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:

Candida albicans: A molecular revolution built on lessons from budding yeast

Key Points

  • The analysis of Candida albicans is complicated by the lack of a complete sexual cycle, which obviates classical genetic approaches, and by the use of an unconventional codon, which prohibits the use of heterologous genes.

  • The availability of the C. albicans genome sequence (×10.4 coverage) has facilitated reverse-genetic and genomic approaches for investigating C. albicans biology.

  • Transformation using a recyclable URA3 marker or PCR-mediated gene targeting with several recently available selectable markers and codon-optimized epitopes has improved the ability to generate genetically altered C. albicans strains.

  • The C. albicans genome sequence has identified many Saccharomyces cerevisiae homologues, as well as many genes with no obvious homologue in S. cerevisiae. Genes that differ from S. cerevisiae might have an important role in virulence.

  • C. albicans grows as yeast, pseudohyphae (elongated budded cells) or true hyphae (cells with parallel sides and no constriction at the site of septation). True hyphae are fundamentally different from pseudohyphae and yeast in the organization of the cell cycle.

  • Morphogenesis is regulated by cell-cycle regulators, such as the major cyclin-dependent kinase Fkh2, which is a transcriptional regulator of B-cyclin expression, and Mad2, which is a spindle checkpoint protein. Although Mad2 is not required for growth in vitro it is important for virulence in mice, indicating that modulation of cell-cycle events might be especially important for C. albicans cells growing in a mammalian host.

  • Different environmental conditions, such as high temperature, high pH and the presence of serum, induce yeast cells to form true hyphae. The cAMP and the mating-pheromone-response–MAP-kinase–signal-transduction pathways target transcription factors, such as Efg1 and Cph1, that promote morphogenesis. The Rim101 pathway responds to pH and the Czf1 pathway responds to the presence of solid matrix.

  • Several partial-genome array studies, and recently reported whole-genome microarray studies, are uncovering genes the transcription of which changes on exposure to anti-fungal drugs or during the yeast-to-hyphal transition.

  • C. albicans has mating-type-like (MTL) genes that resemble S. cerevisiae mating-type genes, and diploid cells that carry only one type of MTL gene can fuse with cells of the opposite mating type to form recombinant tetraploids. The mechanism by which diploids are regenerated is not known.

  • Several systems of phenotypic switching — the epigenetic alteration of colony phenotypes — exist in Candida species. The best-studied phenotypic switching system is the switch between white and opaque colony morphology.

  • The molecular and genomic tools are now in place to enable direct studies of C. albicans that will provide a deeper understanding of pathways and genes, including those that are important for pathogenesis.

Abstract

Candida albicans is an opportunistic fungal pathogen that is found in the normal gastrointestinal flora of most healthy humans. However, in immunocompromised patients, blood-stream infections often cause death, despite the use of anti-fungal therapies. The recent completion of the C. albicans genome sequence, the availability of whole-genome microarrays and the development of tools for rapid molecular-genetic manipulations of the C. albicans genome are generating an explosion of information about the intriguing biology of this pathogen and about its mechanisms of virulence. They also reveal the extent of similarities and differences between C. albicans and its benign relative, Saccharomyces cerevisiae.

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

Access options

Buy this article

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

Figure 1: Methods of gene disruption or deletion.
Figure 2: Colony morphologies of Candida albicans.
Figure 3: Signal-transduction pathways that regulate morphogenesis.
Figure 4: Relationships between mating and white–opaque phenotypic switching.

Similar content being viewed by others

References

  1. Beck-Sague, C. & Jarvis, W. R. Secular trends in the epidemiology of nosocomial fungal infections in the United States, 1980–1990. National Nosocomial Infections Surveillance System. J. Infect. Dis. 167, 1247–1251 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Miller, L. G., Hajjeh, R. A. & Edwards, J. E. Jr. Estimating the cost of nosocomial candidemia in the United States. Clin. Infect. Dis. 32, 1110 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Berbee, M. L. & Taylor, J. W. in The Mycota. Vol. VIIB (eds McLaughlin, D. J. & McLaughlin, E.) 229–246 (Springer, New York, 2000).

    Google Scholar 

  4. Heckman, D. et al. Molecular evidence for the early colonization of land by fungi and plants. Science 293, 1129–1133 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Asleson, C. M. et al. Candida albicans INT1-induced filamentation in Saccharomyces cerevisiae depends on Sla2p. Mol. Cell. Biol. 21, 1272–1284 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Scherer, S. in Candida and Candidiasis (ed. Calderone, R. A.) 259–265 (ASM Press, Washington, DC, 2002).

    Google Scholar 

  7. Hull, C. M. & Johnson, A. D. Identification of a mating type-like locus in the asexual pathogenic yeast Candida albicans. Science 285, 1271–1275 (1999). The Stanford University-generated genome sequence was used to isolate regions of chromosome 5 that are heterozygous and contain genes ( MTLa1, MTLα1 and MTLα2 ) that resemble the mating-locus genes in S. cerevisiae.

    Article  CAS  PubMed  Google Scholar 

  8. Hull, C. M., Raisner, R. M. & Johnson, A. D. Evidence for mating of the 'asexual' yeast Candida albicans in a mammalian host. Science 289, 307–310 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Magee, B. B. & Magee, P. T. Induction of mating in Candida albicans by construction of MTLa and MTLα strains. Science 289, 310–313 (2000). These two papers showed that C. albicans diploid cells that are homozygous for MTLa can generate apparent tetraploid recombinants when mixed with cells that are homozygous for MTLα . Reference 8 showed that this reaction occurs in mice, whereas reference 9 generated in vitro recombinants at room temperature.

    Article  CAS  PubMed  Google Scholar 

  10. Pla, J., Perez-Diaz, R. M., Navarro-Garcia, F., Sanchez, M. & Nombela, C. Cloning of the Candida albicans HIS1 gene by direct complementation of a C. albicans histidine auxotroph using an improved double-ARS shuttle vector. Gene 165, 115–120 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Santos, M. A. & Tuite, M. F. The CUG codon is decoded in vivo as serine and not leucine in Candida albicans. Nucleic Acids Res. 23, 1481–1486 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ernst, J. F. & Bockmühl, D. P. in Candida and Candidiasis (ed. Calderone, R. A.) 267–278 (ASM Press, Washington, DC, 2002).

    Google Scholar 

  13. De Backer, M. D. Magee, P. T. & Pla, J. Recent developments in molecular genetics of Candida albicans. Annu. Rev. Microbiol. 54, 463–498 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Fonzi, W. A. & Irwin, M. Y. Isogenic strain construction and gene mapping in Candida albicans. Genetics 134, 717–728 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sundstrom, P., Cutler, J. E. & Staab, J. F. Reevaluation of the role of HWP1 in systemic candidiasis by use of Candida albicans strains with selectable marker URA3 targeted to the ENO1 locus. Infect. Immun. 70, 3281–3283 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lay, J. et al. Altered expression of selectable marker URA3 in gene-disrupted Candida albicans strains complicates interpretation of virulence studies. Infect. Immun. 66, 5301–5306 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bain, J. M., Stubberfield, C. & Gow, N. A. Ura-status-dependent adhesion of Candida albicans mutants. FEMS Microbiol. Lett. 204, 323–328 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Wach, A. PCR-synthesis of marker cassettes with long flanking homology regions for gene disruptions in S. cerevisiae. Yeast 12, 259–265 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Wilson, R. B., Davis, D., Enloe, B. M. & Mitchell, A. P. A recyclable Candida albicans URA3 cassette for PCR product-directed gene disruptions. Yeast 16, 65–70 (2000). A key methodology paper that describes an efficient PCR-based method for gene disruption that removed the need to first clone the gene before its disruption. This system has now become a standard way to generate homozygous gene deletions in C. albicans.

    Article  CAS  PubMed  Google Scholar 

  20. Wilson, R. B., Davis, D. & Mitchell, A. P. Rapid hypothesis testing with Candida albicans through gene disruption with short homology regions. J. Bacteriol. 181, 1868–1874 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Morschhauser, J., Michel, S. & Staib, P. Sequential gene disruption in Candida albicans by FLP-mediated site-specific recombination. Mol. Microbiol. 32, 547–556 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Biery, M. C., Stewart, F. J., Stellwagen, A. E., Raleigh, E. A. & Craig, N. L. A simple in vitro Tn7-based transposition system with low target site selectivity for genome and gene analysis. Nucleic Acids Res. 28, 1067–1077 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. De Backer, M. D., et al. An antisense-based functional genomics approach for identification of genes critical for growth of Candida albicans. Nature Biotechnol. 19, 235–241 (2001).

    Article  CAS  Google Scholar 

  24. Cormack, B. P. et al. Yeast-enhanced green fluorescent protein (yEGFP) — a reporter of gene expression in Candida albicans. Microbiology 143, 303–311 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Morschhauser, J., Michel, S. & Hacker, J. Expression of a chromosomally integrated, single-copy GFP gene in Candida albicans, and its use as a reporter of gene regulation. Mol. Gen. Genet. 257, 412–420 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Gerami-Nejad, M., Berman, J. & Gale, C. A. Cassettes for PCR-mediated construction of green, yellow and cyan fluorescent protein fusions in Candida albicans. Yeast 18, 859–864 (2001). An important methodology paper that provided convenient tools to study the localization of proteins in C. albicans cells by generating PCR-mediated fusions to CFP, YFP and GFPs.

    Article  CAS  PubMed  Google Scholar 

  27. Devasahayam, G., Chaturvedi, V. & Hanes, S. D. The Ess1 prolyl isomerase is required for growth and morphogenetic switching in Candida albicans. Genetics 160, 37–48 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Whiteway, M., Dignard, D. & Thomas, D. Y. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gale, C. et al. Cloning and expression of a gene encoding an integrin-like protein in Candida albicans. Proc. Natl Acad. Sci. USA 93, 357–361 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gale, C. A. et al. Candida albicans Int1p interacts with the septin ring in yeast and hyphal cells. Mol. Biol. Cell 12, 3538–3549 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gale, C. et al. Linkage of adhesion, fliamentous growth, and virulence in Candida albicans to a single gene, INT1. Science 279, 1355–1358 (1998). References 30 and 31 describe the isolation and characterization of INT1 — a gene that is important for virulence, adhesion and hyphal formation, under some conditions.

    Article  CAS  PubMed  Google Scholar 

  32. Fu, Y. et al. Expression of the Candida albicans gene ALS1 in Saccharomyces cerevisiae induces adherence to endothelial and epithelial cells. Infect. Immun. 66, 1783–1786 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gaur, N. K. & Klotz, S. A. Expression, cloning, and characterization of a Candida albicans gene, ALA1, that confers adherence properties upon Saccharomyces cerevisiae for extracellular matrix proteins. Infect. Immun. 65, 5289–5294 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fu, Y. et al. Cloning and characterization of CAD1/AAF1, a gene from Candida albicans that induces adherence to endothelial cells after expression in Saccharomyces cerevisiae. Infect. Immun. 66, 2078–2084 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu, H., Kö;hler, J. & Fink, G. R. Suppression of hyphal formation in Candida albicans by mutation of a STE12 homolog. Science 266, 1723–1726 (1994).

    Article  CAS  PubMed  Google Scholar 

  36. Romani, L. in Candida and Candidiasis. et al. (ed. Calderone, R. A.) 223–241 (ASM Press, Washington, DC, 2002).

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  38. Lorenz, M. C. & Fink, G. R. The glyoxylate cycle is required for fungal virulence. Nature 412, 83–86 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. De Backer, M. D. et al. Genomic profiling of the response of Candida albicans to itraconazole treatment using a DNA microarray. Antimicrob. Agents Chemother. 45, 1660–1670 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cowen, L. E. et al. Population genomics of drug resistance in experimental populations of Candida albicans. Proc. Natl Acad. Sci. USA 99, 9284–9289 (2002). Transcription profiling using whole-genome arrays to monitor the changes in gene expression in four replicate C. albicans populations during long-term exposure to a fungicide, fluconazole.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Nantel, A. et al. Transcription profiling of C. albicans cells undergoing the yeast to hyphal transition. Mol. Biol. Cell 13, 3452–3465 (2002). This paper describes the first whole-genome array study of the yeast-to-hyphal transition.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Magee, B. B. & Magee, P. T. Electrophoretic karyotypes and chromosome numbers in Candida species. J. Gen. Microbiol. 133, 425–430 (1987).

    CAS  PubMed  Google Scholar 

  43. McEachern, M. J. & Hicks, J. B. Unusually large telomeric repeats in the yeast Candida albicans. Mol. Cell. Biol. 13, 551–560 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Metz, A. M., Love, R. A., Strobel, G. A. & Long, D. M. Two telomerase reverse transcriptases (TERTs) expressed in Candida albicans. Biotechnol. Appl. Biochem. 34, 47–54 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Singh, S. M., Steinberg-Neifach, O., Mian, I. S. & Lue, N. F. Analysis of telomerase in Candida albicans: a potential role in telomere end protection. Eukaryotic Cell 1 (in the press).

  46. Merz, W. G., Connelly, C. & Hieter, P. Variation of electrophoretic karyotypes among clinical isolates of Candida albicans. J. Clin. Microbiol. 26, 842–845 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Magee, P. T., Bowdin, L. & Staudinger, J. Comparison of molecular typing methods for Candida albicans. J. Clin. Microbiol. 30, 2674–2679 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Rustchenko, E. P. & Sherman, F. Physical constitution of ribosomal genes in common strains of Saccharomyces cerevisiae. Yeast 10, 1157–1171 (1994).

    Article  CAS  PubMed  Google Scholar 

  49. Wickes, B. et al. Physical and genetic mapping of Candida albicans: several genes previously assigned to chromosome 1 map to chromosome R, the rDNA-containing linkage group. Infect. Immun. 59, 2480–2484 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Rustchenko, E. P., Curran, T. M. & Sherman, F. Variations in the number of ribosomal DNA units in morphological mutants and normal strains of Candida albicans and in normal strains of Saccharomyces cerevisiae. J. Bacteriol. 175, 7189–7199 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Thrash-Bingham, C. & Gorman, J. A. DNA translocations contribute to chromosome length polymorphisms in Candida albicans. Curr. Genet. 22, 93–100 (1992).

    Article  CAS  PubMed  Google Scholar 

  52. Chu, W. S., Magee, B. B. & Magee, P. T. Construction of an SfiI macrorestriction map of the Candida albicans genome. J. Bacteriol. 175, 6637–6651 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chibana, H., Beckerman, J. L. & Magee, P. T. Fine-resolution physical mapping of genomic diversity in Candida albicans. Genome Res. 10, 1865–1877 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Chindamporn, A. et al. Repetitive sequences (RPSs) in the chromosomes of Candida albicans are sandwiched between two novel stretches, HOK and RB2, common to each chromosome. Microbiology 144, 849–857 (1998).

    Article  CAS  PubMed  Google Scholar 

  55. Hughes, T. R. et al. Widespread aneuploidy revealed by DNA microarray expression profiling. Nature Genet. 25, 333–337 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Janbon, G., Sherman, F. & Rustchenko, E. Monosomy of a specific chromosome determines L-sorbose utilization: a novel regulatory mechanism in Candida albicans. Proc. Natl Acad. Sci. USA 95, 5150–5155 (1998). The authors discovered that forcing cells to grow on sorbose leads to a high level of chromosome 5 loss. When cells are returned to a medium that contains glucose, the remaining chromosome 5 is duplicated, showing plasticity of the C. albicans genome and that loss of a chromosome can confer benefits under some stress conditions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Perepnikhatka, V. et al. Specific chromosome alterations in fluconazole-resistant mutants of Candida albicans. J. Bacteriol. 181, 4041–4049 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Tzung, K. W. et al. Genomic evidence for a complete sexual cycle in Candida albicans. Proc. Natl Acad. Sci. USA 98, 3249–3253 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wolfe, K. H. & Shields, D. C. Molecular evidence for an ancient duplication of the entire yeast genome. Nature 387, 708–713 (1997).

    Article  CAS  PubMed  Google Scholar 

  60. Seoighe, C. et al. Prevalence of small inversions in yeast gene order evolution. Proc. Natl Acad. Sci. USA 97, 14433–14437 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Laprade, L., Boyartchuk, V. L., Dietrich, W. F. & Winston, F. Spt3 plays opposite roles in filamentous growth in Saccharomyces cerevisiae and Candida albicans and is required for C. albicans virulence. Genetics 161, 509–519 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Feng, Q., Summers, E., Guo, B. & Fink, G. Ras signaling is required for serum-induced hyphal differentiation in Candida albicans. J. Bacteriol. 181, 6339–6346 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gow, N. A. R. in Candida and Candidiasis. (ed. Calderone, R. A.) 145–158 (ASM Press, Washington, DC, 2002).

    Google Scholar 

  64. Odds, F. C. Candida and Candidosis 2nd edn (Baillière Tindall, London, 1988).

    Google Scholar 

  65. Merson-Davies, L. A. & Odds, F. C. A morphology index for characterization of cell shape in Candida albicans. J. Gen. Microbiol. 135, 3143–3152 (1989).

    CAS  PubMed  Google Scholar 

  66. Sudbery, P. E. The germ tubes of Candida albicans hyphae and pseudohyphae show different patterns of septin ring localization. Mol. Microbiol. 41, 19–31 (2001). This paper shows that there are fundamental differences in cell-cycle organization between the switch from unbudded yeast cells to hyphae and to pseudohyphae.

    Article  CAS  PubMed  Google Scholar 

  67. Braun, B. R., Head, W. S., Wang, M. X. & Johnson, A. D. Identification and characterization of TUP1-regulated genes in Candida albicans. Genetics 156, 31–44 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gow, N., Brown, A. & Odds, F. Fungal morphogenesis and host invasion. Curr. Opin. Microbiol. 5, 366 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Brown, A. J. P. in Candida and Candidiasis (ed. Calderone, R. A.) 87–93 (ASM Press, Washington, DC, 2002).

    Google Scholar 

  70. Liu, H. Transcriptional control of dimorphism in Candida albicans. Curr. Opin. Microbiol. 4, 728–735 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Kohler, J. R. & Fink, G. R. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Leberer, E. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Riggle, P. J., Andrutis, K. A., Chen, X., Tzipori, S. R. & Kumamoto, C. A. Invasive lesions containing filamentous forms produced by a Candida albicans mutant that is defective in filamentous growth in culture. Infect. Immun. 67, 3649–3652 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Davis, D., Edwards, J. E. Jr, Mitchell, A. P. & Ibrahim, A. S. Candida albicans RIM101 pH response pathway is required for host–pathogen interactions. Infect. Immun. 68, 5953–5959 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. El Barkani, A. et al. Dominant active alleles of RIM101 (PRR2) bypass the pH restriction on filamentation of Candida albicans. Mol. Cell. Biol. 20, 4635–4647 (2000). References 74 and 75 describe the identification of the Rim101 protein as the regulator of hyphal development in response to alkaline pH. At alkaline pH, the carboxyl terminus of Rim101 is removed by proteolytic cleavage. The truncated protein acts a dominant inducer of alkaline-specific genes and a repressor of acid-induced genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Brown, D. H., Giusani, A. D., Chen, X. & Kumamoto, C. A. 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).

    Article  CAS  PubMed  Google Scholar 

  77. Braun, B. R. & Johnson, A. D. Control of filament formation in Candida albicans by the transcriptional repressor TUP1. Science 277, 105–109 (1997).

    Article  CAS  PubMed  Google Scholar 

  78. Braun, B. R., Kadosh, D. & Johnson, A. D. NRG1, a repressor of filamentous growth in C. albicans, is down-regulated during filament induction. EMBO J. 20, 4753–4761 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kadosh, D. & Johnson, A. D. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Braun, B. R. & Johnson, A. D. TUP1, CPH1 and EFG1 make independent contributions to filamentation in Candida albicans. Genetics 155, 57–67 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Staab, J. F., Bradway, S. D., Fidel, P. L. & Sundstrom, P. Adhesive and mammalian transglutaminase substrate properties of Candida albicans Hwp1. Science 283, 1535–1538 (1999).

    Article  CAS  PubMed  Google Scholar 

  83. Murad, A. M. et al. Transcript profiling in Candida albicans reveals new cellular functions for the transcriptional repressors CaTup1, CaMig1 and CaNrg1. Mol. Microbiol. 42, 981–993 (2001). References 79 and 83 describe transcription profiling of more than 2,000 genes in tup1, nrg1 and mig1 mutants. The results broadly confirmed the model that Nrg1 and Mig1 target the repressing activity of Tup1 to different subsets of genes.

    Article  CAS  PubMed  Google Scholar 

  84. Lane, S., Birse, C., Zhou, S., Matson, R. & Liu, H. DNA array studies demonstrate convergent regulation of virulence factors by Cph1, Cph2, and Efg1 in Candida albicans. J. Biol. Chem. 276, 48988–48996 (2001). Transcription profiling experiments that compared the expression of 700 genes in single cph1, cph2 and efg1 mutants showed that each gene transduced signals from different environmental inputs but targeted the induction of a common set of hyphal-specific genes.

    Article  CAS  PubMed  Google Scholar 

  85. Lew, D. J. & Reed, S. I. Cell cycle control of morphogenesis in budding yeast. Curr. Opin. Genet. Dev. 5, 17–23 (1995).

    Article  CAS  PubMed  Google Scholar 

  86. Rua, D., Tobe, B. T. & Kron, S. J. Cell cycle control of yeast filamentous growth. Curr. Opin. Microbiol. 4, 720–727 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Loeb, J. D., Sepulveda-Becerra, M., Hazan, I. & Liu, H. A G1 cyclin is necessary for maintenance of filamentous growth in Candida albicans. Mol. Cell. Biol. 19, 4019–4027 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bensen, E. S., Filler, S. G. & Berman, J. A forkhead transcription factor is important for true hyphal as well as yeast morphogenesis in Candida albicans. Eukaryotic Cell 1, 787–798 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hazan, I., Sepulveda-Becerra, M. & Liu, H. Hyphal elongation is regulated independently of cell cycle in Candida albicans. Mol. Biol. Cell 13, 134–145 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Bai, C., Ramanan, N., Wang, Y. M. & Wang, Y. Spindle assembly checkpoint component CaMad2p is indispensable for Candida albicans survival and virulence in mice. Mol. Microbiol. 45, 31–44 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Slutsky, B., Buffo, J. & Soll, D. R. High-frequency switching of colony morphology in Candida albicans. Science 230, 666–669 (1985).

    Article  CAS  PubMed  Google Scholar 

  92. Pomes, R., Gil, C. & Nombela, C. Genetic analysis of Candida albicans morphological mutants. J. Gen. Microbiol. 131, 2107–2113 (1985).

    CAS  PubMed  Google Scholar 

  93. Soll, D. R. High-frequency switching in Candida albicans. Clin. Microbiol. Rev. 5, 183–203 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Sonneborn, A., Tebarth, B. & Ernst, J. F. Control of white–opaque phenotypic switching in Candida albicans by the Efg1p morphogenetic regulator. Infect. Immun. 67, 4655–4660 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Zhao, R., Lockhart, S. R., Daniels, K. & Soll, D. R. Roles of TUP1 in switching, phase maintenance, and phase-specific gene expression in Candida albicans. Eukaryotic Cell 1, 353–365 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lockhart, S. R., Nguyen, M., Srikantha, T. & Soll, D. R. A MADS box protein consensus binding site is necessary and sufficient for activation of the opaque-phase-specific gene OP4 of Candida albicans. J. Bacteriol. 180, 6607–6616 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Srikantha, T., Tsai, L., Daniels, K., Klar, A. J. S. & Soll, D. R. The histone deacetylase genes HDA1 and RPD3 play distinct roles in regulation of high-frequency phenotypic switching in Candida albicans. J. Bacteriol. 183, 4614–4625 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Klar, A. J., Srikantha, T. & Soll, D. R. A histone deacetylation inhibitor and mutant promote colony-type switching of the human pathogen Candida albicans. Genetics 158, 919–924 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Taylor, J. W., Geiser, D. M., Burt, A. & Koufopanou, V. The evolutionary biology and population genetics underlying fungal strain typing. Clin. Microbiol. Rev. 12, 126–146 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Rustad, T. R., Stevens, D. A., Pfaller, M. A. & White, T. C. Homozygosity at the Candida albicans MTL locus associated with azole resistance. Microbiology 148, 1061–1072 (2002).

    Article  CAS  PubMed  Google Scholar 

  101. Miller, M. G. & Johnson, A. D. White–opaque switching in Candida albicans is controlled by mating-type locus homeodomain proteins and allows efficient mating. Cell 110, 293–302 (2002). The authors revealed an intriguing relationship between white–opaque phenotypic switching and the ability to mate. Cells that have only one MTL locus switch more frequently to the opaque state, and cells that are opaque mate with higher efficiency.

    Article  CAS  PubMed  Google Scholar 

  102. Scherer, S. & Magee, P. T. Genetics of Candida albicans. Microbiol. Rev. 54, 226–241 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kirsch, D. R. & Whitney, R. R. Pathogenicity of Candida albicans auxotrophic mutants in experimental infections. Infect. Immun. 59, 3297–3300 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Kohler, G. A., White, T. C. & Agabian, N. Overexpression of a cloned IMP dehydrogenase gene of Candida albicans confers resistance to the specific inhibitor mycophenolic acid. J. Bacteriol. 179, 2331–2338 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Staib, P. et al. Host-induced, stage-specific virulence gene activation in Candida albicans during infection. Mol. Microbiol. 32, 533–546 (1999).

    Article  CAS  PubMed  Google Scholar 

  106. Beckerman, J., Chibana, H., Turner, J. & Magee, P. T. Single-copy IMH3 allele is sufficient to confer resistance to mycophenolic acid in Candida albicans and to mediate transformation of clinical Candida species. Infect. Immun. 69, 108–114 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Enloe, B., Diamond, A. & Mitchell, A. P. A single-transformation gene function test in diploid Candida albicans. J. Bacteriol. 182, 5730–5736 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Bailey, D. A., Feldmann, P. J., Bovey, M., Gow, N. A. & Brown, A. J. The Candida albicans HYR1 gene, which is activated in response to hyphal development, belongs to a gene family encoding yeast cell wall proteins. J. Bacteriol. 178, 5353–5360 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bertram, G., Swoboda, R. K., Gooday, G. W., Gow, N. A. & Brown, A. J. Structure and regulation of the Candida albicans ADH1 gene encoding an immunogenic alcohol dehydrogenase. Yeast 12, 115–127 (1996).

    Article  CAS  PubMed  Google Scholar 

  110. Delbruck, S. & Ernst, J. F. Morphogenesis-independent regulation of actin transcript levels in the pathogenic yeast Candida albicans. Mol. Microbiol. 10, 859–866 (1993).

    Article  CAS  PubMed  Google Scholar 

  111. Rademacher, F., Kehren, V., Stoldt, V. R. & Ernst, J. F. A Candida albicans chaperonin subunit (CaCct8p) as a suppressor of morphogenesis and Ras phenotypes in C. albicans and Saccharomyces cerevisiae. Microbiology 144, 2951–2960 (1998).

    Article  CAS  PubMed  Google Scholar 

  112. Gorman, J. A., Chan, W. & Gorman, J. W. Repeated use of GAL1 for gene disruption in Candida albicans. Genetics 129, 19–24 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Leuker, C. E., Sonneborn, A., Delbruck, S. & Ernst, J. F. Sequence and promoter regulation of the PCK1 gene encoding phosphoenolpyruvate carboxykinase of the fungal pathogen Candida albicans. Gene 192, 235–240 (1997).

    Article  CAS  PubMed  Google Scholar 

  114. Geber, A., Williamson, P. R., Rex, J. H., Sweeney, E. C. & Bennett, J. E. Cloning and characterization of a maltase gene involved in sucrose utilization. J. Bacteriol. 174, 6992–6996 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Brown, D. H. Jr, Slobodkin, I. V. & Kumamoto, C. A. Stable transformation and regulated expression of an inducible reporter construct in Candida albicans using restriction enzyme-mediated integration. Mol. Gen. Genet. 251, 75–80 (1996).

    CAS  PubMed  Google Scholar 

  116. Care, R. S., Trevethick, J., Binley, K. M. & Sudbery, P. E. The MET3 promoter: a new tool for Candida albicans molecular genetics. Mol. Microbiol. 34, 792–798 (1999).

    Article  CAS  PubMed  Google Scholar 

  117. Nakayama, H. et al. Tetracycline-regulatable system to tightly control gene expression in the pathogenic fungus Candida albicans. Infect. Immun. 68, 6712–6719 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Leuker, C. E., Hahn, A. M. & Ernst, J. F. β-Galactosidase of Kluyveromyces lactis (Lac4p) as reporter of gene expression in Candida albicans and C. tropicalis. Mol. Gen. Genet. 235, 235–241 (1992).

    Article  CAS  PubMed  Google Scholar 

  119. Uhl, M. A. & Johnson, A. D. Development of Streptococcus thermophilus lacZ as a reporter gene for Candida albicans. Microbiology 147, 1189–1195 (2001).

    Article  CAS  PubMed  Google Scholar 

  120. Srikantha, T. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the many Candida albicans researchers who discussed and provided results before publication. J.B. is supported by the National Institutes of Health, USA, and a Burrough Wellcome Scholar Award. P.E.S. is supported by the Wellcome Trust for Biomedical Research, UK.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Judith Berman.

Related links

Related links

DATABASES

European Candida Database

Abp1

arg4

Cph1

Czf1

efg1

his1

HWP1

ICL1

INT1

MAD2

Mig1

MLS1

Nrg1

RBT1

Rim101

SAP4

SAP5

SAP6

spt3

Tup1

URA3

Saccharomyces Genome Database

Cdc28

Clb2

Cln1

Cln2

Fkh1

Fkh2

MATa1

MATα1

MATα2

Ste12

URA3

FURTHER INFORMATION

Candida albicans Genome Information

Candida Genome Sequencing Project

European Candida Database

MicroArray Lab, National Research Council of Canada

Stanford Genome Technology Center

Glossary

OPPORTUNIST

An organism that usually does not cause disease but, under circumstances such as immune deficiency, can become a pathogen.

COMMENSAL

An organism that lives in another without causing injury to its host.

CANDIDIASIS

Infection with a Candida species. It often refers to the infection of mucosal surfaces, such as the mouth, vagina, skin or oesophagus.

FUNGISTATIC

The ability to inhibit the growth of fungi. Fungistatic agents can keep an infection in check but usually do not completely eliminate the fungus from the host.

FUNGICIDAL

The ability to kill fungi. Fungicides have the potential to clear a fungal infection from the host.

CHLAMYDOSPORES

Thick-walled round cells that sometimes form at the ends of hyphae or pseudohyphae in response to nutrient stress or other stresses.

SEPTIN

A protein that forms a ring-shaped scaffold-like structure at the incipient bud site in yeast cells and pseudohyphal cells and at the incipient site of septation in true hyphae.

GERM TUBE

The elongating structure that evaginates from a round yeast cell when it is induced to form true hyphae.

AUXOTROPHIC

Requiring a nutritional supplement to grow.

PROTOTROPH

A cell that can grow in the absence of nutritional supplements.

FLP/FRT SYSTEM

A recombination system that is adapted from the Saccharomyces cerevisiae 2-μm plasmid. FLP encodes a site-specific recombinase, and Frt is the FLP recombinase target site. Expression of FLP mediates excision of any sequence that is flanked by Frt sites.

PHAGOLYSOSOME

An organelle in a phagocytic cell that is formed by fusion of an ingested particle (for example, a Candida cell) with a lysosome, which has hydrolytic enzymes that are used to digest the particle.

GLYOXYLATE CYCLE

A metabolic pathway for converting two acetyl CoA molecules to a four-carbon dicarboxylic acid. The cycle is present in bacteria, plants and fungi, but not in mammals.

PHENOTYPIC SWITCHING

A change in cellular or colony properties that seems to be heritable, but reverses at a rate that is much higher than could be caused by mutation. Examples include colony switching and white–opaque switching in Candida albicans.

CRENULATED

Having an uneven 'saw-tooth'-like edge. Crenulated colonies have filamentous cells that protrude from the edges of them.

ISOTROPIC

Growth in all directions (opposite of polarized growth).

SPINDLE POLE BODY

The microtubule organizing centre in fungi. In Candida albicans, as in Saccharomyces cerevisiae, the spindle pole body is embedded in the nuclear membrane, and this membrane remains intact throughout the cell cycle.

CHECKPOINT PROTEIN

A protein that is involved in one of the pathways that monitor aspects of cellular function (such as replication or spindle formation) that are required for proper cell-cycle progression. If a defect is detected, the checkpoint pathway delays the cell cycle so that the defect can be corrected.

ASCOMYCETE

The class of fungi in which the meitoic progeny (ascospores) are found in sac-like structures (asci).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Berman, J., Sudbery, P. Candida albicans: A molecular revolution built on lessons from budding yeast. Nat Rev Genet 3, 918–931 (2002). https://doi.org/10.1038/nrg948

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg948

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