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:

Development and regulation of single- and multi-species Candida albicans biofilms

Nature Reviews Microbiology volume 16, pages 19–31 (2018)Cite this article

Subjects

Key Points

  • Biofilms are communities of microbial cells adhered to surfaces or present at liquid–air interfaces. Cells within biofilms have properties distinct from their planktonic counterparts.

  • Candida albicans can form biofilms on a wide range of implanted medical devices and host surfaces. These biofilms serve as drug-resistant reservoirs of cells that can multiply and seed bloodstream infections.

  • C. albicans biofilms contain a mixture of yeast-form cells, pseudohyphal cells and hyphal cells surrounded by an extracellular matrix.

  • More than 50 transcriptional regulators have been implicated in biofilm formation to date, and a core network of nine regulators is required for biofilm development in both in vitro and in vivo models. Approximately 1,000 genes are targets of this network.

  • Among the factors contributing to the resistance of C. albicans biofilms to antifungal drugs are the increased expression of drug efflux pumps, the protective features of the extracellular matrix, and the existence of 'persister' cells in the biofilm.

  • C. albicans is the fungal pathogen most frequently isolated from mixed bacterial–fungal infections. These mixed-species biofilms can increase virulence and protect one or multiple species from environmental hazards.

Abstract

Candida albicans is among the most prevalent fungal species of the human microbiota and asymptomatically colonizes healthy individuals. However, it is also an opportunistic pathogen that can cause severe, and often fatal, bloodstream infections. The medical impact of C. albicans typically depends on its ability to form biofilms, which are closely packed communities of cells that attach to surfaces, such as tissues and implanted medical devices. In this Review, we provide an overview of the processes involved in the formation of C. albicans biofilms and discuss the core transcriptional network that regulates biofilm development. We also consider some of the advantages that biofilms provide to C. albicans in comparison with planktonic growth and explore polymicrobial biofilms that are formed by C. albicans and certain bacterial species.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Formation of Candida albicans biofilms.
Figure 2: The core transcriptional network controlling biofilm formation in Candida albicans.
Figure 3: Overview of Candida albicans biofilm antifungal drug resistance.
Figure 4: Multi-species biofilm formation.

Similar content being viewed by others

References

  1. Nobile, C. J. & Johnson, A. D. Candida albicans biofilms and human disease. Annu. Rev. Microbiol. 69, 71–92 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Davey, M. E. & O'Toole, G. A. Microbial biofilms: from ecology to molecular genetics. Microbiol. Mol. Biol. Rev. 64, 847–867 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Kolter, R. & Greenberg, E. P. Microbial sciences: The superficial life of microbes. Nature 441, 300–302 (2006).

    CAS  PubMed  Google Scholar 

  4. Hall-Stoodley, L., Costerton, J. W. & Stoodley, P. Bacterial biofilms: from the natural environment to infectious diseases. Nat. Rev. Microbiol. 2, 95–108 (2004).

    CAS  PubMed  Google Scholar 

  5. Wolcott, R., Costerton, J. W., Raoult, D. & Culter, S. J. The polymicrobial nature of biofilm infection. Clin. Microbiol. Infect. 19, 107–112 (2013).

    CAS  PubMed  Google Scholar 

  6. Fox, E. P. & Nobile, C. J. A sticky situation: untangling the transcriptional network controlling biofilm development in Candida albicans. Transcription 3, 315–322 (2012).

    PubMed  PubMed Central  Google Scholar 

  7. Achkar, J. M. & Fries, B. C. Candida infections of the genitourinary tract. Clin. Microbiol. Rev. 23, 253–273 (2010).

    PubMed  PubMed Central  Google Scholar 

  8. Ganguly, S. & Mitchell, A. P. Mucosal biofilms of Candida albicans. Curr. Opin. Microbiol. 14, 380–385 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Kennedy, M. J. & Volz, P. A. Ecology of Candida albicans gut colonization: inhibition of Candida adhesion, colonization, and dissemination from the gastrointestinal tract by bacterial antagonism. Infect. Immun. 49, 654–663 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Kumamoto, C. A. Candida biofilms. Curr. Opin. Microbiol. 5, 608–611 (2002).

    CAS  PubMed  Google Scholar 

  11. Kumamoto, C. A. Inflammation and gastrointestinal Candida colonization. Curr. Opin. Microbiol. 14, 386–391 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Calderone, R. A. & Fonzi, W. A. Virulence factors of Candida albicans. Trends Microbiol. 9, 327–335 (2001).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  14. Wenzel, R. P. Nosocomial candidemia: risk factors and attributable mortality. Clin. Infect. Dis. 20, 1531–1534 (1995).

    CAS  PubMed  Google Scholar 

  15. Kullberg, B. J. & Oude Lashof, A. M. Epidemiology of opportunistic invasive mycoses. Eur. J. Med. Res. 7, 183–191 (2002).

    CAS  PubMed  Google Scholar 

  16. Weig, M., Gross, U. & Mühlschlegel, F. Clinical aspects and pathogenesis of Candida infection. Trends Microbiol. 6, 468–470 (1998).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Ramage, G., Mowat, E., Jones, B., Williams, C. & Lopez-Ribot, J. Our current understanding of fungal biofilms. Crit. Rev. Microbiol. 35, 340–355 (2009).

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  20. Ramage, G., Martínez, J. P. & López-Ribot, J. L. Candida biofilms on implanted biomaterials: a clinically significant problem. FEMS Yeast Res. 6, 979–986 (2006).

    CAS  PubMed  Google Scholar 

  21. Donlan, R. M. Biofilm formation: a clinically relevant microbiological process. Clin. Infect. Dis. 33, 1387–1392 (2001).

    CAS  PubMed  Google Scholar 

  22. Tumbarello, M. et al. Biofilm production by Candida species and inadequate antifungal therapy as predictors of mortality for patients with candidemia. J. Clin. Microbiol. 45, 1843–1850 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Tumbarello, M. et al. Risk factors and outcomes of candidemia caused by biofilm-forming isolates in a tertiary care hospital. PLoS ONE 7, e33705 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Lebeaux, D., Ghigo, J. M. & Beloin, C. Biofilm-related infections: bridging the gap between clinical management and fundamental aspects of recalcitrance toward antibiotics. Microbiol. Mol. Biol. Rev. 78, 510–543 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Fox, E. P., Singh-Babak, S. D., Hartooni, N. & Nobile, C. J. in Antifungals: From genomics to resistance and the development of Novel Agents (eds Coste, A. T. & Vandeputte, P.) 71–90 (Caister Academic Press, 2015).

    Google Scholar 

  26. Andes, D. R. et al. Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin. Infect. Dis. 54, 1110–1122 (2012).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  28. Uppuluri, P. et al. Dispersion as an important step in the Candida albicans biofilm developmental cycle. PLoS Pathog. 6, e1000828 (2010). This work provides an examination of cell dispersion from biofilms, including regulation, nutrient dependence and the characteristics of dispersed cells.

    PubMed  PubMed Central  Google Scholar 

  29. Hawser, S. P. & Douglas, L. J. Biofilm formation by Candida species on the surface of catheter materials in vitro. Infect. Immun. 62, 915–921 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Nobile, C. J. & Mitchell, A. P. Genetics and genomics of Candida albicans biofilm formation. Cell. Microbiol. 8, 1382–1391 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  32. Gulati, M. & Nobile, C. J. Candida albicans biofilms: development, regulation, and molecular mechanisms. Microbes Infect. 18, 310–321 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Andes, D. et al. Development and characterization of an in vivo central venous catheter Candida albicans biofilm model. Infect. Immun 72, 6023–6031 (2004). This study describes a commonly used and well-established in vivo model of biofilm formation.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Johnson, C. C., Yu, A., Lee, H., Fidel, P. L. & Noverr, M. C. Development of a contemporary animal model of Candida albicans-associated denture stomatitis using a novel intraoral denture system. Infect. Immun. 80, 1736–1743 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Nett, J. E. et al. Rat indwelling urinary catheter model of Candida albicans biofilm infection. Infect. Immun. 82, 4931–4940 (2014).

    PubMed  PubMed Central  Google Scholar 

  36. Harriott, M. M. et al. Candida albicans forms biofilms on the vaginal mucosa. Microbiology 156, 3635–3644 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

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

  39. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Shuford, J. A., Rouse, M. S., Piper, K. E., Steckelberg, J. M. & Patel, R. Evaluation of caspofungin and amphotericin B deoxycholate against Candida albicans biofilms in an experimental intravascular catheter infection model. J. Infect. Dis. 194, 710–713 (2006).

    CAS  PubMed  Google Scholar 

  41. Ramage, G., Tomsett, K., Wickes, B. L., López-Ribot, J. L. & Redding, S. W. Denture stomatitis: a role for Candida biofilms. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 98, 53–59 (2004).

    PubMed  Google Scholar 

  42. Lazzell, A. L. et al. Treatment and prevention of Candida albicans biofilms with caspofungin in a novel central venous catheter murine model of candidiasis. J. Antimicrob. Chemother. 64, 567–570 (2009).

    CAS  PubMed  Google Scholar 

  43. Kakade, P., Sadhale, P., Sanyal, K. & Nagaraja, V. ZCF32, a fungus specific Zn(II)2 Cys6 transcription factor, is a repressor of the biofilm development in the human pathogen Candida albicans. Sci. Rep. 6, 31124 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Ghosh, A. K., Wangsanut, T., Fonzi, W. A. & Rolfes, R. J. The GRF10 homeobox gene regulates filamentous growth in the human fungal pathogen Candida albicans. FEMS Yeast Res. 15, fov093 (2015).

    PubMed  PubMed Central  Google Scholar 

  45. Chen, H. F. & Lan, C. Y. Role of SFP1 in the regulation of Candida albicans biofilm formation. PLoS ONE 10, e0129903 (2015).

    PubMed  PubMed Central  Google Scholar 

  46. Nobile, C. J. et al. A recently evolved transcriptional network controls biofilm development in Candida albicans. Cell 148, 126–138 (2012). This study defines the core transcriptional network regulating C. albicans biofilms.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Fox, E. P. et al. An expanded regulatory network temporally controls Candida albicans biofilm formation. Mol. Microbiol. 96, 1226–1239 (2015). This work expands the core biofilm regulatory circuit while also providing insight into the transcriptional changes that occur temporally between different stages of biofilm development.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Borneman, A. R. et al. Target hub proteins serve as master regulators of development in yeast. Genes Dev. 20, 435–438 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Sorrells, T. R. & Johnson, A. D. Making sense of transcription networks. Cell 161, 714–723 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Dranginis, A. M., Rauceo, J. M., Coronado, J. E. & Lipke, P. N. A biochemical guide to yeast adhesins: glycoproteins for social and antisocial occasions. Microbiol. Mol. Biol. Rev. 71, 282–294 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Alves, C. T. et al. Effect of progesterone on Candida albicans vaginal pathogenicity. Int. J. Med. Microbiol. 304, 1011–1017 (2014).

    CAS  PubMed  Google Scholar 

  54. Sandini, S. et al. The MP65 gene is required for cell wall integrity, adherence to epithelial cells and biofilm formation in Candida albicans. BMC Microbiol. 11, 106 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Frade, J. P. & Arthington-Skaggs, B. A. Effect of serum and surface characteristics on Candida albicans biofilm formation. Mycoses 54, e154–e162 (2011).

    PubMed  Google Scholar 

  56. Salgado, P. S. et al. Structural basis for the broad specificity to host-cell ligands by the pathogenic fungus Candida albicans. Proc. Natl Acad. Sci. USA 108, 15775–15779 (2011).

    CAS  PubMed  Google Scholar 

  57. 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).

    CAS  PubMed  Google Scholar 

  58. Parsek, M. R. & Greenberg, E. P. Sociomicrobiology: the connections between quorum sensing and biofilms. Trends Microbiol. 13, 27–33 (2005).

    CAS  PubMed  Google Scholar 

  59. Desai, J. V. & Mitchell, A. P. Candida albicans biofilm development and its genetic control. Microbiol. Spectr. http://dx.doi.org/10.1128/microbiolspec.MB-0005-2014 (2015).

  60. Sundstrom, P. Adhesion in Candida spp. Cell. Microbiol. 4, 461–469 (2002).

    CAS  PubMed  Google Scholar 

  61. 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).

    PubMed  PubMed Central  Google Scholar 

  62. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Li, F. et al. Eap1p, an adhesin that mediates Candida albicans biofilm formation in vitro and in vivo. Eukaryot. Cell 6, 931–939 (2007).

    PubMed  PubMed Central  Google Scholar 

  64. Finkel, J. S. et al. Portrait of Candida albicans adherence regulators. PLoS Pathog. 8, e1002525 (2012). This study provides a comprehensive examination of the regulation of adherence, the first step in biofilm formation.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Swidergall, M. & Filler, S. G. Oropharyngeal candidiasis: fungal invasion and epithelial cell responses. PLoS Pathog. 13, e1006056 (2017).

    PubMed  PubMed Central  Google Scholar 

  66. Kempf, M. et al. Disruption of Candida albicans IFF4 gene involves modifications of the cell electrical surface properties. Colloids Surf. B. Biointerfaces 58, 250–255 (2007).

    CAS  PubMed  Google Scholar 

  67. Hoyer, L. L. & Cota, E. Candida albicans agglutinin-like sequence (Als) family vignettes: a review of Als protein structure and function. Front. Microbiol. 7, 280 (2016).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Nobile, C. J. et al. Complementary adhesin function in C. albicans biofilm formation. Curr. Biol. 18, 1017–1024 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Zarnowski, R. et al. Novel entries in a fungal biofilm matrix encyclopedia. mBio 5, e01333-4 (2014). This study provides a detailed breakdown of the composition of the biofilm extracellular matrix.

    Google Scholar 

  71. Martins, M. et al. Presence of extracellular DNA in the Candida albicans biofilm matrix and its contribution to biofilms. Mycopathologia 169, 323–331 (2010).

    CAS  PubMed  Google Scholar 

  72. Nobile, C. J. et al. Biofilm matrix regulation by Candida albicans Zap1. PLoS Biol. 7, e1000133 (2009).

    PubMed  PubMed Central  Google Scholar 

  73. Nett, J. E., Sanchez, H., Cain, M. T., Ross, K. M. & Andes, D. R. Interface of Candida albicans biofilm matrix-associated drug resistance and cell wall integrity regulation. Eukaryot. Cell 10, 1660–1669 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Mitchell, K. F. et al. Community participation in biofilm matrix assembly and function. Proc. Natl Acad. Sci. USA 112, 4092–4097 (2015). This study examines the role of many polysaccharide components of the biofilm extracellular matrix.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  76. Ramage, G., Vande Walle, K., López-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).

    CAS  PubMed  Google Scholar 

  77. Schweizer, A., Rupp, S., Taylor, B. N., Röllinghoff, M. & Schröppel, K. The TEA/ATTS transcription factor CaTec1p regulates hyphal development and virulence in Candida albicans. Mol. Microbiol. 38, 435–445 (2000).

    CAS  PubMed  Google Scholar 

  78. Konstantinidou, N. & Morrissey, J. P. Co-occurence of filamentation defects and impaired biofilms in Candida albicans protein kinase mutants. FEMS Yeast Res. 15, fov092 (2015).

    PubMed  Google Scholar 

  79. Rajendran, R. et al. Integrating Candida albicans metabolism with biofilm heterogeneity by transcriptome mapping. Sci. Rep. 6, 35436 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Holland, L. M. et al. Comparative phenotypic analysis of the major fungal pathogens Candida parapsilosis and Candida albicans. PLoS Pathog. 10, e1004365 (2014).

    PubMed  PubMed Central  Google Scholar 

  81. Nobile, C. J. et al. A histone deacetylase complex mediates biofilm dispersal and drug resistance in Candida albicans. mBio 5, e01201-14 (2014).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Hnisz, D. et al. A Histone deacetylase adjusts transcription kinetics at coding sequences during Candida albicans morphogenesis. PLoS Genet. 8, e1003118 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Robbins, N. et al. Hsp90 governs dispersion and drug resistance of fungal biofilms. PLoS Pathog. 7, e1002257 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Granger, B. L. Insight into the antiadhesive effect of yeast wall protein 1 of Candida albicans. Eukaryot. Cell 11, 795–805 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Blankenship, J. R. & Mitchell, A. P. How to build a biofilm: a fungal perspective. Curr. Opin. Microbiol. 9, 588–594 (2006).

    CAS  PubMed  Google Scholar 

  88. Sellam, A. et al. A Candida albicans early stage biofilm detachment event in rich medium. BMC Microbiol. 9, 25 (2009).

    PubMed  PubMed Central  Google Scholar 

  89. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Winter, M. B. et al. Global identification of biofilm-specific proteolysis in Candida albicans. mBio 7, e01514-16 (2016).

    PubMed  PubMed Central  Google Scholar 

  92. Li, P., Seneviratne, C. J., Alpi, E., Vizcaino, J. A. & Jin, L. Delicate metabolic control and coordinated stress response critically determine antifungal tolerance of Candida albicans biofilm persisters. Antimicrob. Agents Chemother. 59, 6101–6112 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Fiori, B. et al. In vitro activities of anidulafungin and other antifungal agents against biofilms formed by clinical isolates of different Candida and Aspergillus species. Antimicrob. Agents Chemother. 55, 3031–3035 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Jacobson, M. J., Steckelberg, K. E., Piper, K. E., Steckelberg, J. M. & Patel, R. In vitro activity of micafungin against planktonic and sessile Candida albicans isolates. Antimicrob. Agents Chemother. 53, 2638–2639 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Pappas, P. G. et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin. Infect. Dis. 48, 503–535 (2009).

    CAS  PubMed  Google Scholar 

  96. Cowen, L. E. The evolution of fungal drug resistance: modulating the trajectory from genotype to phenotype. Nat. Rev. Microbiol. 6, 187–198 (2008).

    CAS  PubMed  Google Scholar 

  97. Anderson, J. B. Evolution of antifungal-drug resistance: mechanisms and pathogen fitness. Nat. Rev. Microbiol. 3, 547–556 (2005).

    CAS  PubMed  Google Scholar 

  98. Ramage, G., Bachmann, S., Patterson, T. F., Wickes, B. L. & Lopez-Ribot, J. L. Investigation of multidrug efflux pumps in relation to fluconazole resistance in Candida albicans biofilms. J. Antimicrob. Chemother. 49, 973–980 (2002).

    CAS  PubMed  Google Scholar 

  99. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Prasad, R., Shah, A. H. & Rawal, M. K. Antifungals: mechanism of action and drug resistance. Adv. Exp. Med. Biol. 892, 327–349 (2016).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Yeater, K. M. et al. Temporal analysis of Candida albicans gene expression during biofilm development. Microbiology 153, 2373–2385 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  105. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Taff, H. T. et al. A Candida biofilm-induced pathway for matrix glucan delivery: implications for drug resistance. PLoS Pathog. 8, e1002848 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Vediyappan, G., Rossignol, T. & D'Enfert, C. Interaction of Candida albicans biofilms with antifungals: transcriptional response and binding of antifungals to beta-glucans. Antimicrob. Agents Chemother. 54, 2096–2111 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. LaFleur, M. D., Kumamoto, C. A. & Lewis, K. Candida albicans biofilms produce antifungal-tolerant persister cells. Antimicrob. Agents Chemother. 50, 3839–3846 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Lewis, K. Persister cells, dormancy and infectious disease. Nat. Rev. Microbiol. 5, 48–56 (2007).

    CAS  PubMed  Google Scholar 

  110. Mathe, L. & Van Dijck, P. Recent insights into Candida albicans biofilm resistance mechanisms. Curr. Genet. 59, 251–264 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Truong, T. et al. Comparative ploidy proteomics of Candida albicans biofilms unraveled the role of the AHP1 gene in the biofilm persistence against Amphotericin B. Mol. Cell. Proteom. 15, 3488–3500 (2016).

    CAS  Google Scholar 

  113. Ghosh, S. et al. Arginine-induced germ tube formation in Candida albicans is essential for escape from murine macrophage line RAW 264.7. Infect. Immun. 77, 1596–1605 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Gropp, K. et al. The yeast Candida albicans evades human complement attack by secretion of aspartic proteases. Mol. Immunol. 47, 465–475 (2009).

    CAS  PubMed  Google Scholar 

  115. Szafranski-Schneider, E. et al. Msb2 shedding protects Candida albicans against antimicrobial peptides. PLoS Pathog. 8, e1002501 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Swidergall, M., Ernst, A. M. & Ernst, J. F. Candida albicans mucin Msb2 is a broad-range protectant against antimicrobial peptides. Antimicrob. Agents Chemother. 57, 3917–3922 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Hirschfeld, J. Dynamic interactions of neutrophils and biofilms. J. Oral Microbiol. 6, 26102 (2014).

    PubMed  Google Scholar 

  118. Xie, Z. et al. Candida albicans biofilms do not trigger reactive oxygen species and evade neutrophil killing. J. Infect. Dis. 206, 1936–1945 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Johnson, C. J. et al. The extracellular matrix of Candida albicans biofilms impairs formation of neutrophil extracellular traps. PLoS Pathog. 12, e1005884 (2016).

    PubMed  PubMed Central  Google Scholar 

  120. Peters, B. M., Jabra-Rizk, M. A., O'May, G. A., Costerton, J. W. & Shirtliff, M. E. Polymicrobial interactions: impact on pathogenesis and human disease. Clin. Microbiol. Rev. 25, 193–213 (2012).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  122. Pammi, M., Zhong, D., Johnson, Y., Revell, P. & Versalovic, J. Polymicrobial bloodstream infections in the neonatal intensive care unit are associated with increased mortality: a case-control study. BMC Infect. Dis. 14, 390 (2014).

    PubMed  PubMed Central  Google Scholar 

  123. Peters, B. M. & Noverr, M. C. Candida albicans-Staphylococcus aureus polymicrobial peritonitis modulates host innate immunity. Infect. Immun. 81, 2178–2189 (2013). This study demonstrates that the combination of C. albicans and S. aureus results in dramatic increases in microbial burden and mortality in a mouse model of peritonitis.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Jarosz, L. M., Deng, D. M., van der Mei, H. C., Crielaard, W. & Krom, B. P. Streptococcus mutans competence-stimulating peptide inhibits Candida albicans hypha formation. Eukaryot. Cell 8, 1658–1664 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Jack, A. A. et al. Streptococcus gordonii comCDE (competence) operon modulates biofilm formation with Candida albicans. Microbiology 161, 411–421 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Lindsay, A. K. & Hogan, D. A. Candida albicans: molecular interactions with Pseudomonas aeruginosa and Staphylococcus aureus. Fungal Biol. Rev. 28, 85–96 (2014).

    Google Scholar 

  128. Bamford, C. V., Nobbs, A. H., Barbour, M. E., Lamont, R. J. & Jenkinson, H. F. Functional regions of Candida albicans hyphal cell wall protein Als3 that determine interaction with the oral bacterium Streptococcus gordonii. Microbiology 161, 18–29 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Beaussart, A. et al. Single-cell force spectroscopy of the medically important Staphylococcus epidermidis-Candida albicans interaction. Nanoscale 5, 10894–10900 (2013).

    CAS  PubMed  Google Scholar 

  130. Hoyer, L. L., Oh, S. H., Jones, R. & Cota, E. A proposed mechanism for the interaction between the Candida albicans Als3 adhesin and streptococcal cell wall proteins. Front. Microbiol. 5, 564 (2014).

    PubMed  PubMed Central  Google Scholar 

  131. Peters, B. M. et al. Staphylococcus aureus adherence to Candida albicans hyphae is mediated by the hyphal adhesin Als3p. Microbiology 158, 2975–2986 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Schlecht, L. M. et al. Systemic Staphylococcus aureus infection mediated by Candida albicans hyphal invasion of mucosal tissue. Microbiology 161, 168–181 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Förster, T. M. et al. Enemies and brothers in arms: Candida albicans and gram-positive bacteria. Cell. Microbiol. 28, 1709–1715 (2016).

    Google Scholar 

  134. Harriott, M. M. & Noverr, M. C. Candida albicans and Staphylococcus aureus form polymicrobial biofilms: effects on antimicrobial resistance. Antimicrob. Agents Chemother. 53, 3914–3922 (2009). This work shows that co-incubation of C. albicans and S. aureus results in increased biofilm formation and vancomycin resistance in S. aureus.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Harriott, M. M. & Noverr, M. C. Ability of Candida albicans mutants to induce Staphylococcus aureus vancomycin resistance during polymicrobial biofilm formation. Antimicrob. Agents Chemother. 54, 3746–3755 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Kong, E. F. et al. Commensal protection of Staphylococcus aureus against antimicrobials by Candida albicans biofilm matrix. mBio 7, e01365-16 (2016). This study identifies the component of the C. albicans extracellular matrix that protects S. aureus from vancomycin.

    PubMed  PubMed Central  Google Scholar 

  137. Fox, E. P. et al. Anaerobic bacteria grow within Candida albicans biofilms and induce biofilm formation in suspension cultures. Curr. Biol. 24, 2411–2416 (2014). This study demonstrates that bacteria can induce C. albicans biofilm formation and use the resulting biofilms for protection from the environment.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Hogan, D. A. & Kolter, R. Pseudomonas-Candida interactions: an ecological role for virulence factors. Science 296, 2229–2232 (2002). This is a foundational study of interactions between C. albicans and bacterial species.

    CAS  PubMed  Google Scholar 

  139. Strus, M. et al. The in vitro activity of vaginal Lactobacillus with probiotic properties against Candida. Infect. Dis. Obstet. Gynecol. 13, 69–75 (2005).

    PubMed  PubMed Central  Google Scholar 

  140. Hogan, D. A., Vik, A. & Kolter, R. A. Pseudomonas aeruginosa quorum-sensing molecule influences Candida albicans morphology. Mol. Microbiol. 54, 1212–1223 (2004).

    CAS  PubMed  Google Scholar 

  141. McAlester, G., O'Gara, F. & Morrissey, J. P. Signal-mediated interactions between Pseudomonas aeruginosa and Candida albicans. J. Med. Microbiol. 57, 563–569 (2008).

    CAS  PubMed  Google Scholar 

  142. Graham, C. E., Cruz, M. R., Garsin, D. A. & Lorenz, M. C. Enterococcus faecalis bacteriocin EntV inhibits hyphal morphogenesis, biofilm formation, and virulence of Candida albicans. Proc. Natl Acad. Sci. USA 114, 4507–4512 (2017).

    CAS  PubMed  Google Scholar 

  143. Seth, E. C. & Taga, M. E. Nutrient cross-feeding in the microbial world. Front. Microbiol. 5, 350 (2014).

    PubMed  PubMed Central  Google Scholar 

  144. Shrestha, P. M. & Rotaru, A. E. Plugging in or going wireless: strategies for interspecies electron transfer. Front. Microbiol. 5, 237 (2014).

    PubMed  PubMed Central  Google Scholar 

  145. Stams, A. J. & Plugge, C. M. Electron transfer in syntrophic communities of anaerobic bacteria and archaea. Nat. Rev. Microbiol. 7, 568–577 (2009).

    CAS  PubMed  Google Scholar 

  146. Morales, D. K. et al. Control of Candida albicans metabolism and biofilm formation by Pseudomonas aeruginosa phenazines. mBio 4, e00526-12 (2013).

    PubMed  PubMed Central  Google Scholar 

  147. Chen, A. I. et al. Candida albicans ethanol stimulates Pseudomonas aeruginosa WspR-controlled biofilm formation as part of a cyclic relationship involving phenazines. PLoS Pathog. 10, e1004480 (2014).

    PubMed  PubMed Central  Google Scholar 

  148. Diaz, P. I. et al. Synergistic interaction between Candida albicans and commensal oral streptococci in a novel in vitro mucosal model. Infect. Immun 80, 620–632 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Vande Velde, G., Kucharíková, S., Schrevens, S., Himmelreich, U. & Van Dijck, P. Towards non-invasive monitoring of pathogen-host interactions during Candida albicans biofilm formation using in vivo bioluminescence. Cell. Microbiol 16, 115–130 (2014). This study describes an in vivo live-animal imaging model of infection.

    CAS  PubMed  Google Scholar 

  150. Vande Velde, G., Kucharíková, S., Van Dijck, P. & Himmelreich, U. Bioluminescence imaging of fungal biofilm development in live animals. Methods Mol. Biol. 1098, 153–167 (2014).

    CAS  PubMed  Google Scholar 

  151. Tournu, H. & Van Dijck, P. Candida biofilms and the host: models and new concepts for eradication. Int. J. Microbiol. 2012, 845352 (2012).

    PubMed  Google Scholar 

  152. Lohse, M. B. et al. Assessment and optimizations of Candida albicans in vitro biofilm assays. Antimicrob. Agents Chemother. 61, e02749-16 (2017).

    PubMed  PubMed Central  Google Scholar 

  153. Ramage, G., Vande Walle, K., Wickes, B. L. & López-Ribot, J. L. Standardized method for in vitro antifungal susceptibility testing of Candida albicans biofilms. Antimicrob. Agents Chemother. 45, 2475–2479 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Nett, J. E., Cain, M. T., Crawford, K. & Andes, D. R. Optimizing a Candida biofilm microtiter plate model for measurement of antifungal susceptibility by tetrazolium salt assay. J. Clin. Microbiol. 49, 1426–1433 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Jin, Y., Yip, H. K., Samaranayake, Y. H., Yau, J. Y. & Samaranayake, L. P. Biofilm-forming ability of Candida albicans is unlikely to contribute to high levels of oral yeast carriage in cases of human immunodeficiency virus infection. J. Clin. Microbiol. 41, 2961–2967 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Wang, X. & Fries, B. C. A murine model for catheter-associated candiduria. J. Med. Microbiol. 60, 1523–1529 (2011).

    PubMed  PubMed Central  Google Scholar 

  158. Doyle, T. C., Nawotka, K. A., Kawahara, C. B., Francis, K. P. & Contag, P. R. Visualizing fungal infections in living mice using bioluminescent pathogenic Candida albicans strains transformed with the firefly luciferase gene. Microb. Pathog. 40, 82–90 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  160. Askew, C. et al. The zinc cluster transcription factor Ahr1p directs Mcm1p regulation of Candida albicans adhesion. Mol. Microbiol. 79, 940–953 (2011).

    CAS  PubMed  Google Scholar 

  161. García-Sánchez, S. et al. Candida albicans biofilms: a developmental state associated with specific and stable gene expression patterns. Eukaryot. Cell 3, 536–545 (2004).

    PubMed  PubMed Central  Google Scholar 

  162. Tsai, P. W. et al. The role of Mss11 in Candida albicans biofilm formation. Mol. Genet. Genom. 289, 807–819 (2014).

    CAS  Google Scholar 

  163. Sellam, A. et al. Role of transcription factor CaNdt80p in cell separation, hyphal growth, and virulence in Candida albicans. Eukaryot. Cell 9, 634–644 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Bonhomme, J. et al. Contribution of the glycolytic flux and hypoxia adaptation to efficient biofilm formation by Candida albicans. Mol. Microbiol. 80, 995–1013 (2011).

    CAS  PubMed  Google Scholar 

  165. Ganguly, S. et al. Zap1 control of cell-cell signaling in Candida albicans biofilms. Eukaryot. Cell 10, 1448–1454 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank Sheena Singh-Babak for comments on the manuscript. Research in the authors' laboratories related to this work is supported by NIH grants R41AI112038 (to C.J.N.) and R01AI083311 (to A.D.J.), and by a Pew Biomedical Scholar Award (to C.J.N.) from the Pew Charitable Trusts. The funders had no role in planning and writing the Review or in the decision to submit the work for publication.

Author information

Author notes

  1. Matthew B. Lohse and Megha Gulati: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology and Immunology, University of California, San Francisco (UCSF), 600 16th Street, San Francisco, 94158, California, USA

    Matthew B. Lohse & Alexander D. Johnson

  2. Department of Molecular and Cell Biology, University of California, Merced (UC Merced), 5200 North Lake Road, Merced, 95343, California, USA

    Megha Gulati & Clarissa J. Nobile

Authors
  1. Matthew B. Lohse
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Megha Gulati
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexander D. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Clarissa J. Nobile
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Alexander D. Johnson or Clarissa J. Nobile.

Ethics declarations

Competing interests

C.J.N. and A.D.J. are cofounders of BioSynesis, Inc., a company developing inhibitors and diagnostics of Candida albicans biofilm formation, and M.L. is a consultant of BioSynesis, Inc. M.G. does not declare competing interests.

Supplementary information

Supplementary information S1 (box)

The host immune response to C. albicans (DOC 29 kb)

PowerPoint slides

Glossary

Yeast-form cells

Spherical fungal cells that form daughter cells, which bud off from the parent cell.

Pseudohyphal cells

Ovoid chains of fungal cells that contain constrictions (rather than septa) at the cell junctions.

Hyphal cells

Elongated, cylindrical fungal cells that contain complete septa at the cell junctions.

Extracellular matrix

A protective physical barrier that surrounds cells in a biofilm and is composed of proteins, carbohydrates, lipids and nucleic acids.

Persister cells

Non-dividing fungal cells with decreased metabolic activity that are resistant to antimicrobial agents.

White–opaque switching

The ability for Candida albicans cells to switch between the 'white' and 'opaque' phenotypic cell types. The switch occurs epigenetically; that is, without a change in the primary DNA sequence of the genome.

Horizontal gene transfer

The process through which genetic material is transferred between microorganisms through mechanisms such as transformation, conjugation and transduction. This process is distinct from vertical gene transfer, in which genetic material is transferred from mother cells to daughter cells.

Quorum sensing

A method of communication that allows microorganisms to sense cell density and microbial community composition and respond as a group. The process involves the production and detection of soluble quorum sensing molecules.

Glycosylphosphatidylinositol (GPI) anchors

Post-translational modifications of proteins in which a glycolipid is covalently attached and anchors the protein in the plasma membrane.

Flow cell

A light microscopy method for observing biofilm formation in vitro under laminar flow conditions.

Glucoamylase

An enzyme that catalyses the hydrolysis of glucosidic linkages in starch, which releases glucose.

Glucan synthase

A glucosyltransferase enzyme that catalyses the synthesis of glucans, which are critical polysaccharide components of the fungal cell wall and the extracellular matrix.

Chromatin-modifying complex

A protein complex that alters the chromatin structure.

Complement system

A group of proteins that, when activated, mediate the innate immune response and inflammatory response to a pathogen.

Mucin

A glycosylated protein that is the major component of mucus.

Ergosterol

A sterol component of the fungal cell membrane necessary for membrane fluidity.

Bacteriocin

A pore-forming peptide produced by some bacterial and archaeal species that is toxic to other microorganisms.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lohse, M., Gulati, M., Johnson, A. et al. Development and regulation of single- and multi-species Candida albicans biofilms. Nat Rev Microbiol 16, 19–31 (2018). https://doi.org/10.1038/nrmicro.2017.107

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro.2017.107

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