Skip to main content
SpringerLink
Log in

Sexual reproduction in the Candida clade: cryptic cycles, diverse mechanisms, and alternative functions

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

To have sex, or not to have sex, is a question posed by many microorganisms. In favor of a sexual lifestyle is the associated rearrangement of genetic material that confers potential fitness advantages, including resistance to antimicrobial agents. The asexual lifestyle also has benefits, as it preserves complex combinations of genes that may be optimal for pathogenesis. For this reason, it was thought that several pathogenic fungi favored strictly asexual modes of reproduction. Recent approaches using genome sequencing, population analysis, and experimental techniques have now revised this simplistic picture. It is now apparent that many pathogenic fungi have retained the ability to undergo sexual reproduction, although reproduction is primarily clonal in origin. In this review, we highlight the current understanding of sexual programs in the Candida clade of species. We also examine evidence that sexual-related processes can be used for functions in addition to mating and recombination in these organisms.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Gargas A, Taylor JW (1995) Phylogeny of Discomycetes and early radiations of the apothecial Ascomycotina inferred from SSU rDNA sequence data. Exp Mycol 19:7–15

    Article  CAS  PubMed  Google Scholar 

  2. Hedges SB (2002) The origin and evolution of model organisms. Nat Rev Genet 3:838–849

    Article  CAS  PubMed  Google Scholar 

  3. Heitman J, Kronstad JW, Taylor JW, Casselton LA (2007) Sex in fungi: molecular determination and evolutionary implications. ASM Press

  4. Butler G (2010) Fungal sex and pathogenesis. Clin Microbiol Rev 23:140–159

    Article  CAS  PubMed  Google Scholar 

  5. Butler G, Rasmussen MD, Lin MF, Santos MA, Sakthikumar S, Munro CA, Rheinbay E, Grabherr M, Forche A, Reedy JL, Agrafioti I, Arnaud MB, Bates S, Brown AJ, Brunke S, Costanzo MC, Fitzpatrick DA, de Groot PW, Harris D, Hoyer LL, Hube B, Klis FM, Kodira C, Lennard N, Logue ME, Martin R, Neiman AM, Nikolaou E, Quail MA, Quinn J, Santos MC, Schmitzberger FF, Sherlock G, Shah P, Silverstein KA, Skrzypek MS, Soll D, Staggs R, Stansfield I, Stumpf MP, Sudbery PE, Srikantha T, Zeng Q, Berman J, Berriman M, Heitman J, Gow NA, Lorenz MC, Birren BW, Kellis M, Cuomo CA (2009) Evolution of pathogenicity and sexual reproduction in eight Candida genomes. Nature 459:657–662

    Article  CAS  PubMed  Google Scholar 

  6. Santos MA, Tuite MF (1995) The CUG codon is decoded in vivo as serine and not leucine in Candida albicans. Nucleic Acids Res 23:1481–1486

    Article  CAS  PubMed  Google Scholar 

  7. Pfaller MA, Diekema DJ (2007) Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev 20:133–163

    Article  CAS  PubMed  Google Scholar 

  8. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB (2004) Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 39:309–317

    Article  PubMed  Google Scholar 

  9. Ruhnke M, Maschmeyer G (2002) Management of mycoses in patients with hematologic disease and cancer—review of the literature. Eur J Med Res 7:227–235

    PubMed  Google Scholar 

  10. Hull CM, Johnson AD (1999) Identification of a mating type-like locus in the asexual pathogenic yeast Candida albicans. Science 285:1271–1275

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Magee BB, Magee PT (2000) Induction of mating in Candida albicans by construction of MTLa and MTLalpha strains. Science 289:310–313

    Article  CAS  PubMed  Google Scholar 

  13. 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 169:189–197

    CAS  PubMed  Google Scholar 

  14. 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 65:4468–4475

    CAS  PubMed  Google Scholar 

  15. 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 72:667–677

    Article  CAS  PubMed  Google Scholar 

  16. 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 67:6652–6662

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  19. 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 162:737–745

    CAS  PubMed  Google Scholar 

  20. Odds FC, Bougnoux ME, Shaw DJ, Bain JM, Davidson AD, Diogo D, Jacobsen MD, Lecomte M, Li SY, Tavanti A, Maiden MC, Gow NA, d’Enfert C (2007) Molecular phylogenetics of Candida albicans. Eukaryot Cell 6:1041–1052

    Article  CAS  PubMed  Google Scholar 

  21. 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 5:1674–1687

    Article  CAS  PubMed  Google Scholar 

  22. 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 103:12813–12818

    Article  CAS  PubMed  Google Scholar 

  23. 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 103:12807–12812

    Article  CAS  PubMed  Google Scholar 

  24. Lachke SA, Srikantha T, Soll DR (2003) The regulation of EFG1 in white-opaque switching in Candida albicans involves overlapping promoters. Mol Microbiol 48:523–536

    Article  CAS  PubMed  Google Scholar 

  25. 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 182:1580–1591

    Article  CAS  PubMed  Google Scholar 

  26. Vinces MD, Haas C, Kumamoto CA (2006) Expression of the Candida albicans morphogenesis regulator gene CZF1 and its regulation by Efg1p and Czf1p. Eukaryot Cell 5:825–835

    Article  CAS  PubMed  Google Scholar 

  27. 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:e256

    Article  PubMed  Google Scholar 

  28. 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 6:465–472

    Article  CAS  PubMed  Google Scholar 

  29. Ramirez-Zavala B, Reuss O, Park YN, Ohlsen K, Morschhauser J (2008) Environmental induction of white-opaque switching in Candida albicans. PLoS Pathog 4:e1000089

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  32. Huang G, Yi S, Sahni N, Daniels KJ, Srikantha T, Soll DR (2010) N-acetylglucosamine induces white to opaque switching, a mating prerequisite in Candida albicans. PLoS Pathog 6:e1000806

    Article  PubMed  Google Scholar 

  33. Dignard D, El-Naggar AL, Logue ME, Butler G, Whiteway M (2007) Identification and characterization of MFA1, the gene encoding Candida albicans a-factor pheromone. Eukaryot Cell 6:487–494

    Article  CAS  PubMed  Google Scholar 

  34. Bennett RJ, Uhl MA, Miller MG, Johnson AD (2003) Identification and characterization of a Candida albicans mating pheromone. Mol Cell Biol 23:8189–8201

    Article  CAS  PubMed  Google Scholar 

  35. Panwar SL, Legrand M, Dignard D, Whiteway M, Magee PT (2003) MFalpha1, the gene encoding the alpha mating pheromone of Candida albicans. Eukaryot Cell 2:1350–1360

    Article  CAS  PubMed  Google Scholar 

  36. Lockhart SR, Daniels KJ, Zhao R, Wessels D, Soll DR (2003) Cell biology of mating in Candida albicans. Eukaryot Cell 2:49–61

    Article  CAS  PubMed  Google Scholar 

  37. Bennett RJ, Miller MG, Chua PR, Maxon ME, Johnson AD (2005) Nuclear fusion occurs during mating in Candida albicans and is dependent on the KAR3 gene. Mol Microbiol 55:1046–1059

    Article  CAS  PubMed  Google Scholar 

  38. Alby K, Schaefer D, Bennett RJ (2009) Homothallic and heterothallic mating in the opportunistic pathogen Candida albicans. Nature 460:890–893

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  40. Forche A, Alby K, Schaefer D, Johnson AD, Berman J, Bennett RJ (2008) The parasexual cycle in Candida albicans provides an alternative pathway to meiosis for the formation of recombinant strains. PLoS Biol 6:e110

    Article  PubMed  Google Scholar 

  41. Ibrahim AS, Magee BB, Sheppard DC, Yang M, Kauffman S, Becker J, Edwards JE Jr, Magee PT (2005) Effects of ploidy and mating type on virulence of Candida albicans. Infect Immun 73:7366–7374

    Article  CAS  PubMed  Google Scholar 

  42. Keeney S, Neale MJ (2006) Initiation of meiotic recombination by formation of DNA double-strand breaks: mechanism and regulation. Biochem Soc Trans 34:523–525

    Article  CAS  PubMed  Google Scholar 

  43. Selmecki A, Forche A, Berman J (2006) Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science 313:367–370

    Article  CAS  PubMed  Google Scholar 

  44. Manney TR (1983) Expression of the BAR1 gene in Saccharomyces cerevisiae: induction by the alpha mating pheromone of an activity associated with a secreted protein. J Bacteriol 155:291–301

    CAS  PubMed  Google Scholar 

  45. Butler G, Kenny C, Fagan A, Kurischko C, Gaillardin C, Wolfe KH (2004) Evolution of the MAT locus and its Ho endonuclease in yeast species. Proc Natl Acad Sci USA 101:1632–1637

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  47. Nielsen K, Heitman J (2007) Sex and virulence of human pathogenic fungi. Adv Genet 57:143–173

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  49. Tsong AE, Tuch BB, Li H, Johnson AD (2006) Evolution of alternative transcriptional circuits with identical logic. Nature 443:415–420

    Article  CAS  PubMed  Google Scholar 

  50. Lockhart SR, Messer SA, Pfaller MA, Diekema DJ (2008) Lodderomyces elongisporus masquerading as Candida parapsilosis as a cause of bloodstream infections. J Clin Microbiol 46:374–376

    Article  CAS  PubMed  Google Scholar 

  51. Pujol C, Daniels KJ, Lockhart SR, Srikantha T, Radke JB, Geiger J, Soll DR (2004) The closely related species Candida albicans and Candida dubliniensis can mate. Eukaryot Cell 3:1015–1027

    Article  CAS  PubMed  Google Scholar 

  52. Li F, Palecek SP (2005) Identification of Candida albicans genes that induce Saccharomyces cerevisiae cell adhesion and morphogenesis. Biotechnol Prog 21:1601–1609

    Article  CAS  PubMed  Google Scholar 

  53. Nguyen VQ, Sil A (2008) 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

    Article  CAS  PubMed  Google Scholar 

  54. Webster RH, Sil A (2008) Conserved factors Ryp2 and Ryp3 control cell morphology and infectious spore formation in the fungal pathogen Histoplasma capsulatum. Proc Natl Acad Sci USA 105:14573–14578

    Article  CAS  PubMed  Google Scholar 

  55. Michielse CB, van Wijk R, Reijnen L, Manders EM, Boas S, Olivain C, Alabouvette C, Rep M (2009) The nuclear protein Sge1 of Fusarium oxysporum is required for parasitic growth. PLoS Pathog 5:e1000637

    Article  PubMed  Google Scholar 

  56. Jackson AP, Gamble JA, Yeomans T, Moran GP, Saunders D, Harris D, Aslett M, Barrell JF, Butler G, Citiulo F, Coleman DC, de Groot PW, Goodwin TJ, Quail MA, McQuillan J, Munro CA, Pain A, Poulter RT, Rajandream MA, Renauld H, Spiering MJ, Tivey A, Gow NA, Barrell B, Sullivan DJ, Berriman M (2009) Comparative genomics of the fungal pathogens Candida dubliniensis and Candida albicans. Genome Res 19:2231–2244

    Article  CAS  PubMed  Google Scholar 

  57. Reedy JL, Floyd AM, Heitman J (2009) Mechanistic plasticity of sexual reproduction and meiosis in the Candida pathogenic species complex. Curr Biol 19:891–899

    Article  CAS  PubMed  Google Scholar 

  58. van der Walt JP (1966) Lodderomyces, a new genus of the Saccharomycetaceae. Antonie Van Leeuwenhoek 32:1–5

    Article  PubMed  Google Scholar 

  59. Jacobsen MD, Davidson AD, Li SY, Shaw DJ, Gow NA, Odds FC (2008) Molecular phylogenetic analysis of Candida tropicalis isolates by multi-locus sequence typing. Fungal Genet Biol 45:1040–1042

    Article  CAS  PubMed  Google Scholar 

  60. Logue ME, Wong S, Wolfe KH, Butler G (2005) A genome sequence survey shows that the pathogenic yeast Candida parapsilosis has a defective MTLa1 allele at its mating type locus. Eukaryot Cell 4:1009–1017

    Article  CAS  PubMed  Google Scholar 

  61. Hensgens LA, Tavanti A, Mogavero S, Ghelardi E, Senesi S (2009) AFLP genotyping of Candida metapsilosis clinical isolates: evidence for recombination. Fungal Genet Biol 46:750–758

    Article  CAS  PubMed  Google Scholar 

  62. Tavanti A, Hensgens LA, Ghelardi E, Campa M, Senesi S (2007) Genotyping of Candida orthopsilosis clinical isolates by amplification fragment length polymorphism reveals genetic diversity among independent isolates and strain maintenance within patients. J Clin Microbiol 45:1455–1462

    Article  CAS  PubMed  Google Scholar 

  63. Goddard MR, Godfray HC, Burt A (2005) Sex increases the efficacy of natural selection in experimental yeast populations. Nature 434:636–640

    Article  CAS  PubMed  Google Scholar 

  64. Magee PT, Magee BB (2004) Through a glass opaquely: the biological significance of mating in Candida albicans. Curr Opin Microbiol 7:661–665

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  66. Magee BB, Legrand M, Alarco AM, Raymond M, Magee PT (2002) Many of the genes required for mating in Saccharomyces cerevisiae are also required for mating in Candida albicans. Mol Microbiol 46:1345–1351

    Article  CAS  PubMed  Google Scholar 

  67. Schwartz MA, Madhani HD (2004) Principles of MAP kinase signaling specificity in Saccharomyces cerevisiae. Annu Rev Genet 38:725–748

    Article  CAS  PubMed  Google Scholar 

  68. Erdman S, Snyder M (2001) A filamentous growth response mediated by the yeast mating pathway. Genetics 159:919–928

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  70. Sahni N, Yi S, Pujol C, Soll DR (2009) The white cell response to pheromone is a general characteristic of Candida albicans strains. Eukaryot Cell 8:251–256

    Article  CAS  PubMed  Google Scholar 

  71. Yi S, Sahni N, Pujol C, Daniels KJ, Srikantha T, Ma N, Soll DR (2009) A Candida albicans-specific region of the alpha-pheromone receptor plays a selective role in the white cell pheromone response. Mol Microbiol 71:925–947

    Article  CAS  PubMed  Google Scholar 

  72. Sahni N, Yi S, Daniels KJ, Srikantha T, Pujol C, Soll DR (2009) Genes selectively up-regulated by pheromone in white cells are involved in biofilm formation in Candida albicans. PLoS Pathog 5:e1000601

    Article  PubMed  Google Scholar 

  73. Schaefer D, Cote P, Whiteway M, Bennett RJ (2007) Barrier activity in Candida albicans mediates pheromone degradation and promotes mating. Eukaryot Cell 6:907–918

    Article  CAS  PubMed  Google Scholar 

  74. Bennett RJ, Johnson AD (2006) The role of nutrient regulation and the Gpa2 protein in the mating pheromone response of C. albicans. Mol Microbiol 62:100–119

    Article  CAS  PubMed  Google Scholar 

  75. Chandra J, Kuhn DM, Mukherjee PK, Hoyer LL, McCormick T, Ghannoum MA (2001) Biofilm formation by the fungal pathogen Candida albicans: development, architecture, and drug resistance. J Bacteriol 183:5385–5394

    Article  CAS  PubMed  Google Scholar 

  76. Ramage G, VandeWalle K, Bachmann SP, Wickes BL, Lopez-Ribot JL (2002) In vitro pharmacodynamic properties of three antifungal agents against preformed Candida albicans biofilms determined by time-kill studies. Antimicrob Agents Chemother 46:3634–3636

    Article  CAS  PubMed  Google Scholar 

  77. Ramage G, Wickes BL, Lopez-Ribot JL (2001) Biofilms of Candida albicans and their associated resistance to antifungal agents. Am Clin Lab 20:42–44

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Work in the author’s laboratory was supported by a PATH award from the Burroughs Wellcome Fund (RJB) as well as the NIH (R21AI081560 to RJB and F31DE019752 to KA). We thank Racquel Sherwood for comments on the manuscript.

Author information

Authors and Affiliations

  1. Department of Molecular Microbiology and Immunology, Brown University, 171 Meeting St, Providence, RI, 02912, USA

    Kevin Alby & Richard J. Bennett

Authors
  1. Kevin Alby
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard J. Bennett
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard J. Bennett.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Alby, K., Bennett, R.J. Sexual reproduction in the Candida clade: cryptic cycles, diverse mechanisms, and alternative functions. Cell. Mol. Life Sci. 67, 3275–3285 (2010). https://doi.org/10.1007/s00018-010-0421-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-010-0421-8

Keywords

Search

Navigation