Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The mycobiota: interactions between commensal fungi and the host immune system

Nature Reviews Immunology volume 14, pages 405–416 (2014)Cite this article

Subjects

Key Points

  • The fungal microbiota, or 'mycobiota', is an understudied component of the microflora that is found on all mucosal surfaces and on the skin.

  • Like other microorganisms, fungi interact with the immune system at these surfaces in ways that are important both for host defence and for regulating the immune system.

  • Investigators who study the mycobiota face both biological and bioinformatic challenges.

  • The study of human genetic disorders and genetic polymorphisms teaches us about the mechanisms by which commensal and pathogenic fungi interact with the immune system.

Abstract

The body is host to a wide variety of microbial communities from which the immune system protects us and that are important for the normal development of the immune system and for the maintenance of healthy tissues and physiological processes. Investigators have mostly focused on the bacterial members of these communities, but fungi are increasingly being recognized to have a role in defining these communities and to interact with immune cells. In this Review, we discuss what is currently known about the makeup of fungal communities in the body and the features of the immune system that are particularly important for interacting with fungi at these sites.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The human mycobiota.
Figure 2: Immune receptors and signalling pathways involved in recognition of fungi.
Figure 3: Mucosal immune responses involved in interacting with fungi at different body sites.

Similar content being viewed by others

References

  1. The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).

  2. Clemente, J. C., Ursell, L. K., Parfrey, L. W. & Knight, R. The impact of the gut microbiota on human health: an integrative view. Cell 148, 1258–1270 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Erturk-Hasdemir, D. & Kasper, D. L. Resident commensals shaping immunity. Curr. Opin. Immunol. 25, 450–455 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tremaroli, V. & Backhed, F. Functional interactions between the gut microbiota and host metabolism. Nature 489, 242–249 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Arumugam, M. et al. Enterotypes of the human gut microbiome. Nature 473, 174–180 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bull-Otterson, L. et al. Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment. PLoS ONE 8, e53028 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sonnenberg, G. F. et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336, 1321–1325 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Devkota, S. et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature 487, 104–108 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nilsson, R. H. et al. Taxonomic reliability of DNA sequences in public sequence databases: a fungal perspective. PLoS ONE 1, e59 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hube, B. From commensal to pathogen: stage- and tissue-specific gene expression of Candida albicans. Curr. Opin. Microbiol. 7, 336–341 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Scupham, A. J. et al. Abundant and diverse fungal microbiota in the murine intestine. Appl. Environ. Microbiol. 72, 793–801 (2006). This was the first culture-independent large-scale analysis of the distribution of fungal rRNA genes in the mammalian intestine and it shows the rich fungal diversity that is present in the mouse gut.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Iliev, I. D. et al. Interactions between commensal fungi and the C-Type lectin receptor dectin-1 influence colitis. Science 336, 1314–1317 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dollive, S. et al. Fungi of the murine gut: episodic variation and proliferation during antibiotic treatment. PLoS ONE 8, e71806 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hoffmann, C. et al. Archaea and fungi of the human gut microbiome: correlations with diet and bacterial residents. PLoS ONE 8, e66019 (2013). This study demonstrates an effect of long-term diet in determining the structure of the human gut microbiome and shows that there are correlations between bacteria, fungi and archaea.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Odds, F. C. et al. Candida albicans strain maintenance, replacement, and microvariation demonstrated by multilocus sequence typing. J. Clin. Microbiol. 44, 3647–3658 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Standaert-Vitse, A. et al. Candida albicans is an immunogen for anti-Saccharomyces cerevisiae antibody markers of Crohn's disease. Gastroenterology 130, 1764–1775 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Ott, S. J. et al. Fungi and inflammatory bowel diseases: Alterations of composition and diversity. Scand. J. Gastroenterol. 43, 831–841 (2008). This study provides the first evidence for increased fungal diversity and an alteration of intestinal mycobiota profiles in patients with IBD.

    Article  CAS  PubMed  Google Scholar 

  20. Scanlan, P. D. & Marchesi, J. R. Micro-eukaryotic diversity of the human distal gut microbiota: qualitative assessment using culture-dependent and -independent analysis of faeces. ISME J. 2, 1183–1193 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Standaert-Vitse, A. et al. Candida albicans colonization and ASCA in familial Crohn's disease. Am. J. Gastroenterol. 104, 1745–1753 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Angebault, C. et al. Candida albicans is not always the preferential yeast colonizing humans: a study in Wayampi Amerindians. J. Infect. Dis. 208, 1705–1716 (2013).

    Article  PubMed  Google Scholar 

  23. Savage, D. C., Dubos, R. & Schaedler, R. W. The gastrointestinal epithelium and its autochthonous bacterial flora. J. Exp. Med. 127, 67–76 (1968).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dominguez-Bello, M. G. et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl Acad. Sci. USA 107, 11971–11975 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Agans, R. et al. Distal gut microbiota of adolescent children is different from that of adults. FEMS Microbiol. Ecol. 77, 404–412 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. Naglik, J. R., Fidel, P. L. Jr & Odds, F. C. Animal models of mucosal Candida infection. FEMS Microbiol. Lett. 283, 129–139 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Noverr, M. C., Falkowski, N. R., McDonald, R. A., McKenzie, A. N. & Huffnagle, G. B. Development of allergic airway disease in mice following antibiotic therapy and fungal microbiota increase: role of host genetics, antigen, and interleukin-13. Infect. Immun. 73, 30–38 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mason, K. L. et al. Candida albicans and bacterial microbiota interactions in the cecum during recolonization following broad-spectrum antibiotic therapy. Infect. Immun. 80, 3371–3380 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Samonis, G. et al. Prospective evaluation of effects of broad-spectrum antibiotics on gastrointestinal yeast colonization of humans. Antimicrob. Agents Chemother. 37, 51–53 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mulligan, M. E., Citron, D. M., McNamara, B. T. & Finegold, S. M. Impact of cefoperazone therapy on fecal flora. Antimicrob. Agents Chemother. 22, 226–230 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Karabinis, A. et al. Risk factors for candidemia in cancer patients: a case-control study. J. Clin. Microbiol. 26, 429–432 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Richardson, M. D. Changing patterns and trends in systemic fungal infections. J. Antimicrob. Chemother. 56, i5–i11 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Zaoutis, T. E. et al. Risk factors and predictors for candidemia in pediatric intensive care unit patients: implications for prevention. Clin. Infect. Dis. 51, e38–45 (2010).

    Article  PubMed  Google Scholar 

  34. Erb-Downward, J. R., Falkowski, N. R., Mason, K. L., Muraglia, R. & Huffnagle, G. B. Modulation of post-antibiotic bacterial community reassembly and host response by Candida albicans. Sci. Rep. 3, 2191 (2013). This study shows that during antibiotic-induced dysbiosis, the exogenous addition of C. albicans will lead to overgrowth and will influence the composition of the bacterial microbiota.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Romani, L. Immunity to fungal infections. Nature Rev. Immunol. 11, 275–288 (2011).

    Article  CAS  Google Scholar 

  37. Khor, B., Gardet, A. & Xavier, R. J. Genetics and pathogenesis of inflammatory bowel disease. Nature 474, 307–317 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Beaudoin, M. et al. Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis. PLoS Genet. 9, e1003723 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Glocker, E. O. et al. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N. Engl. J. Med. 361, 1727–1735 (2009). This was the first paper to demonstrate that genetic impairment of CARD9 leaves individuals highly susceptible to CMC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sokol, H. et al. Card9 mediates intestinal epithelial cell restitution, T-helper 17 responses, and control of bacterial infection in mice. Gastroenterology 145, 591–601 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. De Luca, A. et al. IL-22 defines a novel immune pathway of antifungal resistance. Mucosal. Immunol. 3, 361–373 (2010). This study demonstrates a protective role of IL-22 in the gastrointestinal mucosa during Candida infection.

    Article  CAS  PubMed  Google Scholar 

  43. Zelante, T. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39, 372–385 (2013).

    Article  CAS  PubMed  Google Scholar 

  44. Noverr, M. C., Noggle, R. M., Toews, G. B. & Huffnagle, G. B. Role of antibiotics and fungal microbiota in driving pulmonary allergic responses. Infect. Immun. 72, 4996–5003 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Noverr, M. C., Phare, S. M., Toews, G. B., Coffey, M. J. & Huffnagle, G. B. Pathogenic yeasts Cryptococcus neoformans and Candida albicans produce immunomodulatory prostaglandins. Infect. Immun. 69, 2957–2963 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Erb-Downward, J. R. & Noverr, M. C. Characterization of prostaglandin E2 production by Candida albicans. Infect. Immun. 75, 3498–3505 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Noverr, M. C., Toews, G. B. & Huffnagle, G. B. Production of prostaglandins and leukotrienes by pathogenic fungi. Infect. Immun. 70, 400–402 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kim, Y. G. et al. Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi-induced PGE2 . Cell Host Microbe 15, 95–102 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. van der Velden, W. J. et al. Role of the mycobiome in human acute graft-versus-host disease. Biol. Blood Marrow Transplant. 19, 329–332 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Ghannoum, M. A. et al. Characterization of the oral fungal microbiome (mycobiome) in healthy individuals. PLoS Pathog. 6, e1000713 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Dupuy, A. K. et al. Redefining the human oral mycobiome with improved practices in amplicon-based taxonomy: discovery of Malassezia as a prominent commensal. PLoS ONE 9, e90899 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Smeekens, S. P., van de Veerdonk, F. L., Kullberg, B. J. & Netea, M. G. Genetic susceptibility to Candida infections. EMBO Mol. Med. 5, 805–813 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. van de Veerdonk, F. L. et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N. Engl. J. Med. 365, 54–61 (2011).

    Article  CAS  PubMed  Google Scholar 

  54. Takezaki, S. et al. Chronic mucocutaneous candidiasis caused by a gain-of-function mutation in the STAT1 DNA- binding domain. J. Immunol. 189, 1521–1526 (2012).

    Article  CAS  PubMed  Google Scholar 

  55. Smeekens, S. P. et al. STAT1 hyperphosphorylation and defective IL12R/IL23R signaling underlie defective immunity in autosomal dominant chronic mucocutaneous candidiasis. PLoS ONE 6, e29248 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Puel, A. et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 332, 65–68 (2011). This study demonstrates that genetic deficiencies in the IL-17 signalling pathway predispose individuals to CMC, which provides a link between IL-17 and mucosal antifungal immunity in humans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Boisson, B. et al. An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis. Immunity 39, 676–686 (2013).

    Article  CAS  PubMed  Google Scholar 

  59. Puel, A. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Conti, H. R. 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 a crucial role for IL-17 signalling in controlling Candida in the oral mucosa.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gladiator, A., Wangler, N., Trautwein-Weidner, K. & LeibundGut-Landmann, S. Cutting edge: IL-17-secreting innate lymphoid cells are essential for host defense against fungal infection. J. Immunol. 190, 521–525 (2013).

    Article  CAS  PubMed  Google Scholar 

  62. Lanternier, F. et al. Deep dermatophytosis and inherited CARD9 deficiency. N. Engl. J. Med. 369, 1704–1714 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Drewniak, A. et al. Invasive fungal infection and impaired neutrophil killing in human CARD9 deficiency. Blood 121, 2385–2392 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Bishu, S. et al. The adaptor CARD9 is required for adaptive but not innate immunity to oral mucosal Candida albicans infections. Infect. Immun. 82, 1173–1180 (2013).

    Article  CAS  PubMed  Google Scholar 

  65. Hise, A. G. 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). Using a mouse model of oral infection, this study demonstrates that CLEC7A, NLRP3 and TLR2 are important for controlling C. albicans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ferwerda, B. et al. Human dectin-1 deficiency and mucocutaneous fungal infections. N. Engl. J. Med. 361, 1760–1767 (2009). This was the first paper to demonstrate that genetic impairment of CLEC7A in humans impairs host defence against Candida infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Robinson, M. J. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Grice, E. A. et al. Topographical and temporal diversity of the human skin microbiome. Science 324, 1190–1192 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Costello, E. K. et al. Bacterial community variation in human body habitats across space and time. Science 326, 1694–1697 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Findley, K. et al. Topographic diversity of fungal and bacterial communities in human skin. Nature 498, 367–370 (2013). This study is the most comprehensive culture- independent evaluation to date of the communities of fungi that are associated with the human skin and highlights the dominance of Malassezia species.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Tagami, H. Location-related differences in structure and function of the stratum corneum with special emphasis on those of the facial skin. Int. J. Cosmet. Sci. 30, 413–434 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Grice, E. A. & Segre, J. A. The skin microbiome. Nature Rev. Microbiol. 9, 244–253 (2011).

    Article  CAS  Google Scholar 

  73. Roth, R. R. & James, W. D. Microbial ecology of the skin. Annu. Rev. Microbiol. 42, 441–464 (1988).

    Article  CAS  PubMed  Google Scholar 

  74. Paulino, L. C., Tseng, C. H., Strober, B. E. & Blaser, M. J. Molecular analysis of fungal microbiota in samples from healthy human skin and psoriatic lesions. J. Clin. Microbiol. 44, 2933–2941 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhang, E. et al. Characterization of the skin fungal microbiota in patients with atopic dermatitis and in healthy subjects. Microbiol. Immunol. 55, 625–632 (2011).

    Article  CAS  PubMed  Google Scholar 

  76. Oh, J. et al. The altered landscape of the human skin microbiome in patients with primary immunodeficiencies. Genome Res. 23, 2103–2114 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Smeekens, S. P. et al. Skin microbiome imbalance in patients with STAT1/STAT3 defects impairs innate host defense responses. J. Innate Immun. 6, 253–262 (2014).

    Article  CAS  PubMed  Google Scholar 

  78. Kagami, S., Rizzo, H. L., Kurtz, S. E., Miller, L. S. & Blauvelt, A. 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).

    Article  CAS  PubMed  Google Scholar 

  79. Drell, T. et al. Characterization of the vaginal micro- and mycobiome in asymptomatic reproductive-age Estonian women. PLoS ONE 8, e54379 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Zheng, N. N., Guo, X. C., Lv, W., Chen, X. X. & Feng, G. F. Characterization of the vaginal fungal flora in pregnant diabetic women by 18S rRNA sequencing. Eur. J. Clin. Microbiol. Infect. Dis. 32, 1031–1040 (2013).

    Article  CAS  PubMed  Google Scholar 

  81. Guo, R. et al. Increased diversity of fungal flora in the vagina of patients with recurrent vaginal candidiasis and allergic rhinitis. Microb. Ecol. 64, 918–927 (2012).

    Article  PubMed  Google Scholar 

  82. Boris, S. & Barbes, C. Role played by lactobacilli in controlling the population of vaginal pathogens. Microbes Infect. 2, 543–546 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Boris, S., Suarez, J. E., Vazquez, F. & Barbes, C. Adherence of human vaginal lactobacilli to vaginal epithelial cells and interaction with uropathogens. Infect. Immun. 66, 1985–1989 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Kohler, G. A., Assefa, S. & Reid, G. Probiotic interference of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 with the opportunistic fungal pathogen Candida albicans. Infect. Dis. Obstet. Gynecol. 2012, 636474 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  85. De Luca, A. et al. IL-22 and IDO1 affect immunity and tolerance to murine and human vaginal candidiasis. PLoS Pathog. 9, e1003486 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lev-Sagie, A. 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. e1–6 (2009).

    Article  CAS  PubMed  Google Scholar 

  87. Tomalka, J. et al. A novel role for the NLRC4 inflammasome in mucosal defenses against the fungal pathogen Candida albicans. PLoS Pathog. 7, e1002379 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Wojitani, M. D., de Aguiar, L. M., Baracat, E. C. & Linhares, I. M. Association between mannose-binding lectin and interleukin-1 receptor antagonist gene polymorphisms and recurrent vulvovaginal candidiasis. Arch. Gynecol. Obstet. 285, 149–153 (2012).

    Article  CAS  PubMed  Google Scholar 

  89. Babula, O., Lazdane, G., Kroica, J., Ledger, W. J. & Witkin, S. S. Relation between recurrent vulvovaginal candidiasis, vaginal concentrations of mannose-binding lectin, and a mannose-binding lectin gene polymorphism in Latvian women. Clin. Infect. Dis. 37, 733–737 (2003).

    Article  PubMed  Google Scholar 

  90. Giraldo, P. C. et al. Mannose-binding lectin gene polymorphism, vulvovaginal candidiasis, and bacterial vaginosis. Obstet. Gynecol. 109, 1123–1128 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Crosdale, D. J., Poulton, K. V., Ollier, W. E., Thomson, W. & Denning, D. W. Mannose-binding lectin gene polymorphisms as a susceptibility factor for chronic necrotizing pulmonary aspergillosis. J. Infect. Dis. 184, 653–656 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. van Woerden, H. C. et al. Differences in fungi present in induced sputum samples from asthma patients and non-atopic controls: a community based case control study. BMC Infect. Dis. 13, 69 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Pihet, M. et al. Occurrence and relevance of filamentous fungi in respiratory secretions of patients with cystic fibrosis — a review. Med. Mycol. 47, 387–397 (2009).

    Article  PubMed  Google Scholar 

  94. Delhaes, L. et al. The airway microbiota in cystic fibrosis: a complex fungal and bacterial community — implications for therapeutic management. PLoS ONE 7, e36313 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Dagenais, T. R. & Keller, N. P. Pathogenesis of Aspergillus fumigatus in invasive aspergillosis. Clin. Microbiol. Rev. 22, 447–465 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Agarwal, R. et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clin. Exp. Allergy 43, 850–873 (2013).

    Article  CAS  PubMed  Google Scholar 

  97. Hohl, T. M. et al. Aspergillus fumigatus triggers inflammatory responses by stage-specific β-glucan display. PLoS Pathog. 1, e30 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Gersuk, G. M., Underhill, D. M., Zhu, L. & Marr, K. A. Dectin-1 and TLRs permit macrophages to distinguish between different Aspergillus fumigatus cellular states. J. Immunol. 176, 3717–3724 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Carrion Sde, J. et al. The RodA hydrophobin on Aspergillus fumigatus spores masks dectin-1- and dectin-2-dependent responses and enhances fungal survival in vivo. J. Immunol. 191, 2581–2588 (2013).

    Article  CAS  PubMed  Google Scholar 

  100. Faro-Trindade, I. et al. Characterisation of innate fungal recognition in the lung. PLoS ONE 7, e35675 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Grimm, M. J. et al. Monocyte- and macrophage-targeted NADPH oxidase mediates antifungal host defense and regulation of acute inflammation in mice. J. Immunol. 190, 4175–4184 (2013).

    Article  CAS  PubMed  Google Scholar 

  102. Grimm, M. J. et al. Role of NADPH oxidase in host defense against aspergillosis. Med. Mycol. 49 (Suppl. 1), 144–149 (2011).

    Article  CAS  Google Scholar 

  103. Lass-Florl, C., Roilides, E., Loffler, J., Wilflingseder, D. & Romani, L. Minireview: host defence in invasive aspergillosis. Mycoses 56, 403–413 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Rivera, A. et al. Dectin-1 diversifies Aspergillus fumigatus-specific T cell responses by inhibiting T helper type 1 CD4 T cell differentiation. J. Exp. Med. 208, 369–381 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Gessner, M. A. et al. Dectin-1-dependent interleukin-22 contributes to early innate lung defense against Aspergillus fumigatus. Infect. Immun. 80, 410–417 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Taylor, P. R. et al. Activation of neutrophils by autocrine IL-17A–IL-17RC interactions during fungal infection is regulated by IL-6, IL-23, RORγt and dectin-2. Nature Immunol. 15, 143–151 (2014). This study shows that neutrophils are an important source of IL-17 in response to fungi such as Aspergillus.

    Article  CAS  Google Scholar 

  107. Lilly, L. M. et al. The β-glucan receptor dectin-1 promotes lung immunopathology during fungal allergy via IL-22. J. Immunol. 189, 3653–3660 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Mintz-Cole, R. A. et al. Dectin-1 and IL-17A suppress murine asthma induced by Aspergillus versicolor but not Cladosporium cladosporioides due to differences in β-glucan surface exposure. J. Immunol. 189, 3609–3617 (2012).

    Article  CAS  PubMed  Google Scholar 

  109. Bi, L. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Saijo, S. 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).

    Article  CAS  PubMed  Google Scholar 

  111. Moyes, D. L. et al. Candida albicans yeast and hyphae are discriminated by MAPK signaling in vaginal epithelial cells. PLoS ONE 6, e26580 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Cheng, S. C. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Gantner, B. N., Simmons, R. M. & Underhill, D. M. Dectin-1 mediates macrophage recognition of Candida albicans yeast but not filaments. EMBO J. 24, 1277–1286 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Wheeler, R. T., Kombe, D., Agarwala, S. D. & Fink, G. R. Dynamic, morphotype-specific Candida albicans β-glucan exposure during infection and drug treatment. PLoS Pathog. 4, e1000227 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Pande, K., Chen, C. & Noble, S. M. Passage through the mammalian gut triggers a phenotypic switch that promotes Candida albicans commensalism. Nature Genet. 45, 1088–1091 (2013).

    Article  CAS  PubMed  Google Scholar 

  116. Zhang, Q. et al. Combined immunodeficiency associated with DOCK8 mutations. N. Engl. J. Med. 361, 2046–2055 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Engelhardt, K. R. et al. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. J. Allergy Clin. Immunol. 124, 1289–1302 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Holland, S. M. et al. STAT3 mutations in the hyper IgE syndrome. N. Engl. J. Med. 357, 1608–1619 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Freeman, A. F. et al. Causes of death in hyper-IgE syndrome. J. Allergy Clin. Immunol. 119, 1234–1240 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. Minegishi, Y. et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448, 1058–1062 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Plantinga, T. S. 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).

    Article  CAS  PubMed  Google Scholar 

  123. Ouederni, M. et al. Clinical features of Candidiasis in patients with inherited interleukin 12 receptor β1 deficiency. Clin. Infect. Dis. 58, 204–213 (2014).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors' work relating to this manuscript was funded by the US National Institutes of Health (grant DK098310 to I.D.I. and DK093426 to D.M.U.), as well as the Crohn's and Colitis Foundation of America.

Author information

Authors and Affiliations

  1. F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, 90048, California, USA

    David M. Underhill & Iliyan D. Iliev

Authors
  1. David M. Underhill
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Iliyan D. Iliev
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to David M. Underhill or Iliyan D. Iliev.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

PowerPoint slides

Glossary

Inflammatory bowel disease

(IBD). A group of chronic inflammatory conditions that affect the large and small intestine. The major types are Crohn's disease and ulcerative colitis.

Dysbiosis

A term that was originally coined by the 1908 Nobel laureate Eli Metchnikoff to refer to pathogenic alterations of the bacterial microflora in the gut. Now used more generally to refer to any microbial imbalance in or on the body at sites including the gastrointestinal tract, the skin and exposed mucosal surfaces such as the lungs, vagina or mouth.

Shotgun sequencing

A sequencing approach in which a complex pool of DNA is broken up into random small segments that are sequenced en masse. Computational tools are then used to reassemble and characterize the DNA fragments.

Uncultured

A term that is used in mycobiome sequencing studies to refer to sequences that are identified in the National Center for Biotechnology Information GenBank database as fungal but that are currently of uncharacterized origin.

Candida

A genus of yeasts that includes common species such as Candida albicans, C. tropicalis, C. glabrata, C. parapsilosis and C. krusei. Candida species are normal inhabitants of the skin and mucous membranes and primarily cause disease in immunocompromised individuals. Candidiasis (disease caused by Candida) of the mouth or throat is called thrush or oropharyngeal candidiasis.

Anti-Saccharomyces cerevisiae antibodies

(ASCAs). Antibodies that are commonly found in serum from patients with inflammatory bowel disease. These antibodies are more common in individuals with Crohn's disease than in patients with ulcerative colitis. ASCAs cross-react with mannans from the cell walls of many fungi (including Candida species), which suggests that the name might be misleading.

Caspase recruitment domain-containing protein 9

(CARD9). A signalling adaptor molecule that functions downstream of many immunoreceptor tyrosine- based activation motif (ITAM) receptors that are present in phagocytes, including macrophages and dendritic cells. CARD9 associates with B cell lymphoma 10 (BCL-10) and the paracaspase MALT1 to facilitate signalling through nuclear factor-κB and to promote acute inflammatory responses and the initiation of adaptive immunity.

T helper 1 (TH1) cell-mediated immunity

An immune response that is characterized by T cells that produce IFNγ. This is generally associated with effective host defence against intracellular bacteria and protozoa.

Malassezia

A genus of basidiomycetous fungi that includes species such as Malassezia dermatis, M. furfur and M. restricta. These yeasts are specifically adapted for growth on mammalian skin and they are associated with conditions such as dandruff, atopic eczema and dermatitis, pityriasis versicolor, seborrheic dermatitis and folliculitis.

Chronic mucocutaneous candidiasis

(CMC). A condition that is characterized by recurrent Candida infections of the mouth, skin and other mucosal surfaces.

Onychomycosis

A fungal infection of the toenails or fingernails. These infections are most commonly caused by dermatophytes (Microsporum, Epidermophyton and Trichophyton) but can also be caused by Candida species and non-dermatophytic moulds.

C-type lectin receptor

(CLR). A member of a large family of receptors that bind to carbohydrates, typically in a calcium-dependent manner. Here, we use the term to refer to the set of CLRs that act as 'pattern recognition receptors' in the detection of microbial threats and that activate immune responses. The CLR family includes membrane receptors, such as CLEC6A, CLEC7A and the mannose receptor, and also soluble receptors, such as mannose-binding lectin (MBL). The binding activity of these receptors is mediated by conserved carbohydrate-recognition domains.

a–α mating type

This refers to two haploid sexual forms of yeast. The a-type yeast cells secret an 'a-factor', which is a pheromone that attracts the α-mating type, which, in turn, secretes 'α-factor'. The a-type cells respond to the α-factor by growing a projection (shmoo) towards the α-cells. Haploid cells respond only to a pheromone of the opposite cell type, which allows for mating to only occur between a-type and α-type cells.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Underhill, D., Iliev, I. The mycobiota: interactions between commensal fungi and the host immune system. Nat Rev Immunol 14, 405–416 (2014). https://doi.org/10.1038/nri3684

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri3684

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing