Review Article | Published:

Immunity to fungal infections

Nature Reviews Immunology volume 11, pages 275288 (2011) | Download Citation

Abstract

Fungal diseases represent an important paradigm in immunology, as they can result from either a lack of recognition by the immune system or overactivation of the inflammatory response. Research in this field is entering an exciting period of transition from studying the molecular and cellular bases of fungal virulence to determining the cellular and molecular mechanisms that maintain immune homeostasis with fungi. The fine line between these two research areas is central to our understanding of tissue homeostasis and its possible breakdown in fungal infections and diseases. Recent insights into immune responses to fungi suggest that functionally distinct mechanisms have evolved to achieve optimal host−fungus interactions in mammals.

Key points

  • Fungi can interact with humans in multiple ways, establishing symbiotic, commensal, latent or pathogenic relationships. Although the burdens of fungal diseases may rival those of many of the best-known bacterial diseases, humans have evolved with ubiquitous or commensal fungi in host–fungus relationships that for the most part are positive or neutral.

  • The co-evolution of humans and fungi suggests that complex mechanisms exist to allow the host immune system to respond to fungi and, likewise, that fungi have developed sophisticated mechanisms to antagonize immune responses. Indeed, fungal diseases represent an important paradigm in immunology, as they can result either from lack of recognition or from overactivation of the inflammatory response.

  • We are entering an exciting period of transition from studying the molecular and cellular bases of the virulence of fungal pathogens to determining the mechanisms of immune adaptations that maintain homeostasis with fungi.

  • As the immune system cannot ignore fungi, a fine balance between pro- and anti-inflammatory signals is required for a stable host–fungus relationship, the disruption of which leads to pathological consequences. Thus, the challenge for future studies is to gain a better understanding of the control of inflammation, the molecular bases of regulation and rupture, and the way in which innocuous but opportunistic fungal pathogens maintain 'friendly' relationships, or evade or subvert host inflammation.

  • The use of multidisciplinary approaches, including functional genomics, proteomics and bioinformatics, will have important biomedical implications. These may include the identification of new susceptibility genes, the identification of more accurate biomarkers that predict inflammatory fungal disorders, and the development of multi-pronged therapeutic approaches that target specific inflammatory or metabolic end points in fungal infections and diseases.

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References

  1. 1.

    Fungal adaptation to the host environment. Curr. Opin. Microbiol. 12, 347–349 (2009).

  2. 2.

    , & Infection-related gene expression in Candida albicans. Curr. Opin. Microbiol. 10, 307–313 (2007).

  3. 3.

    & Fungal adaptation to the mammalian host: it is a new world, after all. Curr. Opin. Microbiol. 11, 511–516 (2008).

  4. 4.

    et al. A role for the unfolded protein response (UPR) in virulence and antifungal susceptibility in Aspergillus fumigatus. PLoS Pathog. 5, e1000258 (2009).

  5. 5.

    Opportunistic fungi: a view to the future. Am. J. Med. Sci. 340, 253–257 (2010).

  6. 6.

    , , , & Invasive fungal disease in autosomal-dominant hyper-IgE syndrome. J. Allergy Clin. Immunol. 125, 1389–1390 (2010).

  7. 7.

    & Global warming will bring new fungal diseases for mammals. MBio 1, e00061-10 (2010).

  8. 8.

    et al. Transcriptome of Pneumocystis carinii during fulminate infection: carbohydrate metabolism and the concept of a compatible parasite. PLoS ONE 2, e423 (2007).

  9. 9.

    & Two ways to survive infection: what resistance and tolerance can teach us about treating infectious diseases. Nature Rev. Immunol. 8, 889–895 (2008).

  10. 10.

    Immunity to fungal infections. Nature Rev. Immunol. 4, 1–23 (2004).

  11. 11.

    et al. Host responses to a versatile commensal: PAMPs and PRRs interplay leading to tolerance or infection by Candida albicans. Cell. Microbiol. 11, 1007–1015 (2009).

  12. 12.

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

  13. 13.

    , , , & Fungal attacks on mammalian hosts: pathogen elimination requires sensing and tasting. Curr. Opin. Microbiol. 13, 401–408 (2010).

  14. 14.

    et al. The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice. J. Clin. Invest. 120, 1914–1924 (2010). This paper describes a unique susceptibility of patients with diabetic ketoacidosis to mucormycosis and provides a foundation for the development of new therapeutic interventions aimed at targeting the receptor 78 kDa glucose-regulated protein in endothelial cells.

  15. 15.

    Tasting the fungal cell wall. Cell. Microbiol. 12, 863–872 (2010).

  16. 16.

    Innate antifungal immunity: the key role of phagocytes. Annu. Rev. Immunol. 29, 1–21 (2011).

  17. 17.

    & Signalling through C-type lectin receptors: shaping immune responses. Nature Rev. Immunol. 9, 465–479 (2009).

  18. 18.

    et al. Human dectin-1 deficiency and mucocutaneous fungal infections. N. Engl. J. Med. 361, 1760–1767 (2009). The first study to describe the association between the Tyr238X mutation in dectin 1 and mucocutaneous candidiasis owing to defective IL-17, IL-6 and TNF production.

  19. 19.

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

  20. 20.

    et al. Dectin-1 is required for β-glucan recognition and control of fungal infection. Nature Immunol. 8, 31–38 (2007). References 19 and 20 were the first two studies to indicate a function for β-glucan recognition by dectin 1 in antifungal immunity and demonstrate that a non-TLR signalling pathway is required for the induction of protective immune responses.

  21. 21.

    et al. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N. Engl. J. Med. 361, 1727–1735 (2009). The first study to show an association between susceptibility to chronic mucocutaneous candidiasis and homozygous mutations in CARD9.

  22. 22.

    et al. Inborn errors of mucocutaneous immunity to Candida albicans in humans: a role for IL-17 cytokines? Curr. Opin. Immunol. 22, 467–474 (2010).

  23. 23.

    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).

  24. 24.

    et al. Dectin-2 recognition of α-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans. Immunity 32, 681–691 (2010).

  25. 25.

    et al. C-type lectin Mincle is an activating receptor for pathogenic fungus, Malassezia. Proc. Natl Acad. Sci. USA 106, 1897–1902 (2009).

  26. 26.

    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).

  27. 27.

    , & Effect of differential N-linked and O-linked mannosylation on recognition of fungal antigens by dendritic cells. PLoS ONE 2, e1009 (2007).

  28. 28.

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

  29. 29.

    et al. The macrophage mannose receptor induces IL-17 in response to Candida albicans. Cell Host Microbe 5, 329–340 (2009). This study identifies the macrophage mannose receptor as the specific PRR that triggers TH17 cell responses to C. albicans in humans.

  30. 30.

    et al. Dual specificity of Langerin to sulfated and mannosylated glycans via a single C-type carbohydrate recognition domain. J. Biol. Chem. 285, 6390–6400 (2010).

  31. 31.

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

  32. 32.

    , , & Role of the mannose receptor in a murine model of Cryptococcus neoformans infection. Infect. Immun. 76, 2362–2367 (2008).

  33. 33.

    et al. PPARγ controls dectin-1 expression required for host antifungal defense against Candida albicans. PLoS Pathog. 6, e1000714 (2010).

  34. 34.

    et al. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N. Engl. J. Med. 359, 1766–1777 (2008). This report provides strong evidence for the association between a donor TLR4 polymorphism and the risk of invasive aspergillosis among recipients of haematopoietic cell transplants from unrelated donors.

  35. 35.

    et al. Polymorphisms in Toll-like receptor genes and susceptibility to infections in allogeneic stem cell transplantation. Exp. Hematol. 37, 1022–1029 (2009).

  36. 36.

    et al. Polymorphisms in Toll-like receptor genes and susceptibility to pulmonary aspergillosis. J. Infect. Dis. 197, 618–621 (2008).

  37. 37.

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

  38. 38.

    & On regulation of phagosome maturation and antigen presentation. Nature Immunol. 7, 1029–1035 (2006).

  39. 39.

    et al. The contribution of PARs to inflammation and immunity to fungi. Mucosal Immunol. 1, 156–168 (2008). This study shows that recognition of fungi occurs through a dual sensor system involving crosstalk between TLRs that sense fungal PAMPs and PARs that sense fungal virulence.

  40. 40.

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

  41. 41.

    , & The role of secreted proteins in diseases of plants caused by rust, powdery mildew and smut fungi. Curr. Opin. Microbiol. 10, 326–331 (2007).

  42. 42.

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

  43. 43.

    , , & Aspergillus fumigatus stimulates the NLRP3 inflammasome through a pathway requiring ROS production and the Syk tyrosine kinase. PLoS ONE 5, e10008 (2010).

  44. 44.

    et al. Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 442, 651–656 (2006). This study defines a new innate immune pathway involving CARD9 as a key transducer of dectin 1 signalling and mediator of innate antifungal immunity.

  45. 45.

    et al. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 459, 433–436 (2009). This study describes the molecular basis for IL-1β production in candidiasis and identifies a crucial function for the NLRP3 inflammasome in antifungal host defence in vivo.

  46. 46.

    et al. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 32, 379–391 (2010).

  47. 47.

    , & Lessons from the inflammasome: a molecular sentry linking Candida and Crohn's disease. Trends Immunol. 31, 171–175 (2010).

  48. 48.

    DAMPs, PAMPs and alarmins: all we need to know about danger. J. Leukoc. Biol. 81, 1–5 (2007).

  49. 49.

    et al. The danger signal S100B integrates pathogen- and danger-sensing pathways to restrain inflammation. PLoS Pathog. (in the press).

  50. 50.

    & Oxylipins as developmental and host–fungal communication signals. Trends Microbiol. 15, 109–118 (2007).

  51. 51.

    et al. Candida albicans modulates host defense by biosynthesizing the pro-resolving mediator resolvin E1. PLoS ONE 2, e1316 (2007).

  52. 52.

    & Fungal stealth technology. Trends Immunol. 29, 18–24 (2008).

  53. 53.

    Innate recognition of fungal cell walls. PLoS Pathog. 6, e1000758 (2010).

  54. 54.

    , & Histoplasma capsulatum α-(1,3)-glucan blocks innate immune recognition by the β-glucan receptor. Proc. Natl Acad. Sci. USA 104, 1366–1370 (2007). This work highlights that α-(1,3)-glucans contribute to the pathogenesis of histoplasmosis by concealing immunostimulatory β-glucans from dectin 1.

  55. 55.

    et al. Surface hydrophobin prevents immune recognition of airborne fungal spores. Nature 460, 1117–1121 (2009). This work shows that surface hydrophobins on dormant airborne fungal conidia mask their recognition by the immune system and prevent immune responses.

  56. 56.

    Antigenic variation in Pneumocystis. J. Eukaryot. Microbiol. 54, 8–13 (2007).

  57. 57.

    Fungal capsular polysaccharide and T-cell suppression: the hidden nature of poor immunogenicity. Crit. Rev. Immunol. 27, 547–557 (2007).

  58. 58.

    & Phagosome extrusion and host-cell survival after Cryptococcus neoformans phagocytosis by macrophages. Curr. Biol. 16, 2161–2165 (2006).

  59. 59.

    et al. Evidence of a role for monocytes in dissemination and brain invasion by Cryptococcus neoformans. Infect. Immun. 77, 120–127 (2009).

  60. 60.

    et al. A role for fungal β-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice. J. Exp. Med. 201, 949–960 (2005).

  61. 61.

    et al. A comprehensive analysis of pattern recognition receptors in normal and inflamed human epidermis: upregulation of Dectin-1 in psoriasis. J. Invest. Dermatol. 130, 2611–2620 (2010).

  62. 62.

    et al. Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nature Med. 15, 401–409 (2009).

  63. 63.

    & A systems biology approach to the mutual interaction between yeast and the immune system. Immunobiology 215, 762–769 (2010).

  64. 64.

    et al. Distinct patterns of dendritic cell cytokine release stimulated by fungal β-glucans and Toll-like receptor agonists. Infect. Immun. 77, 1774–1781 (2009).

  65. 65.

    , , & Cooperative stimulation of dendritic cells by Cryptococcus neoformans mannoproteins and CpG oligodeoxynucleotides. PLoS ONE 3, e2046 (2008). This study provides a rationale for combining mannosylated antigens with TLR ligands in the design of immune modulators and vaccines against fungi.

  66. 66.

    et al. Intranasally delivered siRNA targeting PI3K/Akt/mTOR inflammatory pathways protects from aspergillosis. Mucosal Immunol. 3, 193–205 (2010).

  67. 67.

    et al. Balancing inflammation and tolerance in vivo through dendritic cells by the commensal Candida albicans. Mucosal Immunol. 2, 362–374 (2009).

  68. 68.

    , & Dynamic interplay among monocyte-derived, dermal, and resident lymph node dendritic cells during the generation of vaccine immunity to fungi. Cell Host Microbe 7, 474–487 (2010).

  69. 69.

    & How are TH2-type immune responses initiated and amplified? Nature Rev. Immunol. 10, 225–235 (2010).

  70. 70.

    et al. Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO. Cell. Mol. Immunol. 7, 459–470 (2010).

  71. 71.

    , , , & T helper 1-inducing adjuvant protects against experimental paracoccidioidomycosis. PLoS Negl. Trop. Dis. 2, e183 (2008).

  72. 72.

    , , & Polyfunctional T lymphocytes are in the peripheral blood of donors naturally immune to coccidioidomycosis and are not induced by dendritic cells. Infect. Immun. 78, 309–315 (2010).

  73. 73.

    et al. Robust Th1 and Th17 immunity supports pulmonary clearance but cannot prevent systemic dissemination of highly virulent Cryptococcus neoformans H99. Am. J. Pathol. 175, 2489–2500 (2009).

  74. 74.

    et al. Antibody titer threshold predicts anti-candidal vaccine efficacy even though the mechanism of protection is induction of cell-mediated immunity. J. Infect. Dis. 197, 967–971 (2008).

  75. 75.

    , & Direct inhibition of T-cell responses by the Cryptococcus capsular polysaccharide glucuronoxylomannan. PLoS Pathog. 2, e120 (2006).

  76. 76.

    , , , & Immunological basis for the gender differences in murine Paracoccidioides brasiliensis infection. PLoS ONE 5, e10757 (2010).

  77. 77.

    et al. Analysis of memory T cells in the human paracoccidioidomycosis before and during chemotherapy treatment. Immunol. Lett. 114, 23–30 (2007).

  78. 78.

    Pathogenesis of tinea. J. Dtsch Dermatol. Ges. 8, 780–786 (2010).

  79. 79.

    et al. IL-13 induces disease-promoting type 2 cytokines, alternatively activated macrophages and allergic inflammation during pulmonary infection of mice with Cryptococcus neoformans. J. Immunol. 179, 5367–5377 (2007).

  80. 80.

    & The CCL7–CCL2–CCR2 axis regulates IL-4 production in lungs and fungal immunity. J. Immunol. 183, 1964–1974 (2009).

  81. 81.

    et al. Vitamin D3 attenuates Th2 responses to Aspergillus fumigatus mounted by CD4+ T cells from cystic fibrosis patients with allergic bronchopulmonary aspergillosis. J. Clin. Invest. 120, 3242–3254 (2010). This study suggests that the induction of TReg cells by vitamin D3 may prevent or treat ABPA in patients with cystic fibrosis.

  82. 82.

    et al. Relationship of Pneumocystis jiroveci humoral immunity to prevention of colonization and chronic obstructive pulmonary disease in a primate model of HIV infection. Infect. Immun. 78, 4320–4330 (2010).

  83. 83.

    , , , & Monoclonal antibodies to heat shock protein 60 alter the pathogenesis of Histoplasma capsulatum. Infect. Immun. 77, 1357–1367 (2009).

  84. 84.

    et al. The absence of serum IgM enhances the susceptibility of mice to pulmonary challenge with Cryptococcus neoformans. J. Immunol. 184, 5755–5767 (2010).

  85. 85.

    et al. A monoclonal antibody to Histoplasma capsulatum alters the intracellular fate of the fungus in murine macrophages. Eukaryot. Cell 7, 1109–1117 (2008).

  86. 86.

    , , & Ab binding alters gene expression in Cryptococcus neoformans and directly modulates fungal metabolism. J. Clin. Invest. 120, 1355–1361 (2010). This paper describes a new mode of action for antibody-mediated immunity based on the modulation of microbial gene expression and metabolism.

  87. 87.

    et al. Conserved natural IgM antibodies mediate innate and adaptive immunity against the opportunistic fungus Pneumocystis murina. J. Exp. Med. 207, 2907–2919 (2010).

  88. 88.

    , , , & An insight into the antifungal pipeline: selected new molecules and beyond. Nature Rev. Drug Discov. 9, 719–727 (2010).

  89. 89.

    & A reappraisal of humoral immunity based on mechanisms of antibody-mediated protection against intracellular pathogens. Adv. Immunol. 91, 1–44 (2006).

  90. 90.

    , , , & Refractory disseminated coccidioidomycosis and mycobacteriosis in interferon-γ receptor 1 deficiency. Clin. Infect. Dis. 49, e62–e65 (2009).

  91. 91.

    , , & Interleukin-17 is not required for classical macrophage activation in a pulmonary mouse model of Cryptococcus neoformans infection. Infect. Immun. 78, 5341–5351 (2010).

  92. 92.

    et al. Coevolution of TH1, TH2, and TH17 responses during repeated pulmonary exposure to Aspergillus fumigatus conidia. Infect. Immun. 79, 125–135 (2010).

  93. 93.

    et al. IL-23 and the Th17 pathway promote inflammation and impair antifungal immune resistance. Eur. J. Immunol. 37, 2695–2706 (2007).

  94. 94.

    et al. Generation of IL-23 producing dendritic cells (DCs) by airborne fungi regulates fungal pathogenicity via the induction of TH-17 responses. PLoS ONE 5, e12955 (2010).

  95. 95.

    & Interleukins 17 and 23 influence the host response to Histoplasma capsulatum. J. Infect. Dis. 200, 142–151 (2009).

  96. 96.

    & CCR5 dictates the equilibrium of proinflammatory IL-17+ and regulatory Foxp3+ T cells in fungal infection. J. Immunol. 184, 5224–5231 (2010).

  97. 97.

    et al. Impaired interferon-γ responses, increased interleukin-17 expression, and a tumor necrosis factor-α transcriptional program in invasive aspergillosis. J. Infect. Dis. 200, 1341–1351 (2009).

  98. 98.

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

  99. 99.

    et al. IL-22 defines a novel immune pathway of antifungal resistance. Mucosal Immunol. 3, 361–373 (2010). This work defines a staged response in mucosal candidiasis, involving an early IL-22-dominated response that provides antifungal resistance, followed by a TH1 or TReg cell response that prevents fungal dissemination and provides immunological memory.

  100. 100.

    et al. IL-23 enhances the inflammatory cell response in Cryptococcus neoformans infection and induces a cytokine pattern distinct from IL-12. J. Immunol. 176, 1098–1106 (2006).

  101. 101.

    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).

  102. 102.

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

  103. 103.

    et al. Immune sensing of Aspergillus fumigatus proteins, glycolipids, and polysaccharides and the impact on Th immunity and vaccination. J. Immunol. 183, 2407–2414 (2009). In contrast to reference 54, this study shows that A. fumigatus α-(1,3)-glucans induce immune activation in aspergillosis. Therefore, evasion of this recognition may contribute to the pathogenic potential of dimorphic fungal pathogens but not opportunistic fungi.

  104. 104.

    et al. Anti-Aspergillus human host defence relies on type 1 T helper (Th1), rather than type 17 T helper (Th17), cellular immunity. Immunology 130, 46–54 (2010).

  105. 105.

    et al. Vaccine-induced protection against 3 systemic mycoses endemic to North America requires Th17 cells in mice. J. Clin. Invest. 121, 554–568 (2010).

  106. 106.

    et al. Impaired dendritic cell maturation and cytokine production in patients with chronic mucocutanous candidiasis with or without APECED. Clin. Exp. Immunol. 154, 406–414 (2008).

  107. 107.

    et al. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J. Exp. Med. 206, 299–311 (2009). This study shows the importance of the TH17 cell pathway in the control of oropharyngeal candidiasis. The work in reference 99 describes that TH17 cells are not essential in gastric candidiasis. These studies raise the question as to whether the activity of the TH17 cell subset is compartmentalized.

  108. 108.

    , , & Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J. Infect. Dis. 190, 624–631 (2004).

  109. 109.

    et al. Th1-Th17 cells mediate protective adaptive immunity against Staphylococcus aureus and Candida albicans infection in mice. PLoS Pathog. 5, e1000703 (2009).

  110. 110.

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

  111. 111.

    , , & TLR2 is a negative regulator of Th17 cells and tissue pathology in a pulmonary model of fungal infection. J. Immunol. 183, 1279–1290 (2009).

  112. 112.

    et al. Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur. J. Immunol. 41, 235–245 (2011).

  113. 113.

    & Protective tolerance to fungi: the role of IL-10 and tryptophan catabolism. Trends Microbiol. 14, 183–189 (2006).

  114. 114.

    , , , & Involvement of regulatory T cells in the immunosuppression characteristic of patients with paracoccidioidomycosis. Infect. Immun. 78, 4392–4401 (2010).

  115. 115.

    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).

  116. 116.

    The role of microorganisms in atopic dermatitis. Clin. Exp. Immunol. 144, 1–9 (2006).

  117. 117.

    , , , & IL-17 and therapeutic kynurenines in pathogenic inflammation to fungi. J. Immunol. 180, 5157–5162 (2008).

  118. 118.

    , , , & Indoleamine 2,3-dioxygenase in infection: the paradox of an evasive strategy that benefits the host. Microbes Infect. 11, 133–141 (2009).

  119. 119.

    et al. Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nature Med. 13, 579–586 (2007). This paper indicates that the induction of IDO expression could be an important mechanism underlying the anti-inflammatory action of corticosteroids in fungal allergy.

  120. 120.

    & Interleukin-22: a novel T- and NK-cell derived cytokine that regulates the biology of tissue cells. Cytokine Growth Factor Rev. 17, 367–380 (2006).

  121. 121.

    et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J. Exp. Med. 206, 1465–1472 (2009).

  122. 122.

    et al. Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452, 773–776 (2008). This work reports that TH17 cell responses to C. albicans are defective in patients with autosomal dominant hyper-IgE syndrome.

  123. 123.

    , , & 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).

  124. 124.

    et al. Memory IL-22-producing CD4+ T cells specific for Candida albicans are present in humans. Eur. J. Immunol. 39, 1472–1479 (2009).

  125. 125.

    , , , & Chronic mucocutaneous candidiasis, from bench to bedside. Eur. J. Dermatol. 20, 260–265 (2010).

  126. 126.

    , , , & Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Proc. Natl Acad. Sci. USA 88, 9543–9547 (1991).

  127. 127.

    , , , & Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from TH17, TH1 and TH2 cells. Nature Immunol. 10, 864–871 (2009).

  128. 128.

    et al. Activation of the Ah receptor by tryptophan and tryptophan metabolites. Biochemistry 37, 11508–11515 (1998).

  129. 129.

    , , , & IL-17/Th17 in anti-fungal immunity: what's new? Eur. J. Immunol. 39, 645–648 (2009).

  130. 130.

    et al. Deficiency of indoleamine 2,3-dioxygenase enhances commensal-induced antibody responses and protects against Citrobacter rodentium-induced colitis. Infect. Immun. 76, 3045–3053 (2008).

  131. 131.

    , , , & IL-23 and IL-17A, but not IL-12 and IL-22, are required for optimal skin host defense against Candida albicans. J. Immunol. 185, 5453–5462 (2010).

  132. 132.

    Fungal vaccines: real progress from real challenges. Lancet Infect. Dis. 8, 114–124 (2008).

  133. 133.

    , & Advances in combating fungal diseases: vaccines on the threshold. Nature Rev. Microbiol. 5, 13–28 (2007). References 132 and 133 are comprehensive reviews summarizing how the elucidation of the mechanisms of protective immunity against fungal diseases has renewed interest in the development of vaccines against the mycoses.

  134. 134.

    , & Genetic susceptibility to infections with Aspergillus fumigatus. Crit. Rev. Microbiol. 36, 168–177 (2010).

  135. 135.

    et al. Adjuvant corticosteroid therapy for chronic disseminated candidiasis. Clin. Infect. Dis. 46, 696–702 (2008).

  136. 136.

    et al. Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease. Nature 451, 211–215 (2008). The first direct demonstration of the causal link between defective tryptophan catabolism and susceptibility to fungal infections owing to uncontrolled inflammatory responses.

  137. 137.

    & Immune reconstitution syndrome and exacerbation of infections after pregnancy. Clin. Infect. Dis. 45, 1192–1199 (2007). A comprehensive overview of clinical conditions in which immunological recovery and an imbalance characterized by either suboptimal or excessive immune responses can also be harmful to the host by adversely affecting the resolution of infection.

  138. 138.

    et al. Polymorphisms in the chemokine (C-X-C motif) ligand 10 are associated with invasive aspergillosis after allogeneic stem-cell transplantation and influence CXCL10 expression in monocyte-derived dendritic cells. Blood 111, 534–536 (2008).

  139. 139.

    et al. Genetic variation of innate immune genes in HIV-infected african patients with or without oropharyngeal candidiasis. J. Acquir. Immune Defic. Syndr. 55, 87–94 (2010).

  140. 140.

    et al. Dectin-1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient- and donor-dependent mechanisms of antifungal immunity. Blood 116, 5394–5402 (2010).

  141. 141.

    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).

  142. 142.

    , , , & Single-nucleotide polymorphisms (SNPs) in human β-defensin 1: high-throughput SNP assays and association with Candida carriage in type I diabetics and nondiabetic controls. J. Clin. Microbiol. 41, 90–96 (2003).

  143. 143.

    , , & Cytokine profiling of pulmonary aspergillosis. Int. J. Immunogenet. 33, 297–302 (2006).

  144. 144.

    , , & IL1 gene cluster polymorphisms and its haplotypes may predict the risk to develop invasive pulmonary aspergillosis and modulate C-reactive protein level. J. Clin. Immunol. 28, 473–485 (2008).

  145. 145.

    et al. Association between chronic disseminated candidiasis in adult acute leukemia and common IL4 promoter haplotypes. J. Infect. Dis. 187, 1153–1156 (2003).

  146. 146.

    et al. Frequency of interleukin-4 (IL-4) -589 gene polymorphism and vaginal concentrations of IL-4, nitric oxide, and mannose-binding lectin in women with recurrent vulvovaginal candidiasis. Clin. Infect. Dis. 40, 1258–1262 (2005).

  147. 147.

    , , , & Interferon-γ and interleukin-4 single nucleotide gene polymorphisms in paracoccidioidomycosis. Cytokine 48, 212–217 (2009).

  148. 148.

    , , & IL-4 alpha chain receptor (IL-4Rα) polymorphisms in allergic bronchopulmonary aspergillosis. Clin. Mol. Allergy 4, 3 (2006).

  149. 149.

    et al. Interleukin-10 promoter polymorphism as risk factor to develop invasive pulmonary aspergillosis. Immunol. Lett. 109, 76–82 (2007).

  150. 150.

    et al. Protective role of interleukin-10 promoter gene polymorphism in the pathogenesis of invasive pulmonary aspergillosis after allogeneic stem cell transplantation. Bone Marrow Transplant. 36, 1089–1095 (2005).

  151. 151.

    et al. Influence of interleukin-10 on Aspergillus fumigatus infection in patients with cystic fibrosis. J. Infect. Dis. 191, 1988–1991 (2005).

  152. 152.

    et al. Prognostic significance of genetic variants in the IL-23/Th17 pathway for the outcome of T cell-depleted allogeneic stem cell transplantation. Bone Marrow Transplant. 45, 1645–1652 (2010).

  153. 153.

    et al. Mannan-binding lectin pathway deficiencies and invasive fungal infections following allogeneic stem cell transplantation. Exp. Hematol. 34, 1435–1441 (2006).

  154. 154.

    , , , & Mannose-binding lectin gene polymorphism and resistance to therapy in women with recurrent vulvovaginal candidiasis. BJOG 115, 1225–1231 (2008).

  155. 155.

    et al. Elevated levels of mannan-binding lectin (MBL) and eosinophilia in patients of bronchial asthma with allergic rhinitis and allergic bronchopulmonary aspergillosis associate with a novel intronic polymorphism in MBL. Clin. Exp. Immunol. 143, 414–419 (2006).

  156. 156.

    et al. Polymorphism in a gene coding for the inflammasome component NALP3 and recurrent vulvovaginal candidiasis in women with vulvar vestibulitis syndrome. Am. J. Obstet. Gynecol. 200, 303.e1–303.e6 (2009).

  157. 157.

    et al. Plasminogen alleles influence susceptibility to invasive aspergillosis. PLoS Genet. 4, e1000101 (2008).

  158. 158.

    , , , & Association of polymorphisms in the collagen region of SP-A2 with increased levels of total IgE antibodies and eosinophilia in patients with allergic bronchopulmonary aspergillosis. J. Allergy Clin. Immunol. 111, 1001–1007 (2003).

  159. 159.

    et al. Distinct alleles of mannose-binding lectin (MBL) and surfactant proteins A (SP-A) in patients with chronic cavitary pulmonary aspergillosis and allergic bronchopulmonary aspergillosis. Clin. Chem. Lab. Med. 45, 183–186 (2007).

  160. 160.

    et al. TLR1 and TLR6 polymorphisms are associated with susceptibility to invasive aspergillosis after allogeneic stem cell transplantation. Ann. NY Acad. Sci. 1062, 95–103 (2005).

  161. 161.

    et al. TNFR1 mRNA expression level and TNFR1 gene polymorphisms are predictive markers for susceptibility to develop invasive pulmonary aspergillosis. Int. J. Immunopathol. Pharmacol. 23, 423–436 (2010).

  162. 162.

    et al. Variable number of tandem repeats of TNF receptor type 2 promoter as genetic biomarker of susceptibility to develop invasive pulmonary aspergillosis. Hum. Immunol. 68, 41–50 (2007).

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Acknowledgements

I thank the large number of researchers who have contributed to this field and whose work was not cited or was cited through the review articles of others because of space limitations. This work is supported by the EU Specific Targeted Research Projects SYBARIS (FP7-Health-2009-single-stage, contract number 242220) and ALLFUN (FP7-Health-2010-single-stage, contract number 260338) and by the Fondazione per la Ricerca sulla Fibrosi Cistica (project number FFC21/2010). I also thank C. Massi Benedetti of the University of Perugia for editorial assistance and my numerous collaborators for their dedicated work in my laboratory.

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  1. Department of Experimental Medicine and Biochemical Sciences, Microbiology Section, University of Perugia, Via del Giochetto, 06122 Perugia, Italy.  lromani@unipg.it

    • Luigina Romani

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Competing interests

The author declares no competing financial interests.

Glossary

Yeast

A unicellular form of a fungus, consisting of oval or spherical cells, usually about 3 to 5 μm in diameter, that reproduce asexually by a process termed blastoconidia formation (budding) or by fission.

Spore

An asexual or sexual reproductive element of a fungus.

Toll-like receptors

(TLRs). A family of membrane-spanning proteins that recognize pathogen-associated molecular patterns (which are shared by various microorganisms), as well as damaged host cell components. TLRs signal to the host that a microbial pathogen is present or that tissue damage has occurred. They are characterized by an ectodomain that has varying numbers of leucine-rich repeat motifs and a cytoplasmic Toll/IL-1 receptor (TIR) domain that recruits adaptors, such as the myeloid differentiation primary response protein 88 (MYD88) and TIR domain-containing adaptor protein inducing IFNβ (TRIF; also known as TICAM1).

C-type lectin receptors

(CLRs). A large family of proteins that have one or more carbohydrate-recognition domains. CLRs exist as transmembrane and soluble proteins, and include the mannose receptor, dectin 1, dectin 2 and DC-SIGN, as well as soluble molecules, such as the complement-activating mannose-binding lectins, which are involved in antifungal immunity.

Inflammasome

A large multiprotein complex that contains certain NOD-like receptors, RIGI-like receptors and IFI200 proteins, the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC; also known as PYCARD) and pro-caspase 1. Assembly of the inflammasome leads to the activation of caspase 1, which cleaves pro-interleukin-1β (pro-IL-1β) and pro-IL-18 to generate the active cytokines.

Allergic bronchopulmonary aspergillosis

(ABPA). A condition that is characterized by an exaggerated airway inflammation (hypersensitivity response) to Aspergillus spp. (most commonly Aspergillus fumigatus). It occurs most often in patients with asthma or cystic fibrosis.

Protease-activated receptors

(PARs). A family of four G protein-coupled receptors. Proteolytic cleavage within the extracellular amino terminus exposes a tethered ligand domain, which activates the receptors to initiate multiple signalling cascades. Many proteases that activate PARs are produced during tissue damage, and PARs make important contributions to tissue responses to injury, including haemostasis, repair, cell survival, inflammation and pain.

NOD-like receptors

(NLRs). A family of cytosolic proteins that recognize pathogen-associated molecular patterns and endogenous ligands. The recognition of ligands induces a signalling cascade leading to activation of nuclear factor-κB, or the inflammasome, to produce pro-inflammatory cytokines. NLRs are also involved in signalling for cell death.

Hyphae

In moulds, spores germinate to produce branching filaments called hyphae, which are 2–10 μm in diameter and which may form a mass of intertwining strands called a mycelium.

Hydrophobins

A family of small, moderately hydrophobic proteins that are characterized by the conserved spacing of eight cysteine residues. Hydrophobins are present on the surface of many fungal conidia, and are responsible for the rodlet configuration of the outer conidial layer.

Delayed-type hypersensitivity response

A cellular immune response to antigen that develops over a period of 24–72 hours. The response is characterized by the infiltration of T cells and monocytes and depends on the production of T helper 1-type cytokines.

Paracoccidioidomycosis

A chronic granulomatous disease involving the lungs, skin, mucous membranes, lymph nodes and internal organs that is caused by Paracoccidioides brasiliensis. Symptoms include skin ulcers, adenitis and pain owing to abdominal organ involvement.

Symbiont

An intestinal microorganism that contributes to host nutrition and fitness through a mutualistic, beneficial interaction.

Pathobiont

A microbial symbiont that can cause diseases as a consequence of the perturbation of intestinal homeostasis.

Dysbiosis

Alteration of the symbiont microbial community.

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DOI

https://doi.org/10.1038/nri2939

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