced inflammasome activation for the regulation of interleukin-1β production by the fungal pathogen Candida albicans. J. Infect. Dis. 199, 1087–1096 (2009).

  134. 134.

    , & The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28, 454–467 (2008).

  135. 135.

    et al. IL-22 and TNF-α represent a key cytokine combination for epidermal integrity during infection with Candida albicans. Eur. J. Immunol. 41, 1894–1901 (2011).

  136. 136.

    et al. ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1β and IL-18 secretion in an autocrine way. Proc. Natl Acad. Sci. USA 105, 8067–8072 (2008). An important study highlighting the link between the commensal microbial flora and mucosal TH17 cell immune responses.

  137. 137.

    et al. ATP drives lamina propria TH17 cell differentiation. Nature 455, 808–812 (2008).

  138. 138.

    et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

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N.A.R.G. and A.J.P.B. are supported by the UK Wellcome Trust (grant 080088), the European Commission (through the ALLFUN project; the FINSysB project grant PITN-GA-2008-214004; and the STRIFE project grant ERC-2009-AdG-249793) and the UK Biotechnology and Biological Sciences Research Council (grant BB/F00513X/1). M.G.N. was supported by a Vici grant from the Netherlands Organization for Scientific Research (NWO). F.L.v.d.V. was supported by a Veni grant from NWO.

Author information


  1. Aberdeen Fungal Group, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK.

    • Neil A. R. Gow
    •  & Alistair J. P. Brown
  2. Department of Medicine and Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University, Nijmegen Medical Center, Nijmegen 6500HB, The Netherlands.

    • Frank L. van de Veerdonk
    •  & Mihai G. Netea


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The authors declare no competing financial interests.

Corresponding author

Correspondence to Mihai G. Netea.



Cells produced by a series of synchronous budding events in which each daughter cell remains attached to its mother cell, thus forming a chain of elongated yeast cells with obvious constrictions at the septal junctions.


A mucosal fungal infection that can be caused by any of the pathogenic Candida species, of which Candida albicans is the most common.


Cell surface glycoproteins in the fungal cell wall that facilitate microbial adhesion or adherence to other cells or to an inanimate surface; virulence factors.


Proteins that are produced by microorganisms to promote microbial penetration into mammalian cells.

Bud scars

Scars located on the surface of the mother cell, representing the remnants of the septum formed between mother and daughter cells during cell division.

Muramyl dipeptide

The minimal structural unit of peptidoglycan in Gram-positive bacteria that is recognized by the intracellular receptor NOD2 (nucleotide-binding oligomerization domain-containing 2).


A family of proteins for which expression is normally periodic within the cell cycle and which control the progression of cells through the cell cycle by activating cyclin-dependent kinases.


Evolutionarily conserved proteins that have essential functions in bud evagination and cytokinesis, and more subtle roles throughout the cell cycle.


Thick-walled spores that are produced by Candida albicans on carbohydrate-rich media in vivo. The presence of chlamydospores in human tissues has yet to be firmly established.


Pertaining to a substance: able to cause mutations by damaging DNA.


White blood cells produced by the differentiation of monocytes in tissues. Monocytes and macrophages are phagocytes and are important for host defence against Candida albicans infection.


A cell wall preparation that is obtained from the yeast Saccharomyces cerevisiae and comprises a protein–carbohydrate complex rich in β-1,3-glucan.

Myeloid cells

A class of important innate immune cells that are derived from bone marrow and consist of monocytic populations (monocytes and their precursors) and granulocytic populations (granulocytes and their precursors).

T helper 17 cell

(TH17 cell). A newly discovered subset of TH cells that produce interleukin-17 (IL-17), IL-21 and IL-22. These are developmentally distinct from TH1 and TH2 cells and are thought to have a protective role in fungal infection.


Phagocytic cells that are one of the first inflammatory cell types to migrate to the site of inflammation.


A group of small antimicrobial peptides that have direct activity against microorganims.


A protein platform that triggers activation of inflammatory caspases, which process pro-interleukin-1β.


(Interleukin-1β). A polypeptide that is produced after infection, injury or antigenic challenge and is highly pro-inflammatory. IL-1β is primarily produced by macrophages through a pathway that is tightly regulated by the inflammasome.

T helper 1-type

(TH1-type). A response characterized by the TH1-type cytokine, interferon-γ.


One of the cadherin proteins, which are a class of type-1 transmembrane protein that plays an important part in cell-to cell adhesion in mammalian tissues.

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