Skip to main content

Advertisement

Log in

Regulation of white-opaque switching in Candida albicans

  • Review
  • Published:
Medical Microbiology and Immunology Aims and scope Submit manuscript

Abstract

The yeast Candida albicans is part of the microflora in most healthy people, but can become a pathogen when host defenses are compromised. The phenotypic plasticity of C. albicans, which includes switching between different morphologies, contributes to its ability to colonize and infect virtually all body locations. A particularly fascinating developmental program is white-opaque switching, a reversible transition between the normal yeast morphology (white) and an elongated cell type (opaque), which is the mating-competent form of this fungus. Although opaque cells are much less able than white cells to cause a systemic infection, they are better adapted for colonization of specific host niches, like skin. White-opaque switching is controlled by the mating type locus (MTL), which in most C. albicans strains exists in two alleles, MTL a and MTLα. These strains produce a heterodimeric repressor, a1-α2, which suppresses switching to the opaque phase by inhibiting expression of the master regulator Wor1. Loss of MTL heterozygosity relieves this repression, a mechanism that ensures that only MTL homozygous cells can switch to the mating-competent opaque form. Several transcriptional feedback loops, including positive autoregulation of Wor1, result in bistable expression of the master regulator (low in white and high in opaque cells) and epigenetic inheritance of the two phases. White-opaque switching occurs stochastically at a low frequency, but certain environmental conditions can drive the switch from one phase to the other by affecting either the activity of the transcriptional feedback loops or accumulation of Wor1 protein in a cell. Such environmental regulation of phenotypic switching may restrict mating to suitable host niches, while allowing a C. albicans population to withstand the various challenges encountered in different tissues.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Odds FC (1988) Candida and candidosis: a review and bibliography. Bailliere Tindall, London

    Google Scholar 

  2. Brock M (2009) Fungal metabolism in host niches. Curr Opin Microbiol 12(4):371–376

    Article  PubMed  CAS  Google Scholar 

  3. Sundstrom P (2002) Adhesion in Candida spp. Cell Microbiol 4(8):461–469

    Article  PubMed  CAS  Google Scholar 

  4. Kumamoto CA, Vinces MD (2005) Contributions of hyphae and hypha-co-regulated genes to Candida albicans virulence. Cell Microbiol 7(11):1546–1554

    Article  PubMed  CAS  Google Scholar 

  5. Slutsky B, Staebell M, Anderson J, Risen L, Pfaller M, Soll DR (1987) “White-opaque transition”: a second high-frequency switching system in Candida albicans. J Bacteriol 169(1):189–197

    PubMed  CAS  Google Scholar 

  6. Miller MG, Johnson AD (2002) White-opaque switching in Candida albicans is controlled by mating-type locus homeodomain proteins and allows efficient mating. Cell 110(3):293–302

    Article  PubMed  CAS  Google Scholar 

  7. Lockhart SR, Pujol C, Daniels KJ, Miller MG, Johnson AD, Pfaller MA, Soll DR (2002) In Candida albicans, white-opaque switchers are homozygous for mating type. Genetics 162(2):737–745

    PubMed  CAS  Google Scholar 

  8. Srikantha T, Soll DR (1993) A white-specific gene in the white-opaque switching system of Candida albicans. Gene 131(1):53–60

    Article  PubMed  CAS  Google Scholar 

  9. Morrow B, Srikantha T, Soll DR (1992) Transcription of the gene for a pepsinogen, PEP1, is regulated by white-opaque switching in Candida albicans. Mol Cell Biol 12(7):2997–3005

    PubMed  CAS  Google Scholar 

  10. Morrow B, Srikantha T, Anderson J, Soll DR (1993) Coordinate regulation of two opaque-phase-specific genes during white-opaque switching in Candida albicans. Infect Immun 61(5):1823–1828

    PubMed  CAS  Google Scholar 

  11. Tsong AE, Miller MG, Raisner RM, Johnson AD (2003) Evolution of a combinatorial transcriptional circuit: a case study in yeasts. Cell 115(4):389–399

    Article  PubMed  CAS  Google Scholar 

  12. Lan CY, Newport G, Murillo LA, Jones T, Scherer S, Davis RW, Agabian N (2002) Metabolic specialization associated with phenotypic switching in Candida albicans. Proc Natl Acad Sci USA 99(23):14907–14912

    Article  PubMed  CAS  Google Scholar 

  13. Kennedy MJ, Rogers AL, Hanselmen LR, Soll DR, Yancey RJ Jr (1988) Variation in adhesion and cell surface hydrophobicity in Candida albicans white and opaque phenotypes. Mycopathologia 102(3):149–156

    Article  PubMed  CAS  Google Scholar 

  14. Kvaal C, Lachke SA, Srikantha T, Daniels K, McCoy J, Soll DR (1999) 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(12):6652–6662

    PubMed  CAS  Google Scholar 

  15. Lachke SA, Lockhart SR, Daniels KJ, Soll DR (2003) Skin facilitates Candida albicans mating. Infect Immun 71(9):4970–4976

    Article  PubMed  CAS  Google Scholar 

  16. Anderson J, Cundiff L, Schnars B, Gao MX, Mackenzie I, Soll DR (1989) Hypha formation in the white-opaque transition of Candida albicans. Infect Immun 57(2):458–467

    PubMed  CAS  Google Scholar 

  17. Soll DR (1992) High-frequency switching in Candida albicans. Clin Microbiol Rev 5(2):183–203

    PubMed  CAS  Google Scholar 

  18. Kolotila MP, Diamond RD (1990) Effects of neutrophils and in vitro oxidants on survival and phenotypic switching of Candida albicans WO-1. Infect Immun 58(5):1174–1179

    PubMed  CAS  Google Scholar 

  19. Geiger J, Wessels D, Lockhart SR, Soll DR (2004) Release of a potent polymorphonuclear leukocyte chemoattractant is regulated by white-opaque switching in Candida albicans. Infect Immun 72(2):667–677

    Article  PubMed  CAS  Google Scholar 

  20. Lohse MB, Johnson AD (2008) Differential phagocytosis of white versus opaque Candida albicans by Drosophila and mouse phagocytes. PLoS One 3(1):e1473

    Article  PubMed  Google Scholar 

  21. Kvaal CA, Srikantha T, Soll DR (1997) Misexpression of the white-phase-specific gene WH11 in the opaque phase of Candida albicans affects switching and virulence. Infect Immun 65(11):4468–4475

    PubMed  CAS  Google Scholar 

  22. Wu W, Lockhart SR, Pujol C, Srikantha T, Soll DR (2007) Heterozygosity of genes on the sex chromosome regulates Candida albicans virulence. Mol Microbiol 64(6):1587–1604

    Article  PubMed  CAS  Google Scholar 

  23. Wu W, Pujol C, Lockhart SR, Soll DR (2005) Chromosome loss followed by duplication is the major mechanism of spontaneous mating-type locus homozygosis in Candida albicans. Genetics 169(3):1311–1327

    Article  PubMed  CAS  Google Scholar 

  24. Bennett RJ, Johnson AD (2003) Completion of a parasexual cycle in Candida albicans by induced chromosome loss in tetraploid strains. EMBO J 22(10):2505–2515

    Article  PubMed  CAS  Google Scholar 

  25. Huang G, Wang H, Chou S, Nie X, Chen J, Liu H (2006) Bistable expression of WOR1, a master regulator of white-opaque switching in Candida albicans. Proc Natl Acad Sci USA 103(34):12813–12818

    Article  PubMed  CAS  Google Scholar 

  26. Srikantha T, Borneman AR, Daniels KJ, Pujol C, Wu W, Seringhaus MR, Gerstein M, Yi S, Snyder M, Soll DR (2006) TOS9 regulates white-opaque switching in Candida albicans. Eukaryot Cell 5(10):1674–1687

    Article  PubMed  CAS  Google Scholar 

  27. Zordan RE, Galgoczy DJ, Johnson AD (2006) Epigenetic properties of white-opaque switching in Candida albicans are based on a self-sustaining transcriptional feedback loop. Proc Natl Acad Sci USA 103(34):12807–12812

    Article  PubMed  CAS  Google Scholar 

  28. Zordan RE, Miller MG, Galgoczy DJ, Tuch BB, Johnson AD (2007) Interlocking transcriptional feedback loops control white-opaque switching in Candida albicans. PLoS Biol 5(10):e256

    Article  PubMed  Google Scholar 

  29. Ramírez-Zavala B, Reuß O, Park YN, Ohlsen K, Morschhäuser J (2008) Environmental induction of white-opaque switching in Candida albicans. PLoS Pathog 4(6):e1000089 (Publication funded by the SFB 479)

    Article  PubMed  Google Scholar 

  30. Vinces MD, Kumamoto CA (2007) The morphogenetic regulator Czf1p is a DNA-binding protein that regulates white opaque switching in Candida albicans. Microbiology 153(Pt 9):2877–2884

    Article  PubMed  CAS  Google Scholar 

  31. Sonneborn A, Tebarth B, Ernst JF (1999) Control of white-opaque phenotypic switching in Candida albicans by the Efg1p morphogenetic regulator. Infect Immun 67(9):4655–4660

    PubMed  CAS  Google Scholar 

  32. Srikantha T, Tsai LK, Daniels K, Soll DR (2000) EFG1 null mutants of Candida albicans switch but cannot express the complete phenotype of white-phase budding cells. J Bacteriol 182(6):1580–1591

    Article  PubMed  CAS  Google Scholar 

  33. Hnisz D, Schwarzmuller T, Kuchler K (2009) Transcriptional loops meet chromatin: a dual-layer network controls white-opaque switching in Candida albicans. Mol Microbiol 74(1):1–15

    Article  PubMed  CAS  Google Scholar 

  34. Tuch BB, Galgoczy DJ, Hernday AD, Li H, Johnson AD (2008) The evolution of combinatorial gene regulation in fungi. PLoS Biol 6(2):e38

    Article  PubMed  Google Scholar 

  35. Klar AJ, Srikantha T, Soll DR (2001) A histone deacetylation inhibitor and mutant promote colony-type switching of the human pathogen Candida albicans. Genetics 158(2):919–924

    PubMed  CAS  Google Scholar 

  36. Srikantha T, Tsai L, Daniels K, Klar AJ, Soll DR (2001) The histone deacetylase genes HDA1 and RPD3 play distinct roles in regulation of high-frequency phenotypic switching in Candida albicans. J Bacteriol 183(15):4614–4625

    Article  PubMed  CAS  Google Scholar 

  37. Pendrak ML, Yan SS, Roberts DD (2004) Hemoglobin regulates expression of an activator of mating-type locus alpha genes in Candida albicans. Eukaryot Cell 3(3):764–775

    Article  PubMed  CAS  Google Scholar 

  38. Legrand M, Lephart P, Forche A, Mueller FM, Walsh T, Magee PT, Magee BB (2004) Homozygosity at the MTL locus in clinical strains of Candida albicans: karyotypic rearrangements and tetraploid formation. Mol Microbiol 52(5):1451–1462

    Article  PubMed  CAS  Google Scholar 

  39. Morrow B, Anderson J, Wilson J, Soll DR (1989) Bidirectional stimulation of the white-opaque transition of Candida albicans by ultraviolet irradiation. J Gen Microbiol 135(5):1201–1208

    PubMed  CAS  Google Scholar 

  40. Rikkerink EH, Magee BB, Magee PT (1988) Opaque-white phenotype transition: a programmed morphological transition in Candida albicans. J Bacteriol 170(2):895–899

    PubMed  CAS  Google Scholar 

  41. Bergen MS, Voss E, Soll DR (1990) Switching at the cellular level in the white-opaque transition of Candida albicans. J Gen Microbiol 136(10):1925–1936

    PubMed  CAS  Google Scholar 

  42. Alby K, Bennett RJ (2009) Stress-induced phenotypic switching in Candida albicans. Mol Biol Cell 20(14):3178–3191

    Article  PubMed  CAS  Google Scholar 

  43. Soll DR (2004) Mating-type locus homozygosis, phenotypic switching and mating: a unique sequence of dependencies in Candida albicans. Bioessays 26(1):10–20

    Article  PubMed  CAS  Google Scholar 

  44. Davies BS, Rine J (2006) A role for sterol levels in oxygen sensing in Saccharomyces cerevisiae. Genetics 174(1):191–201

    Article  PubMed  CAS  Google Scholar 

  45. Brown DH Jr, Giusani AD, Chen X, Kumamoto CA (1999) Filamentous growth of Candida albicans in response to physical environmental cues and its regulation by the unique CZF1 gene. Mol Microbiol 34(4):651–662

    Article  PubMed  CAS  Google Scholar 

  46. Dumitru R, Navarathna DH, Semighini CP, Elowsky CG, Dumitru RV, Dignard D, Whiteway M, Atkin AL, Nickerson KW (2007) In vivo and in vitro anaerobic mating in Candida albicans. Eukaryot Cell 6(3):465–472

    Article  PubMed  CAS  Google Scholar 

  47. Huang G, Srikantha T, Sahni N, Yi S, Soll DR (2009) CO2 regulates white-to-opaque switching in Candida albicans. Curr Biol 19(4):330–334

    Article  PubMed  CAS  Google Scholar 

  48. Klengel T, Liang WJ, Chaloupka J, Ruoff C, Schroppel K, Naglik JR, Eckert SE, Mogensen EG, Haynes K, Tuite MF, Levin LR, Buck J, Muhlschlegel FA (2005) Fungal adenylyl cyclase integrates CO2 sensing with cAMP signaling and virulence. Curr Biol 15(22):2021–2026

    Article  PubMed  CAS  Google Scholar 

  49. Hull CM, Raisner RM, Johnson AD (2000) Evidence for mating of the “asexual” yeast Candida albicans in a mammalian host. Science 289(5477):307–310

    Article  PubMed  CAS  Google Scholar 

  50. Johnson A (2003) The biology of mating in Candida albicans. Nat Rev Microbiol 1(2):106–116

    Article  PubMed  CAS  Google Scholar 

  51. Lohse MB, Johnson AD (2009) White-opaque switching in Candida albicans. Curr Opin Microbiol 12(6):650–654

    Article  PubMed  CAS  Google Scholar 

  52. Soll DR (2009) Why does Candida albicans switch? FEMS Yeast Res 9(7):973–989

    Article  PubMed  CAS  Google Scholar 

  53. Daniels KJ, Srikantha T, Lockhart SR, Pujol C, Soll DR (2006) Opaque cells signal white cells to form biofilms in Candida albicans. EMBO J 25(10):2240–2252

    Article  PubMed  CAS  Google Scholar 

  54. Park YN, Strauß A, Morschhäuser J (2004) The white-phase-specific gene WH11 is not required for white-opaque switching in Candida albicans. Mol Genet Genomics 272(1):88–97

    Article  PubMed  CAS  Google Scholar 

  55. Park YN, Morschhäuser J (2005) Candida albicans MTLα tup1Δ mutants can reversibly switch to mating-competent, filamentous growth forms. Mol Microbiol 58(5):1288–1302

    Article  PubMed  CAS  Google Scholar 

  56. Strauß A, Michel S, Morschhäuser J (2001) Analysis of phase-specific gene expression at the single-cell level in the white-opaque switching system of Candida albicans. J Bacteriol 183(12):3761–3769

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Work in the author’s lab was supported by the Deutsche Forschungsgemeinschaft through Sonderforschungsbereich 479.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joachim Morschhäuser.

Additional information

This article is published as part of the Special Issue on Pathogen Variation and Host Response in Infectious Disease.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morschhäuser, J. Regulation of white-opaque switching in Candida albicans . Med Microbiol Immunol 199, 165–172 (2010). https://doi.org/10.1007/s00430-010-0147-0

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00430-010-0147-0

Keywords

Navigation