Review Article | Published:

Candida albicans cell-type switching and functional plasticity in the mammalian host

Nature Reviews Microbiology volume 15, pages 96108 (2017) | Download Citation

Abstract

Candida albicans is a ubiquitous commensal of the mammalian microbiome and the most prevalent fungal pathogen of humans. A cell-type transition between yeast and hyphal morphologies in C. albicans was thought to underlie much of the variation in virulence observed in different host tissues. However, novel yeast-like cell morphotypes, including opaque(a/α), grey and gastrointestinally induced transition (GUT) cell types, were recently reported that exhibit marked differences in vitro and in animal models of commensalism and disease. In this Review, we explore the characteristics of the classic cell types — yeast, hyphae, pseudohyphae and chlamydospores — as well as the newly identified yeast-like morphotypes. We highlight emerging knowledge about the associations of these different morphotypes with different host niches and virulence potential, as well as the environmental cues and signalling pathways that are involved in the morphological transitions.

Key points

  • Candida albicans is a ubiquitous fungal constituent of the mammalian gut, genitourinary and skin microbiota.

  • C. albicans can infect most human tissues and causes superficial and disseminated disease syndromes in both healthy and immunocompromised hosts.

  • C. albicans shares the ability to change shape in different environments with other fungi. At least nine different cell morphologies have been documented in this species.

  • Yeast can adopt several morphologies in addition to the standard white(a/α) morphology. White(a or α) and opaque(a or α) cells occur in a genetically distinct strain background, whereas the more recently reported opaque(a/α), grey and gastrointestinally induced transition (GUT) cell types occur in the predominant strain background. Similarly to the classic cell types, each yeast-like morphotype differs to some extent in cell shape, in vitro properties and interactions with the host.

  • Different C. albicans cell types vary in their ability to colonize the host or cause disease, as well as to inhabit different host niches. Metabolic differences seem to account for some of the differences in fitness.

  • C. albicans has introduced an unusual cell-type switch into its mating programme.

  • Researchers have identified numerous environmental (host) signals that trigger morphological transitions in C. albicans in vitro.

  • Signalling pathways in C. albicans transmit and integrate environmental information and induce morphological changes through fungal-specific transcription factors.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Archaea and fungi of the human gut microbiome: correlations with diet and bacterial residents. PLoS ONE 8, e66019 (2013).

  2. 2.

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

  3. 3.

    et al. Topographic diversity of fungal and bacterial communities in human skin. Nature 498, 367–370 (2013).

  4. 4.

    & Fungal flora of human toe webs. Mycoses 45, 488–491 (2002).

  5. 5.

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

  6. 6.

    et al. Colonization by Candida species of the oral and vaginal mucosa in HIV-infected and noninfected women. AIDS Res. Hum. Retroviruses 29, 30–34 (2013).

  7. 7.

    Candida and Candidosis, a Review and Bibliography 2nd edn (W. B. Saunders, 1988).

  8. 8.

    & Natural history of Candida species and yeasts in the oral cavities of infants. Arch. Oral Biol. 18, 957–962 (1973).

  9. 9.

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

  10. 10.

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

  11. 11.

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

  12. 12.

    & Epidemiology of invasive candidiasis: a persistent public health problem. Clin. Microbiol. Rev. 20, 133–163 (2007).

  13. 13.

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

  14. 14.

    et al. White–opaque switching in natural MTLa/α isolates of Candida albicans: evolutionary implications for roles in host adaptation, pathogenesis, and sex. PLoS Biol. 11, e1001525 (2013). This paper identifies opaque(a/α) cells and describes their fitness in a neonatal skin colonization model.

  15. 15.

    et al. Discovery of a “white–gray–opaque” tristable phenotypic switching system in Candida albicans: roles of non-genetic diversity in host adaptation. PLoS Biol. 12, e1001830 (2014). This paper identifies grey cells and describes their fitness in an ex vivo tongue infection model.

  16. 16.

    , & Passage through the mammalian gut triggers a phenotypic switch that promotes Candida albicans commensalism. Nat. Genet. 45, 1088–1091 (2013). This article identifies GUT cells and describes their fitness in the mammalian digestive tract.

  17. 17.

    Microsporidiosis: an emerging and opportunistic infection in humans and animals. Acta Trop. 94, 61–76 (2005).

  18. 18.

    , , , & Coarse-scale population structure of pathogenic Armillaria species in a mixed-conifer forest in the Blue Mountains of northeast Oregon. Can. J. For. Res. 33, 612–623 (2003).

  19. 19.

    et al. Histoplasma yeast and mycelial transcriptomes reveal pathogenic-phase and lineage-specific gene expression profiles. BMC Genomics 14, 695 (2013).

  20. 20.

    , & Global control of dimorphism and virulence in fungi. Science 312, 583–588 (2006).

  21. 21.

    , , & A temperature-responsive network links cell shape and virulence traits in a primary fungal pathogen. PLoS Biol. 11, e1001614 (2013).

  22. 22.

    , & The distinct morphogenic states of Candida albicans. Trends Microbiol. 12, 317–324 (2004).

  23. 23.

    , & Coevolution of morphology and virulence in Candida species. Eukaryot. Cell 10, 1173–1182 (2011).

  24. 24.

    Growth of Candida albicans hyphae. Nat. Rev. Microbiol. 9, 737–748 (2011).

  25. 25.

    & Chlamydospore formation in Candida albicans and Candida dubliniensis — an enigmatic developmental programme. Mycoses 50, 1–12 (2007).

  26. 26.

    & Septin function in Candida albicans morphogenesis. Mol. Biol. Cell 13, 2732–2746 (2002).

  27. 27.

    et al. Expression levels of a filament-specific transcriptional regulator are sufficient to determine Candida albicans morphology and virulence. Proc. Natl Acad. Sci. USA 106, 599–604 (2009).

  28. 28.

    & Induction, morphogenesis, and germination of the chlamydospore of Candida albicans. J. Bacteriol. 104, 910–921 (1970).

  29. 29.

    & Morphogenesis in Candida albicans. Annu. Rev. Microbiol. 61, 529–553 (2007).

  30. 30.

    , & Cell cycle dynamics and quorum sensing in Candida albicans chlamydospores are distinct from budding and hyphal growth. Eukaryot. Cell 4, 1191–1202 (2005).

  31. 31.

    et al. Contact-induced apical asymmetry drives the thigmotropic responses of Candida albicans hyphae. Cell. Microbiol. 17, 342–354 (2015).

  32. 32.

    & Mechanisms of hypha orientation of fungi. Curr. Opin. Microbiol. 12, 350–357 (2009).

  33. 33.

    & Induction of the Candida albicans filamentous growth program by relief of transcriptional repression: a genome-wide analysis. Mol. Biol. Cell 16, 2903–2912 (2005).

  34. 34.

    , , , & DNA array studies demonstrate convergent regulation of virulence factors by Cph1, Cph2, and Efg1 in Candida albicans. J. Biol. Chem. 276, 48988–48996 (2001).

  35. 35.

    et al. Transcription profiling of Candida albicans cells undergoing the yeast-to-hyphal transition. Mol. Biol. Cell 13, 3452–3465 (2002).

  36. 36.

    et al. Candidalysin is a fungal peptide toxin critical for mucosal infection. Nature 532, 64–68 (2016).

  37. 37.

    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). This paper determines differences between white(a/α)yeast and hyphae in a reconstituted human oral epithelial infection model.

  38. 38.

    et al. Als3 is a Candida albicans invasin that binds to cadherins and induces endocytosis by host cells. PLoS Biol. 5, e64 (2007).

  39. 39.

    et al. Fungal morphogenetic pathways are required for the hallmark inflammatory response during Candida albicans vaginitis. Infect. Immun. 82, 532–543 (2014).

  40. 40.

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

  41. 41.

    et al. Candida albicans–epithelial interactions: dissecting the roles of active penetration, induced endocytosis and host factors on the infection process. PLoS ONE 7, e36952 (2012).

  42. 42.

    et al. Surgical pathology and the diagnosis of invasive visceral yeast infection: two case reports and literature review. World J. Emerg. Surg. 8, 38 (2013).

  43. 43.

    et al. Multi-step pathogenesis and induction of local immune response by systemic Candida albicans infection in an intravenous challenge mouse model. Int. J. Mol. Sci. 15, 14848–14867 (2014).

  44. 44.

    Fungal infections and the kidney. Indian J. Nephrol. 11, 147–154 (2001).

  45. 45.

    & Control of filament formation in Candida albicans by the transcriptional repressor TUP1. Science 277, 105–109 (1997).

  46. 46.

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

  47. 47.

    et al. NRG1 represses yeast–hypha morphogenesis and hypha-specific gene expression in Candida albicans. EMBO J. 20, 4742–4752 (2001).

  48. 48.

    , , & 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). The paper dissects the roles of white(a/α) yeast versus hyphae in disseminated infections through the use of a doxycycline-regulatable strain that can be forced into either morphology.

  49. 49.

    & Candida albicans biofilm development and its genetic control. Microbiol. Spectr. 3, MB-0005-2014 (2015).

  50. 50.

    , , , & Our current understanding of fungal biofilms. Crit. Rev. Microbiol. 35, 340–355 (2009).

  51. 51.

    , , , & Rapid production of Candida albicans chlamydospores in liquid media under various incubation conditions. Nihon Ishinkin Gakkai Zasshi 47, 231–234 (2006).

  52. 52.

    , , & Purification and germination of Candida albicans and Candida dubliniensis chlamydospores cultured in liquid media. FEMS Yeast Res. 9, 1051–1060 (2009).

  53. 53.

    , , & Candida albicans chlamydospores observed in vivo in a patient with AIDS. Ann. Biol. Clin. (Paris) 46, 817–818 (in French) (1988).

  54. 54.

    , , & Chlamydospore-like cells of Candida albicans in the gastrointestinal tract of infected, immunocompromised mice. Can. J. Microbiol. 37, 637–646 (1991).

  55. 55.

    et al. “White–opaque transition”: a second high-frequency switching system in Candida albicans. J. Bacteriol. 169, 189–197 (1987). The first paper to identify opaque(a) cells.

  56. 56.

    Candida biofilms and their role in infection. Trends Microbiol. 11, 30–36 (2003).

  57. 57.

    , & Ultrastructure and antigenicity of the unique cell wall pimple of the Candida opaque phenotype. J. Bacteriol. 172, 224–235 (1990).

  58. 58.

    & Differential phagocytosis of white versus opaque Candida albicans by Drosophila and mouse phagocytes. PLoS ONE 3, e1473 (2008).

  59. 59.

    , , , & White–opaque switching of Candida albicans allows immune evasion in an environment-dependent fashion. Eukaryot. Cell 12, 50–58 (2013).

  60. 60.

    , , , & Candida albicans white and opaque cells undergo distinct programs of filamentous growth. PLoS Pathog. 9, e1003210 (2013).

  61. 61.

    et al. Bcr1 plays a central role in the regulation of opaque cell filamentation in Candida albicans. Mol. Microbiol. 89, 732–750 (2013).

  62. 62.

    et al. The transcriptomes of two heritable cell types illuminate the circuit governing their differentiation. PLoS Genet. 6, e1001070 (2011).

  63. 63.

    , , & Evolution of a combinatorial transcriptional circuit: a case study in yeasts. Cell 115, 389–399 (2003).

  64. 64.

    et al. Metabolic specialization associated with phenotypic switching in Candida albicans. Proc. Natl Acad. Sci. USA 99, 14907–14912 (2002).

  65. 65.

    , , , & CO2 regulates white-to-opaque switching in Candida albicans. Curr. Biol. 19, 330–334 (2009).

  66. 66.

    et al. N-Acetylglucosamine induces white to opaque switching, a mating prerequisite in Candida albicans. PLoS Pathog. 6, e1000806 (2010).

  67. 67.

    et al. pH regulates white–opaque switching and sexual mating in Candida albicans. Eukaryot. Cell 14, 1127–1134 (2015).

  68. 68.

    & White–opaque switching in Candida albicans is controlled by mating-type locus homeodomain proteins and allows efficient mating. Cell 110, 293–302 (2002). This study establishes links between the opaque(a or α) phenotype, MTL genotype and competency for mating.

  69. 69.

    From a to α: Yeast as a Model for Cellular Differentiation (Cold Spring Harbor Laboratory Press, 2007).

  70. 70.

    , & Evidence for mating of the “asexual” yeast Candida albicans in a mammalian host. Science 289, 307–310 (2000).

  71. 71.

    & Induction of mating in Candida albicans by construction of MTLa and MTLα strains. Science 289, 310–313 (2000).

  72. 72.

    & Identification of a mating type-like locus in the asexual pathogenic yeast Candida albicans. Science 285, 1271–1275 (1999).

  73. 73.

    et al. Bistable expression of WOR1, a master regulator of white–opaque switching in Candida Albicans. Proc. Natl Acad. Sci. USA 103, 12813–12818 (2006).

  74. 74.

    et al. TOS9 regulates white–opaque switching in Candida albicans. Eukaryot. Cell 5, 1674–1687 (2006).

  75. 75.

    , & Epigenetic properties of white–opaque switching in Candida albicans are based on a self-sustaining transcriptional feedback loop. Proc. Natl Acad. Sci. USA 103, 12807–12812 (2006).

  76. 76.

    , , , & Impact of environmental conditions on the form and function of Candida albicans biofilms. Eukaryot. Cell 12, 1389–1402 (2013).

  77. 77.

    , , , & Candida albicans forms a specialized “sexual” as well as “pathogenic” biofilm. Eukaryot. Cell 12, 1120–1131 (2013).

  78. 78.

    et al. Mating is rare within as well as between clades of the human pathogen Candida albicans. Fungal Genet. Biol. 45, 221–231 (2008).

  79. 79.

    et al. Molecular markers reveal that population structure of the human pathogen Candida albicans exhibits both clonality and recombination. Proc. Natl Acad. Sci. USA 93, 12473–12477 (1996).

  80. 80.

    et al. Homozygosity at the MTL locus in clinical strains of Candida albicans: karyotypic rearrangements and tetraploid formation. Mol. Microbiol. 52, 1451–1462 (2004).

  81. 81.

    et al. In Candida albicans, white–opaque switchers are homozygous for mating type. Genetics 162, 737–745 (2002).

  82. 82.

    et al. Misexpression of the opaque-phase-specific gene PEP1 (SAP1) in the white phase of Candida albicans confers increased virulence in a mouse model of cutaneous infection. Infect. Immun. 67, 6652–6662 (1999).

  83. 83.

    , , , & Increased virulence and competitive advantage of a/α over a/a or α/α offspring conserves the mating system of Candida albicans. Genetics 169, 1883–1890 (2005).

  84. 84.

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

  85. 85.

    & The Mep2p ammonium permease controls nitrogen starvation-induced filamentous growth in Candida albicans. Mol. Microbiol. 56, 649–669 (2005).

  86. 86.

    , & N-Acetyl-d-glucosamine induces germination in Candida albicans through a mechanism sensitive to inhibitors of cAMP-dependent protein kinase. Cell Signal. 10, 713–719 (1998).

  87. 87.

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

  88. 88.

    et al. Fungal adenylyl cyclase integrates CO2 sensing with cAMP signaling and virulence. Curr. Biol. 15, 2021–2026 (2005).

  89. 89.

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

  90. 90.

    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).

  91. 91.

    et al. The quorum-sensing molecules farnesol/homoserine lactone and dodecanol operate via distinct modes of action in Candida albicans. Eukaryot. Cell 10, 1034–1042 (2011).

  92. 92.

    et al. Ras links cellular morphogenesis to virulence by regulation of the MAP kinase and cAMP signalling pathways in the pathogenic fungus Candida albicans. Mol. Microbiol. 42, 673–687 (2001).

  93. 93.

    & RA domain-mediated interaction of Cdc35 with Ras1 is essential for increasing cellular cAMP level for Candida albicans hyphal development. Mol. Microbiol. 61, 484–496 (2006).

  94. 94.

    et al. Signaling through adenylyl cyclase is essential for hyphal growth and virulence in the pathogenic fungus Candida albicans. Mol. Biol. Cell 12, 3631–3643 (2001).

  95. 95.

    , , & Candida albicans Cyr1, Cap1 and G-actin form a sensor/effector apparatus for activating cAMP synthesis in hyphal growth. Mol. Microbiol. 75, 579–591 (2010).

  96. 96.

    et al. A Candida albicans cyclic nucleotide phosphodiesterase: cloning and expression in Saccharomyces cerevisiae and biochemical characterization of the recombinant enzyme. Microbiology 140, 1533–1542 (1994).

  97. 97.

    , , , & Distinct and redundant roles of the two protein kinase A isoforms Tpk1p and Tpk2p in morphogenesis and growth of Candida albicans. Mol. Microbiol. 42, 1243–1257 (2001).

  98. 98.

    et al. Protein kinase A encoded by TPK2 regulates dimorphism of Candida albicans. Mol. Microbiol. 35, 386–396 (2000).

  99. 99.

    , , , & Candida albicans homolog of CDC25 is functional in Saccharomyces cerevisiae. Eur. J. Biochem. 213, 195–204 (1993).

  100. 100.

    , & A single-transformation gene function test in diploid Candida albicans. J. Bacteriol. 182, 5730–5736 (2000).

  101. 101.

    , , & The Candida albicans ELMO homologue functions together with Rac1 and Dck1, upstream of the MAP Kinase Cek1, in invasive filamentous growth. Mol. Microbiol. 76, 1572–1590 (2010).

  102. 102.

    et al. Roles of the Candida albicans mitogen-activated protein kinase homolog, Cek1p, in hyphal development and systemic candidiasis. Infect. Immun. 66, 2713–2721 (1998).

  103. 103.

    et al. Signal transduction through homologs of the Ste20p and Ste7p protein kinases can trigger hyphal formation in the pathogenic fungus Candida Albicans. Proc. Natl Acad. Sci. USA 93, 13217–13222 (1996).

  104. 104.

    et al. Derepressed hyphal growth and reduced virulence in a VH1 family-related protein phosphatase mutant of the human pathogen Candida albicans. Mol. Biol. Cell 8, 2539–2551 (1997).

  105. 105.

    & Candida albicans strains heterozygous and homozygous for mutations in mitogen-activated protein kinase signaling components have defects in hyphal development. Proc. Natl Acad. Sci. USA 93, 13223–13228 (1996).

  106. 106.

    , & Regulatory circuitry governing fungal development, drug resistance, and disease. Microbiol. Mol. Biol. Rev. 75, 213–267 (2011).

  107. 107.

    , , , & Many of the genes required for mating in Saccharomyces cerevisiae are also required for mating in Candida albicans. Mol. Microbiol. 46, 1345–1351 (2002).

  108. 108.

    , , & Identification and characterization of a Candida albicans mating pheromone. Mol. Cell. Biol. 23, 8189–8201 (2003).

  109. 109.

    , & CEK2, a novel MAPK from Candida albicans complement the mating defect of fus3/kss1 mutant. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai) 32, 299–304 (2000).

  110. 110.

    , & Dominant negative selection of heterologous genes: isolation of Candida albicans genes that interfere with Saccharomyces cerevisiae mating factor-induced cell cycle arrest. Proc. Natl Acad. Sci. USA 89, 9410–9414 (1992).

  111. 111.

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

  112. 112.

    , , , & The transmembrane protein Opy2 mediates activation of the Cek1 MAP kinase in Candida albicans. Fungal Genet. Biol. 50, 21–32 (2013).

  113. 113.

    , , & Msb2 signaling mucin controls activation of Cek1 mitogen-activated protein kinase in Candida albicans. Eukaryot. Cell 8, 1235–1249 (2009).

  114. 114.

    , , & The MAP kinase signal transduction network in Candida albicans. Microbiology 152, 905–912 (2006).

  115. 115.

    , & Yeast Cdc42 GTPase and Ste20 PAK-like kinase regulate Sho1-dependent activation of the Hog1 MAPK pathway. EMBO J. 19, 4623–4631 (2000).

  116. 116.

    et al. CDC42 is required for polarized growth in human pathogen Candida albicans. Eukaryot. Cell 1, 95–104 (2002).

  117. 117.

    , & The Sho1 adaptor protein links oxidative stress to morphogenesis and cell wall biosynthesis in the fungal pathogen Candida albicans. Mol. Cell. Biol. 25, 10611–10627 (2005).

  118. 118.

    & Osmotic activation of the HOG MAPK pathway via Ste11p MAPKKK: scaffold role of Pbs2p MAPKK. Science 276, 1702–1705 (1997).

  119. 119.

    , , , & A conserved stress-activated protein kinase regulates a core stress response in the human pathogen Candida albicans. Mol. Biol. Cell 15, 4179–4190 (2004).

  120. 120.

    et al. Role of the mitogen-activated protein kinase Hog1p in morphogenesis and virulence of Candida albicans. J. Bacteriol. 181, 3058–3068 (1999).

  121. 121.

    , , & The Pbs2 MAP kinase kinase is essential for the oxidative-stress response in the fungal pathogen Candida albicans. Microbiology 151, 1033–1049 (2005).

  122. 122.

    , & Defective hyphal development and avirulence caused by a deletion of the SSK1 response regulator gene in Candida albicans. Infect. Immun. 68, 518–525 (2000).

  123. 123.

    & The β-arrestin-like protein Rim8 is hyperphosphorylated and complexes with Rim21 and Rim101 to promote adaptation to neutral-alkaline pH. Eukaryot. Cell 11, 683–693 (2012).

  124. 124.

    , , & The Candida albicans ESCRT pathway makes Rim101-dependent and -independent contributions to pathogenesis. Eukaryot. Cell 9, 1203–1215 (2010).

  125. 125.

    , , , & Candida albicans Rim13p, a protease required for Rim101p processing at acidic and alkaline pHs. Eukaryot. Cell 3, 741–751 (2004).

  126. 126.

    , & RIM101-dependent and-independent pathways govern pH responses in Candida albicans. Mol. Cell. Biol. 20, 971–978 (2000).

  127. 127.

    , , , & Synergistic regulation of hyphal elongation by hypoxia, CO2, and nutrient conditions controls the virulence of Candida albicans. Cell Host Microbe 14, 499–509 (2013).

  128. 128.

    , & The protein kinase Tor1 regulates adhesin gene expression in Candida albicans. PLoS Pathog. 5, e1000294 (2009).

  129. 129.

    et al. Self-regulation of Candida albicans population size during GI colonization. PLoS Pathog. 3, e184 (2007).

  130. 130.

    , , & Efg1p, an essential regulator of morphogenesis of the human pathogen Candida albicans, is a member of a conserved class of bHLH proteins regulating morphogenetic processes in fungi. EMBO J. 16, 1982–1991 (1997).

  131. 131.

    , & Control of white–opaque phenotypic switching in Candida albicans by the Efg1p morphogenetic regulator. Infect. Immun. 67, 4655–4660 (1999).

  132. 132.

    , & Chlamydospore formation in Candida albicans requires the Efg1p morphogenetic regulator. Infect. Immun. 67, 5514–5517 (1999).

  133. 133.

    & Sok2 regulates yeast pseudohyphal differentiation via a transcription factor cascade that regulates cell–cell adhesion. Mol. Cell. Biol. 20, 8364–8372 (2000).

  134. 134.

    , & StuAp is a sequence-specific transcription factor that regulates developmental complexity in Aspergillus nidulans. EMBO J. 16, 5710–5721 (1997).

  135. 135.

    , , & Asm-1+, a Neurospora crassa gene related to transcriptional regulators of fungal development. Genetics 144, 991–1003 (1996).

  136. 136.

    et al. The Botrytis cinerea Reg1 protein, a putative transcriptional regulator, is required for pathogenicity, conidiogenesis, and the production of secondary metabolites. Mol. Plant Microbe Interact. 24, 1074–1085 (2011).

  137. 137.

    , , & The Wor1-like protein Fgp1 regulates pathogenicity, toxin synthesis and reproduction in the phytopathogenic fungus Fusarium graminearum. PLoS Pathog. 8, e1002724 (2012).

  138. 138.

    & Temperature-induced switch to the pathogenic yeast form of Histoplasma capsulatum requires Ryp1, a conserved transcriptional regulator. Proc. Natl Acad. Sci. USA 105, 4880–4885 (2008).

  139. 139.

    , , , & Interlocking transcriptional feedback loops control white–opaque switching in Candida albicans. PLoS Biol. 5, e256 (2007). This paper describes a genetic analysis of the regulatory circuit that controls the white(a)-to-opaque(a) switch.

  140. 140.

    et al. Target specificity of the Candida albicans Efg1 regulator. Mol. Microbiol. 82, 602–618 (2011).

  141. 141.

    et al. Candida albicans Zcf37, a zinc finger protein, is required for stabilization of the white state. FEBS Lett. 585, 797–802 (2011).

  142. 142.

    et al. Identification and characterization of a previously undescribed family of sequence-specific DNA-binding domains. Proc. Natl Acad. Sci. USA 110, 7660–7665 (2013).

  143. 143.

    et al. Ssn6 defines a new level of regulation of white–opaque switching in Candida albicans and is required for the stochasticity of the switch. mBio 7, e01565–15 (2016).

  144. 144.

    et al. Systematic genetic screen for transcriptional regulators of the Candida albicans white–opaque switch. Genetics 203, 1679–1692 (2016).

  145. 145.

    & Identification and characterization of Wor4, a new transcriptional regulator of white–opaque switching. G3 (Bethesda) 6, 721–729 (2016).

  146. 146.

    et al. Structure of the transcriptional network controlling white–opaque switching in Candida albicans. Mol. Microbiol. 90, 22–35 (2013).

  147. 147.

    in Principles and Practice of Infectious Diseases 8th edn (eds Bennett, J. E., Dolin, R. & Blaser, M. J.) 2879–2894 (Saunders, 2014).

  148. 148.

    & Candida albicans biofilms and human disease. Annu. Rev. Microbiol. 69, 71–92 (2015).

  149. 149.

    & Plasticity of Candida albicans biofilms. Microbiol. Mol. Biol. Rev. 80, 565–595 (2016).

  150. 150.

    et al. UME6, a novel filament-specific regulator of Candida albicans hyphal extension and virulence. Mol. Biol. Cell 19, 1354–1365 (2008).

  151. 151.

    et al. UME6 is a crucial downstream target of other transcriptional regulators of true hyphal development in Candida albicans. FEMS Yeast Res. 9, 126–142 (2009).

  152. 152.

    , , & Filamentous growth of Candida albicans in response to physical environmental cues and its regulation by the unique CZF1 gene. Mol. Microbiol. 34, 651–662 (1999).

  153. 153.

    , & GATA transcription factor recruits Hda1 in response to reduced Tor1 signaling to establish a hyphal chromatin state in Candida albicans. PLoS Pathog. 8, e1002663 (2012).

  154. 154.

    , & Reduced TOR signaling sustains hyphal development in Candida albicans by lowering Hog1 basal activity. Mol. Biol. Cell 24, 385–397 (2013).

  155. 155.

    , & NRG1, a repressor of filamentous growth in C.albicans, is down-regulated during filament induction. EMBO J. 20, 4753–4761 (2001).

  156. 156.

    & Rfg1, a protein related to the Saccharomyces cerevisiae hypoxic regulator Rox1, controls filamentous growth and virulence in Candida albicans. Mol. Cell. Biol. 21, 2496–2505 (2001).

  157. 157.

    & The DNA binding protein Rfg1 is a repressor of filamentation in Candida albicans. Genetics 157, 1503–1512 (2001).

  158. 158.

    , , , & Biochemical and genetic characterization of Rbf1p, a putative transcription factor of Candida albicans. Microbiology 143, 429–435 (1997).

  159. 159.

    et al. Genes selectively up-regulated by pheromone in white cells are involved in biofilm formation in Candida albicans. PLoS Pathog. 5, e1000601 (2009).

  160. 160.

    et al. Unique aspects of gene expression during Candida albicans mating and possible G1 dependency. Eukaryot. Cell 4, 1175–1190 (2005).

  161. 161.

    et al. The sea pansy Renilla reniformis luciferase serves as a sensitive bioluminescent reporter for differential gene expression in Candida albicans. J. Bacteriol. 178, 121–129 (1996).

  162. 162.

    , , , & The basic helix–loop–helix transcription factor Cph2 regulates hyphal development in Candida albicans partly via TEC1. Mol. Cell. Biol. 21, 6418–6428 (2001).

  163. 163.

    , , & Deletion of EFG1 promotes Candida albicans opaque formation responding to pH via Rim101. Acta Biochim. Biophys. Sin. (Shanghai) 42, 735–744 (2010).

  164. 164.

    & 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).

  165. 165.

    , , & Efg1, a morphogenetic regulator in Candida albicans, is a sequence-specific DNA binding protein. J. Bacteriol. 183, 4090–4093 (2001).

  166. 166.

    et al. Adaptation of the Efg1p morphogenetic pathway in Candida albicans by negative autoregulation and PKA-dependent repression of the EFG1 gene. J. Mol. Biol. 329, 949–962 (2003).

  167. 167.

    et al. APSES proteins regulate morphogenesis and metabolism in Candida albicans. Mol. Biol. Cell 15, 3167–3180 (2004).

Download references

Acknowledgements

The authors are grateful to H. Madhani for helpful comments regarding this Review. The laboratory of S.N. is supported by the US National Institutes of Health (grant R01AI108992), an Investigators in the Pathogenesis of Infectious Disease award from the Burroughs Wellcome Fund, and a Scholar in the Biomedical Sciences award from the Pew Charitable Trusts. In addition, B.A.G. is supported by the US National Science Foundation (grant 1144247) and J.W. is supported by the US National Institutes of Health (grant T32AI060537).

Author information

Affiliations

  1. Department of Microbiology and Immunology, University of California San Francisco (UCSF) School of Medicine.

    • Suzanne M. Noble
    • , Brittany A. Gianetti
    •  & Jessica N. Witchley
  2. Infectious Diseases Division, Department of Medicine, University of California San Francisco (UCSF) School of Medicine, San Francisco, California 94143, USA.

    • Suzanne M. Noble

Authors

  1. Search for Suzanne M. Noble in:

  2. Search for Brittany A. Gianetti in:

  3. Search for Jessica N. Witchley in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Suzanne M. Noble.

Glossary

Budding

A form of asexual reproduction by yeast cells, in which a new cell develops as a focal outgrowth of the mother cell, followed by detachment once growth is complete.

Cytokinesis

Division of the cytoplasm between a mother cell and daughter cell after mitosis (or meiosis) is complete.

Suspensor cells

Terminal cells in mycelial networks that produce chlamydospores under nutrient-poor and oxygen-depleted conditions.

Thigmotropism

The ability of hyphal tip cells to alter the direction of polarized growth in response to irregularities in an underlying surface.

Meiosis

A type of cell division that produces four daughter cells, each containing half of the DNA content of the mother. This process is used to generate sexually competent cells such as a and α-cells in Saccharomyces cerevisiae.

Dimorphic fungi

A set of human fungal pathogens that grow as mycelia in the environment but as yeast (or spherules, in the case of Coccidioides immitis) in mammalian hosts. These pathogens include Blastomyces dermatitidis, C. immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, Talaromyces marneffei (formerly known as Penicillium marneffei) and Sporothrix schenckii.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrmicro.2016.157

Further reading