[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
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:

Genetic control of Candida albicans biofilm development

Nature Reviews Microbiology volume 9, pages 109–118 (2011)Cite this article

Subjects

Key Points

  • Biofilm formation by Candida albicans on implanted medical devices is a major source of infection.

  • Advances in expression profiling and genetic manipulation have provided insights into the mechanisms and regulatory pathways that govern C. albicans biofilm formation and biofilm-based drug resistance. Major regulatory genes and their targets have been connected to biofilm formation. Relevant targets include many cell surface proteins; some are adhesins, but many are still not understood mechanistically. Identifying the regulators has provided insight into the signals that control biofilm development, including nutrients, hyphae formation and quorum sensing molecules.

  • Increasingly, mechanistic studies have focused on diverse biofilms, including mucosal infection models, in vivo implanted-device models and mixed-species biofilms. One of the common themes to emerge is the requirement for hyphae formation and for the transcription factor biofilm and cell wall regulator 1 (Bcr1).

  • Biofilm induction assays have shown a unique biological function for non-mating white cells in creating cohesive biofilms that promote mating, and have uncovered a hybrid signal transduction pathway that mediates this behaviour.

  • Biofilms of most species are associated with epigenetic resistance to antimicrobials. Resistance of C. albicans biofilms is conferred by multiple mechanisms that include drug binding by extracellular matrix material and the production of persisters.

  • Finally, the cells released from a preformed biofilm have unique properties that favour invasive infection. The dispersed cells are yeast-form cells, and their production depends on several regulators of the yeast–hypha transition.

Abstract

Candida species cause frequent infections owing to their ability to form biofilms — surface-associated microbial communities — primarily on implanted medical devices. Increasingly, mechanistic studies have identified the gene products that participate directly in the development of Candida albicans biofilms, as well as the regulatory circuitry and networks that control their expression and activity. These studies have uncovered new mechanisms and signals that govern C. albicans biofilm development and associated drug resistance, thus providing biological insight and therapeutic foresight.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

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

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

Figure 1: Candida albicans biofilm structure in vitro and in vivo.
Figure 2: Proteins that function in biofilm development.
Figure 3: Restoration of biofilm formation in a biofilm and cell wall regulator 1 (BCR1)-null background by overexpression of surface protein gene agglutinin-like sequence 3 (ALS3).

Similar content being viewed by others

References

  1. Pfaller, M. A. & Diekema, D. J. Epidemiology of invasive mycoses in North America. Crit. Rev. Microbiol. 36, 1–53 (2010).

    Article  PubMed  Google Scholar 

  2. Pappas, P. G. et al. Guidelines for treatment of candidiasis. Clin. Infect. Dis. 38, 161–189 (2004).

    Article  PubMed  Google Scholar 

  3. Costerton, J. W., Stewart, P. S. & Greenberg, E. P. Bacterial biofilms: a common cause of persistent infections. Science 284, 1318–1322 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Marrie, T. J. & Costerton, J. W. Scanning and transmission electron microscopy of in situ bacterial colonization of intravenous and intraarterial catheters. J. Clin. Microbiol. 19, 687–693 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Donlan, R. M. & Costerton, J. W. Biofilms: survival mechanisms of clinically relevant microorganisms. Clin. Microbiol. Rev. 15, 167–193 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kojic, E. M. & Darouiche, R. O. Candida infections of medical devices. Clin. Microbiol. Rev. 17, 255–267 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Viudes, A. et al. Candidemia at a tertiary-care hospital: epidemiology, treatment, clinical outcome and risk factors for death. Eur. J. Clin. Microbiol. Infect. Dis. 21, 767–774 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Wilson, L. S. et al. The direct cost and incidence of systemic fungal infections. Value Health 5, 26–34 (2002).

    Article  PubMed  Google Scholar 

  10. Pfaller, M. A. & Diekema, D. J. Epidemiology of invasive candidiasis: a persistent public health problem. Clin. Microbiol. Rev. 20, 133–163 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Andes, D. et al. Development and characterization of an in vivo central venous catheter Candida albicans biofilm model. Infect. Immun. 72, 6023–6031 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chandra, J. et al. Biofilm formation by the fungal pathogen Candida albicans: development, architecture, and drug resistance. J. Bacteriol. 183, 5385–5394 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Baillie, G. S. & Douglas, L. J. Role of dimorphism in the development of Candida albicans biofilms. J. Med. Microbiol. 48, 671–679 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Ramage, G., VandeWalle, K., Lopez-Ribot, J. L. & Wickes, B. L. The filamentation pathway controlled by the Efg1 regulator protein is required for normal biofilm formation and development in Candida albicans. FEMS Microbiol. Lett. 214, 95–100 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Hornby, J. M. et al. Quorum sensing in the dimorphic fungus Candida albicans is mediated by farnesol. Appl. Environ. Microbiol. 67, 2982–2992 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Oh, K. B., Miyazawa, H., Naito, T. & Matsuoka, H. Purification and characterization of an autoregulatory substance capable of regulating the morphological transition in Candida albicans. Proc. Natl Acad. Sci. USA 98, 4664–4668 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ramage, G., Saville, S. P., Wickes, B. L. & Lopez-Ribot, J. L. Inhibition of Candida albicans biofilm formation by farnesol, a quorum-sensing molecule. Appl. Environ. Microbiol. 68, 5459–5463 (2002). This paper reports that farnesol functions as a quorum sensing molecule in C. albicans biofilms, and that biofilm density and morphology are altered by high concentrations of farnesol.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Alem, M. A., Oteef, M. D., Flowers, T. H. & Douglas, L. J. Production of tyrosol by Candida albicans biofilms and its role in quorum sensing and biofilm development. Euk. Cell 5, 1770–1779 (2006).

    Article  CAS  Google Scholar 

  19. Ghosh, S., Kebaara, B. W., Atkin, A. L. & Nickerson, K. W. Regulation of aromatic alcohol production in Candida albicans. Appl. Environ. Microbiol. 74, 7211–7218 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Martins, M. et al. Morphogenesis control in Candida albicans and Candida dubliniensis through signaling molecules produced by planktonic and biofilm cells. Euk. Cell 6, 2429–2436 (2007).

    Article  CAS  Google Scholar 

  21. Li, F. & Palecek, S. P. Distinct domains of the Candida albicans adhesin Eap1p mediate cell-cell and cell-substrate interactions. Microbiology 154, 1193–1203 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Nobile, C. J. et al. Complementary adhesin function in C. albicans biofilm formation. Curr. Biol. 18, 1017–1024 (2008). This paper reports that Als1, Als3 and Hwp1 function as complementary adhesins in biofilms both in vivo and in vitro .

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nobile, C. J., Nett, J. E., Andes, D. R. & Mitchell, A. P. Function of Candida albicans adhesin Hwp1 in biofilm formation. Euk. Cell 5, 1604–1610 (2006).

    Article  CAS  Google Scholar 

  24. Stewart, P. S. & Franklin, M. J. Physiological heterogeneity in biofilms. Nature Rev. Microbiol. 6, 199–210 (2008).

    Article  CAS  Google Scholar 

  25. Domergue, R. et al. Nicotinic acid limitation regulates silencing of Candida adhesins during UTI. Science 308, 866–870 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Verstrepen, K. J. & Fink, G. R. Genetic and epigenetic mechanisms underlying cell-surface variability in protozoa and fungi. Annu. Rev. Genet. 43, 1–24 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Nobile, C. J. & Mitchell, A. P. Regulation of cell-surface genes and biofilm formation by the C. albicans transcription factor Bcr1p. Curr. Biol. 15, 1150–1155 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Nobile, C. J. et al. Critical role of Bcr1-dependent adhesins in C. albicans biofilm formation in vitro and in vivo. PLoS Pathog. 2, e63 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nobile, C. J. et al. Biofilm matrix regulation by Candida albicans Zap1. PLoS Biol. 7, e1000133 (2009). This paper shows that transcription factor Zap1 is a key regulator of extracellular matrix production by biofilms in vitro and in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mukherjee, P. K. et al. Alcohol dehydrogenase restricts the ability of the pathogen Candida albicans to form a biofilm on catheter surfaces through an ethanol-based mechanism. Infect. Immun. 74, 3804–3816 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hazelwood, L. A., Daran, J. M., van Maris, A. J., Pronk, J. T. & Dickinson, J. R. The Ehrlich pathway for fusel alcohol production: a century of research on Saccharomyces cerevisiae metabolism. Appl. Environ. Microbiol. 74, 2259–2266 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen, H. & Fink, G. R. Feedback control of morphogenesis in fungi by aromatic alcohols. Genes Dev. 20, 1150–1161 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nett, J. E., Marchillo, K., Spiegel, C. A. & Andes, D. Development and validation of an in vivo Candida albicans biofilm denture model. Infect. Immun. 78, 3650–3659 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ricicova, M. et al. Candida albicans biofilm formation in a new in vivo rat model. Microbiology 156, 909–919 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Schinabeck, M. K. et al. Rabbit model of Candida albicans biofilm infection: liposomal amphotericin B antifungal lock therapy. Antimicrob. Agents Chemother. 48, 1727–1732 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kuhn, D. M., Chandra, J., Mukherjee, P. K. & Ghannoum, M. A. Comparison of biofilms formed by Candida albicans and Candida parapsilosis on bioprosthetic surfaces. Infect. Immun. 70, 878–888 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Baillie, G. S. & Douglas, L. J. Matrix polymers of Candida biofilms and their possible role in biofilm resistance to antifungal agents. J. Antimicrob. Chemother. 46, 397–403 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Stichternoth, C. & Ernst, J. F. Hypoxic adaptation by Efg1 regulates biofilm formation by Candida albicans. Appl. Environ. Microbiol. 75, 3663–3672 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dongari-Bagtzoglou, A., Kashleva, H., Dwivedi, P., Diaz, P. & Vasilakos, J. Characterization of mucosal Candida albicans biofilms. PLoS ONE 4, e7967 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Harriott, M. M., Lilly, E. A., Rodriguez, T. E., Fidel, P. L. & Noverr, M. C. Candida albicans forms biofilms on the vaginal mucosa. Microbiology 156, 3635–3644 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kumamoto, C. A. Niche-specific gene expression during C. albicans infection. Curr. Opin. Microbiol. 11, 325–330 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Klotz, S. A., Chasin, B. S., Powell, B., Gaur, N. K. & Lipke, P. N. Polymicrobial bloodstream infections involving Candida species: analysis of patients and review of the literature. Diagn. Microbiol. Infect. Dis. 59, 401–406 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Chrissoheris, M. P. et al. Endocarditis complicating central venous catheter bloodstream infections: a unique form of health care associated endocarditis. Clin. Cardiol. 32, E48–E54 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Morales, D. K. & Hogan, D. A. Candida albicans interactions with bacteria in the context of human health and disease. PLoS Pathog. 6, e1000886 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Adam, B., Baillie, G. S. & Douglas, L. J. Mixed species biofilms of Candida albicans and Staphylococcus epidermidis. J. Med. Microbiol. 51, 344–349 (2002).

    Article  PubMed  Google Scholar 

  46. Bamford, C. V. et al. Streptococcus gordonii modulates Candida albicans biofilm formation through intergeneric communication. Infect. Immun. 77, 3696–3704 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jabra-Rizk, M. A., Meiller, T. F., James, C. E. & Shirtliff, M. E. Effect of farnesol on Staphylococcus aureus biofilm formation and antimicrobial susceptibility. Antimicrob. Agents Chemother. 50, 1463–1469 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kuroda, M., Nagasaki, S., Ito, R. & Ohta, T. Sesquiterpene farnesol as a competitive inhibitor of lipase activity of Staphylococcus aureus. FEMS Microbiol. Lett. 273, 28–34 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Hogan, D. A., Vik, A. & Kolter, R. A Pseudomonas aeruginosa quorum-sensing molecule influences Candida albicans morphology. Mol. Microbiol. 54, 1212–1223 (2004). This study shows that a molecule produced by P. aeruginosa mimics the actions of the C. albicans quorum sensing molecule farnesol, thus providing P. aeruginosa with a competitive advantage in the host.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  51. Shirtliff, M. E. et al. Farnesol-induced apoptosis in Candida albicans. Antimicrob. Agents Chemother. 53, 2392–2401 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Shirtliff, M. E., Peters, B. M. & Jabra-Rizk, M. A. Cross-kingdom interactions: Candida albicans and bacteria. FEMS Microbiol. Lett. 299, 1–8 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Li, F. et al. Eap1p, an adhesin that mediates Candida albicans biofilm formation in vitro and in vivo. Euk. Cell 6, 931–939 (2007). Eap1 is shown to be a GPI-anchored, glucan-cross-linked cell wall protein that acts as an adhesin and is required for biofilm formation in vitro as well as in vivo.

    Article  CAS  Google Scholar 

  54. Chaffin, W. L. Candida albicans cell wall proteins. Microbiol. Mol. Biol. Rev. 72, 495–544 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Richard, M. L. & Plaine, A. Comprehensive analysis of glycosylphosphatidylinositol-anchored proteins in Candida albicans. Euk. Cell 6, 119–133 (2007).

    Article  CAS  Google Scholar 

  56. Li, F. & Palecek, S. P. EAP1, a Candida albicans gene involved in binding human epithelial cells. Euk. Cell 2, 1266–1273 (2003).

    Article  CAS  Google Scholar 

  57. Hoyer, L. L. The ALS gene family of Candida albicans. Trends Microbiol. 9, 176–180 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Sheppard, D. C. et al. Functional and structural diversity in the Als protein family of Candida albicans. J. Biol. Chem. 279, 30480–30489 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Green, C. B., Zhao, X., Yeater, K. M. & Hoyer, L. L. Construction and real-time RT-PCR validation of Candida albicans PALS-GFP reporter strains and their use in flow cytometry analysis of ALS gene expression in budding and filamenting cells. Microbiology 151, 1051–1060 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Murillo, L. A. et al. Genome-wide transcription profiling of the early phase of biofilm formation by Candida albicans. Euk. Cell 4, 1562–1573 (2005).

    Article  CAS  Google Scholar 

  61. Mateus, C., Crow, S. A., Jr & Ahearn, D. G. Adherence of Candida albicans to silicone induces immediate enhanced tolerance to fluconazole. Antimicrob. Agents Chemother. 48, 3358–3366 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zucchi, P. C., Davis, T. R. & Kumamoto, C. A. A Candida albicans cell wall-linked protein promotes invasive filamentation into semi-solid medium. Mol. Microbiol. 76, 733–748 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kumamoto, C. A. Molecular mechanisms of mechanosensing and their roles in fungal contact sensing. Nature Rev. Microbiol. 6, 667–673 (2008).

    Article  CAS  Google Scholar 

  64. Kumamoto, C. A. A contact-activated kinase signals Candida albicans invasive growth and biofilm development. Proc. Natl Acad. Sci. USA 102, 5576–5581 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Daniels, K. J., Srikantha, T., Lockhart, S. R., Pujol, C. & Soll, D. R. Opaque cells signal white cells to form biofilms in Candida albicans. EMBO J. 25, 2240–2252 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Sahni, N. et al. Tec1 mediates the pheromone response of the white phenotype of Candida albicans: insights into the evolution of new signal transduction pathways. PLoS Biol. 8, e1000363 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ene, I. V. & Bennett, R. J. Hwp1 and related adhesins contribute to both mating and biofilm formation in Candida albicans. Euk. Cell 8, 1909–1913 (2009).

    Article  CAS  Google Scholar 

  68. Sahni, N. et al. Genes selectively up-regulated by pheromone in white cells are involved in biofilm formation in Candida albicans. PLoS Pathog. 5, e1000601 (2009). This work identifies several genes that are upregulated in white cells in the presence of mating pheromone. It also finds that white cells use their pheromone response pathway to produce a mature biofilm.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Bennett, R. J. & Johnson, A. D. Mating in Candida albicans and the search for a sexual cycle. Annu. Rev. Microbiol. 59, 233–255 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Singleton, D. R. & Hazen, K. C. Differential surface localization and temperature-dependent expression of the Candida albicans CSH1 protein. Microbiology 150, 285–292 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Zhao, X. et al. Candida albicans Als3p is required for wild-type biofilm formation on silicone elastomer surfaces. Microbiology 152, 2287–2299 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Ding, C. & Butler, G. Development of a gene knockout system in Candida parapsilosis reveals a conserved role for BCR1 in biofilm formation. Euk. Cell 6, 1310–1319 (2007). This paper reports that transcription factor Bcr1 is a conserved regulator of biofilm formation in C. parapsilosis.

    Article  CAS  Google Scholar 

  73. Firon, A. et al. The SUN41 and SUN42 genes are essential for cell separation in Candida albicans. Mol. Microbiol. 66, 1256–1275 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Perez, A. et al. Biofilm formation by Candida albicans mutants for genes coding fungal proteins exhibiting the eight-cysteine-containing CFEM domain. FEMS Yeast Res. 6, 1074–1084 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Norice, C. T., Smith, F. J. Jr, Solis, N., Filler, S. G. & Mitchell, A. P. Requirement for Candida albicans Sun41 in biofilm formation and virulence. Euk. Cell 6, 2046–2055 (2007).

    Article  CAS  Google Scholar 

  76. Hiller, E., Heine, S., Brunner, H. & Rupp, S. Candida albicans Sun41p, a putative glycosidase, is involved in morphogenesis, cell wall biogenesis, and biofilm formation. Euk. Cell 6, 2056–2065 (2007).

    Article  CAS  Google Scholar 

  77. Rossignol, T. et al. Correlation between biofilm formation and the hypoxic response in Candida parapsilosis. Euk. Cell 8, 550–559 (2009).

    Article  CAS  Google Scholar 

  78. Blankenship, J. R., Fanning, S., Hamaker, J. J. & Mitchell, A. P. An extensive circuitry for cell wall regulation in Candida albicans. PLoS Pathog. 6, e1000752 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Al-Fattani, M. A. & Douglas, L. J. Biofilm matrix of Candida albicans and Candida tropicalis: chemical composition and role in drug resistance. J. Med. Microbiol. 55, 999–1008 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Nett, J. et al. Putative role of beta-1,3 glucans in Candida albicans biofilm resistance. Antimicrob. Agents Chemother. 51, 510–520 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Martinez-Gomariz, M. et al. Proteomic analysis of cytoplasmic and surface proteins from yeast cells, hyphae, and biofilms of Candida albicans. Proteomics 9, 2230–2252 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Martins, M. et al. Presence of extracellular DNA in the Candida albicans biofilm matrix and its contribution to biofilms. Mycopathologia 169, 323–331 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bayles, K. W. The biological role of death and lysis in biofilm development. Nature Rev. Microbiol. 5, 721–726 (2007).

    Article  CAS  Google Scholar 

  84. Kim, W. I., Lee, W. B., Song, K. & Kim, J. Identification of a putative DEAD-box RNA helicase and a zinc-finger protein in Candida albicans by functional complementation of the S. cerevisiae rok1 mutation. Yeast 16, 401–409 (2000).

    Article  CAS  PubMed  Google Scholar 

  85. Kim, M. J., Kil, M., Jung, J. H. & Kim, J. Roles of zinc-responsive transcription factor Csr1 in filamentous growth of the pathogenic yeast Candida albicans. J. Microbiol. Biotechnol. 18, 242–247 (2008).

    CAS  PubMed  Google Scholar 

  86. Delneri, D., Gardner, D. C., Bruschi, C. V. & Oliver, S. G. Disruption of seven hypothetical aryl alcohol dehydrogenase genes from Saccharomyces cerevisiae and construction of a multiple knock-out strain. Yeast 15, 1681–1689 (1999).

    Article  CAS  PubMed  Google Scholar 

  87. Dickinson, J. R., Salgado, L. E. & Hewlins, M. J. The catabolism of amino acids to long chain and complex alcohols in Saccharomyces cerevisiae. J. Biol. Chem. 278, 8028–8034 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Chen, H., Fujita, M., Feng, Q., Clardy, J. & Fink, G. R. Tyrosol is a quorum-sensing molecule in Candida albicans. Proc. Natl Acad. Sci. USA 101, 5048–5052 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Mukherjee, P. K., Chandra, J., Kuhn, D. M. & Ghannoum, M. A. Mechanism of fluconazole resistance in Candida albicans biofilms: phase-specific role of efflux pumps and membrane sterols. Infect. Immun. 71, 4333–4340 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Garcia-Sanchez, S. et al. Candida albicans biofilms: a developmental state associated with specific and stable gene expression patterns. Euk. Cell 3, 536–545 (2004).

    Article  CAS  Google Scholar 

  91. Nett, J. E., Lepak, A. J., Marchillo, K. & Andes, D. R. Time course global gene expression analysis of an in vivo Candida biofilm. J. Infect. Dis. 200, 307–313 (2009). This study is the first in vivo characterization of C. albicans biofilms to be carried out through microarray analysis.

    Article  CAS  PubMed  Google Scholar 

  92. Khot, P. D., Suci, P. A., Miller, R. L., Nelson, R. D. & Tyler, B. J. A small subpopulation of blastospores in Candida albicans biofilms exhibit resistance to amphotericin B associated with differential regulation of ergosterol and β-1,6-glucan pathway genes. Antimicrob. Agents Chemother. 50, 3708–3716 (2006).

    Article  CAS  Google Scholar 

  93. Lewis, K. Persister cells. Annu. Rev. Microbiol. 64, 357–372 (2010).

    Article  CAS  PubMed  Google Scholar 

  94. LaFleur, M. D., Kumamoto, C. A. & Lewis, K. Candida albicans biofilms produce antifungal-tolerant persister cells. Antimicrob. Agents Chemother. 50, 3839–3846 (2006). This paper reports the discovery of persisters that contribute to drug resistance in C. albicans biofilms.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Lafleur, M. D., Qi, Q. & Lewis, K. Patients with long-term oral carriage harbor high-persister mutants of Candida albicans. Antimicrob. Agents Chemother. 54, 39–44 (2010).

    Article  CAS  PubMed  Google Scholar 

  96. Selmecki, A., Forche, A. & Berman, J. Genomic plasticity of the human fungal pathogen Candida albicans. Euk. Cell 9, 991–1008 (2010).

    Article  CAS  Google Scholar 

  97. Nett, J. E., Sanchez, H., Cain, M. T. & Andes, D. R. Genetic basis of Candida biofilm resistance due to drug-sequestering matrix glucan. J. Infect. Dis. 202, 171–175 (2010). This study defines β-glucan levels as a key determinant of in vivo biofilm-based azole drug resistance.

    Article  CAS  PubMed  Google Scholar 

  98. Uppuluri, P. et al. Dispersion as an important step in the Candida albicans biofilm developmental cycle. PLoS Pathog. 6, e1000828 (2010). This article describes a novel assay for biofilm cell dispersal in C. albicans , the unique virulence properties of the dispersed cells, and genetic regulators of dispersal.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Uppuluri, P. et al. The transcriptional regulator Nrg1p controls Candida albicans biofilm formation and dispersion. Euk. Cell 9, 1531–1537 (2010).

    Article  CAS  Google Scholar 

  100. Keller, L. & Surette, M. G. Communication in bacteria: an ecological and evolutionary perspective. Nature Rev. Microbiol. 4, 249–258 (2006).

    Article  CAS  Google Scholar 

  101. Peleg, A. Y., Hogan, D. A. & Mylonakis, E. Medically important bacterial-fungal interactions. Nature Rev. Microbiol. 8, 340–349 (2010).

    Article  CAS  Google Scholar 

  102. Siehnel, R. et al. A unique regulator controls the activation threshold of quorum-regulated genes in Pseudomonas aeruginosa. Proc. Natl Acad. Sci. USA 107, 7916–7921 (2010).

    Article  CAS  PubMed  Google Scholar 

  103. Nasmyth, K. A. Molecular genetics of yeast mating type. Annu. Rev. Genet. 16, 439–500 (1982).

    Article  CAS  PubMed  Google Scholar 

  104. Bennett, R. J., Uhl, M. A., Miller, M. G. & Johnson, A. D. Identification and characterization of a Candida albicans mating pheromone. Mol. Cell Biol. 23, 8189–8201 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Rikkerink, E. H., Magee, B. B. & Magee, P. T. Opaque-white phenotype transition: a programmed morphological transition in Candida albicans. J. Bacteriol. 170, 895–899 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Soll, D. R., Lockhart, S. R. & Zhao, R. Relationship between switching and mating in Candida albicans. Euk. Cell 2, 390–397 (2003).

    Article  CAS  Google Scholar 

  107. Lockhart, S. R., Zhao, R., Daniels, K. J. & Soll, D. R. a-pheromone-induced “shmooing” and gene regulation require white-opaque switching during Candida albicans mating. Euk. Cell 2, 847–855 (2003).

    Article  CAS  Google Scholar 

  108. 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).

    Article  CAS  PubMed  Google Scholar 

  109. Zordan, R. E., Miller, M. G., Galgoczy, D. J., Tuch, B. B. & Johnson, A. D. Interlocking transcriptional feedback loops control white-opaque switching in Candida albicans. PLoS Biol. 5, e256 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ramirez-Zavala, B., Reuss, O., Park, Y. N., Ohlsen, K. & Morschhauser, J. Environmental induction of white–opaque switching in Candida albicans. PLoS Pathog. 4, e1000089 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Huang, G. et al. N-acetylglucosamine induces white to opaque switching, a mating prerequisite in Candida albicans. PLoS Pathog. 6, e1000806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Magee, B. B. & Magee, P. T. Induction of mating in Candida albicans by construction of MTLa and MTLa strains. Science 289, 310–313 (2000).

    Article  CAS  PubMed  Google Scholar 

  113. 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 

  114. Alby, K., Schaefer, D. & Bennett, R. J. Homothallic and heterothallic mating in the opportunistic pathogen Candida albicans. Nature 460, 890–893 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Bennett, R. J. A Candida-based view of fungal sex and pathogenesis. Genome Biol. 10, 230 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Forche, A. et al. The parasexual cycle in Candida albicans provides an alternative pathway to meiosis for the formation of recombinant strains. PLoS Biol. 6, e110 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  118. Kelly, M. T. et al. The Candida albicans CaACE2 gene affects morphogenesis, adherence and virulence. Mol. Microbiol. 53, 969–983 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. Sanchez, A. A. et al. Relationship between Candida albicans virulence during experimental hematogenously disseminated infection and endothelial cell damage in vitro. Infect. Immun. 72, 598–601 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Kumamoto, C. A. & Vinces, M. D. Alternative Candida albicans lifestyles: growth on surfaces. Annu. Rev. Microbiol. 59, 113–133 (2005).

    Article  CAS  PubMed  Google Scholar 

  121. Lewis, R. E., Lo, H. J., Raad, II & Kontoyiannis, D. P. Lack of catheter infection by the efg1/efg1 cph1/cph1 double-null mutant, a Candida albicans strain that is defective in filamentous growth. Antimicrob. Agents Chemother. 46, 1153–1155 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Cao, Y. Y. et al. cDNA microarray analysis of differential gene expression in Candida albicans biofilm exposed to farnesol. Antimicrob. Agents Chemother. 49, 584–589 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Zhao, X., Oh, S. H., Yeater, K. M. & Hoyer, L. L. Analysis of the Candida albicans Als2p and Als4p adhesins suggests the potential for compensatory function within the Als family. Microbiology 151, 1619–1630 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Hashash, R. et al. Characterisation of Pga1, a putative Candida albicans cell wall protein necessary for proper adhesion and biofilm formation. Mycoses 6th April 2010 (doi: 10.1111/j.1439–05072010.01883.x).

  125. Peltroche-Llacsahuanga, H., Goyard, S., d'Enfert, C., Prill, S. K. & Ernst, J. F. Protein O-mannosyltransferase isoforms regulate biofilm formation in Candida albicans. Antimicrob. Agents Chemother. 50, 3488–3491 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Granger, B. L., Flenniken, M. L., Davis, D. A., Mitchell, A. P. & Cutler, J. E. Yeast wall protein 1 of Candida albicans. Microbiology 151, 1631–1644 (2005).

    Article  CAS  PubMed  Google Scholar 

  127. Nobile, C. J. & Mitchell, A. P. Large-scale gene disruption using the UAU1 cassette. Methods Mol. Biol. 499, 175–194 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Goyard, S. et al. The Yak1 kinase is involved in the initiation and maintenance of hyphal growth in Candida albicans. Mol. Biol. Cell 19, 2251–2266 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Kruppa, M. et al. The two-component signal transduction protein Chk1p regulates quorum sensing in Candida albicans. Euk. Cell 3, 1062–1065 (2004).

    Article  CAS  Google Scholar 

  130. Bastidas, R. J., Heitman, J. & Cardenas, M. E. The protein kinase Tor1 regulates adhesin gene expression in Candida albicans. PLoS Pathog. 5, e1000294 (2009). This study connects biofilm adhesin expression to global nutrient sensing via the conserved Tor pathway.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Strijbis, K. et al. Carnitine-dependent transport of acetyl coenzyme A in Candida albicans is essential for growth on nonfermentable carbon sources and contributes to biofilm formation. Euk. Cell 7, 610–618 (2008).

    Article  CAS  Google Scholar 

  132. Richard, M. L., Nobile, C. J., Bruno, V. M. & Mitchell, A. P. Candida albicans biofilm-defective mutants. Euk. Cell 4, 1493–1502 (2005).

    Article  CAS  Google Scholar 

  133. Liu, G., Vellucci, V. F., Kyc, S. & Hostetter, M. K. Simvastatin inhibits Candida albicans biofilm in vitro. Pediatr. Res. 66, 600–604 (2009).

    Article  CAS  PubMed  Google Scholar 

  134. Melo, A. S. et al. The Candida albicans AAA ATPase homologue of Saccharomyces cerevisiae Rix7p (YLL034c) is essential for proper morphology, biofilm formation and activity of secreted aspartyl proteinases. Genet. Mol. Res. 5, 664–687 (2006).

    CAS  PubMed  Google Scholar 

  135. Palanisamy, S. K., Ramirez, M. A., Lorenz, M. & Lee, S. A. Candida albicans PEP12 is required for biofilm integrity and in vivo virulence. Euk. Cell 9, 266–277 (2009).

    Article  CAS  Google Scholar 

  136. Bernardo, S. M., Khalique, Z., Kot, J., Jones, J. K. & Lee, S. A. Candida albicans VPS1 contributes to protease secretion, filamentation, and biofilm formation. Fungal Genet. Biol. 45, 861–877 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to J. Blankenship, S. Fanning, S. Ganguly, E. Hill and C. Woolford for comments on this manuscript. Our studies on biofilm formation have been supported by US National Institutes of Health grant R01 AI067703 (to A.P.M.) and fellowship F32 AI085521 (to J.S.F.).

Author information

Authors and Affiliations

  1. Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, 15213, Pennsylvania, USA

    Jonathan S. Finkel & Aaron P. Mitchell

Authors
  1. Jonathan S. Finkel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aaron P. Mitchell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aaron P. Mitchell.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (table)

Candida albicans genes that function in biofilm development (PDF 256 kb)

Related links

Related links

FURTHER INFORMATION

Aaron P. Mitchell's homepage

Glossary

Pseudohypha

A chain of attached, elongated cells with constrictions at the septa.

Quorum sensing

Communication between neighbouring cells, carried out through secreted signalling molecules, allowing populations to sense organism density and alter gene expression accordingly.

Ergosterol

The main sterol in the fungal cell membrane. Ergosterol is responsible, and essential, for structural and regulatory membrane features such as fluidity and permeability (equivalent to cholesterol in mammalian cells).

Azole

A class of antifungal drug that inhibits a late step in the biosynthesis of ergosterol; this includes the triazoles (for example, fluconazole, voriconazole and posaconazole) and the imidazoles.

Polyene

A class of antifungal drug that intercalates into ergosterol-containing fungal membranes, thereby forming membrane-spanning channels that lead to the leakage of cellular components and cell death.

Persister

A metabolically quiescent cell that neither grows nor dies when exposed to cidal concentrations of antimicrobial compounds.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Finkel, J., Mitchell, A. Genetic control of Candida albicans biofilm development. Nat Rev Microbiol 9, 109–118 (2011). https://doi.org/10.1038/nrmicro2475

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro2475

This article is cited by

Search

Advanced search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

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