Growth of Candida albicans hyphae

Key Points

  • Candida albicans is a common cause of mucosal infections. In certain groups of immunocompromised patients it also causes life-threatening bloodstream infections that are disseminated to internal organs. It is a polymorphic fungus, being able to grow in yeast, hyphal and pseudohyphal forms. The hyphal form penetrates epithelia and endothelia, causing tissue damage and allowing access to the bloodstream.

  • C. albicans is exquisitely sensitive to the multiple environments that it encounters in the human host and forms hyphae in response to cues such as 37 °C temperature, serum, CO2 and O2 tension, and neutral pH. The morphological switch is also regulated by the presence of not only other C. albicans cells but also bacterial cells, both of which are sensed through quorum sensing compounds.

  • Environmental signals are transduced through multiple pathways that target multiple transcription factors, resulting in the expression of a panel of hypha-specific genes. A key pathway is based on cyclic AMP and targets the transcription factor enhanced filamentous growth protein (Efg1). In this pathway, adenylyl cyclase, which is encoded by CYR1, integrates multiple cues in Ras-dependent and Ras-independent ways. Negative regulation is exerted by the general transcriptional corepressor Tup1, which is targeted to hypha-specific genes by the DNA-binding proteins Nrg1 and Rox1p-like regulator of filamentous growth (Rfg1).

  • The key outputs of the signal transduction pathway are the expression of three genes, UME6, EED1 and hyphal G1 cyclin protein 1 (HGC1). Overexpression of the transcription factor Ume6 forces ectopic hyphal growth. The role of Eed1 is currently unclear, but current research suggests that it lies upstream of Ume6. Hgc1 is the C. albicans homologue of the S. cerevisiae Ccn1 and Cln2 G1 cyclin pair, which activate the cyclin-dependent kinase cell division control 28 (Cdc28).

  • Hyphae grow in a highly polarized manner from their tip. This requires the delivery of secretory vesicles along actin cables. These vesicles accumulate in a subapical region called the Spitzenkörper before they fuse with the plasma membrane at the tip after docking with a multiprotein structure called the exocyst.

  • Cell separation after cytokinesis is suppressed in hyphae. This suppression involves phosphorylation of Efg1, which then associates with the promoters of genes encoding septum-degrading enzymes, repressing their Ace2-mediated transcription. A second mechanism suppressing cell separation involves the exclusion of the Cdc14 phosphatase from the septin ring, the subunits of which have different dynamic properties in yeast and hyphae.

  • A key role for kinases is emerging in the cell biology of hyphal growth. Hgc1–Cdc28 targets Rga2, Sec2 and Mob2, as well as Efg1. Rga2 is a GTPase-activating protein (GAP) that negatively regulates the GTPase Cdc42, which has a central role in orchestrating polarized growth. Sec2 is the guanosine exchange factor (GEF) that activates the GTPase Sec4, which is required for polarized exocytosis. Mob2 is the activating partner of the kinase Cbk1, which is absolutely required for hyphal growth. Upon hyphal induction, Cdc28 is partnered by a different cyclin, Ccn1, and cooperates with another kinase, growth-inhibitory protein 4 (Gin4), to phosphorylate the septin Cdc11.

Abstract

The fungus Candida albicans is often a benign member of the mucosal flora; however, it commonly causes mucosal disease with substantial morbidity and in vulnerable patients it causes life-threatening bloodstream infections. A striking feature of its biology is its ability to grow in yeast, pseudohyphal and hyphal forms. The hyphal form has an important role in causing disease by invading epithelial cells and causing tissue damage. This Review describes our current understanding of the network of signal transduction pathways that monitors environmental cues to activate a programme of hypha-specific gene transcription, and the molecular processes that drive the highly polarized growth of hyphae.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Morphology of yeast, hyphal and pseudohyphal forms.
Figure 2: Signal transduction pathways leading to expression of hypha-specific genes.
Figure 3: Cell biology of hyphal development.
Figure 4: The polarized growth machinery.
Figure 5: Mechanism of cell separation suppression in hyphae.
Figure 6: The hyphal induction programme.

References

  1. 1

    Odds, F. C. Candida and Candidosis (Balliere Tindall, London, 1988).

    Google Scholar 

  2. 2

    Runke, M. in Candida and Candidiasis (ed. Calderone, R.) 307–325 (ASM Press, Washington, 2002).

    Google Scholar 

  3. 3

    Sobel, J. D. Vaginitis. N. Engl. J. Med. 337, 1896–1903 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4

    Kullberg, B. J. & Filler, S. G. in Candida and Candidiasis (ed. Calderone, R. A.) 327–340 (ASM Press, Washington DC, 2002).

    Google Scholar 

  5. 5

    Beck-Sague, C. M. & Jarvis, W. R. National nosocomial infections surveillance system. Secular trends in the epidemiology of nosocomial fungal infections in the United states 1980–1990. J. Inf. Dis. 167, 1247–1251 (1993).

    CAS  Article  Google Scholar 

  6. 6

    Kibbler, C. C. et al. Management and outcome of bloodstream infections due to Candida species in England and Wales. J. Hosp. Infect. 54, 18–24 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Pfaller, M. A., Jones, R. N., Messer, S. A., Edmond, M. B. & Wenzel, R. P. National surveillance of nosocomial blood stream infection due to species of Candida other than Candida albicans: frequency of occurrence and antifungal susceptibility in the SCOPE program. Diagn. Microbiol. Infect. Dis. 30, 121–129 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Wisplinghoff, H. et al. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin. Infect. Dis. 39, 309–317 (2004).

    Article  Google Scholar 

  9. 9

    Odds, F. C. Candida and Candidosis. 42–59 (Balliere Tindall, London, 1988). A masterly review from one of the founding fathers of modern C. albicans research sets out many of the observations concerning morphogenesis that are now taken for granted.

    Google Scholar 

  10. 10

    Sudbery, P. E., Gow, N. A. R. & Berman, J. The distinct morphogenic states of Candida albicans. Trends Microbiol. 12, 317–324 (2004).

    CAS  Article  Google Scholar 

  11. 11

    Dalle, F. et al. Cellular interactions of Candida albicans with human oral epithelial cells and enterocytes. Cell. Microbiol. 12, 248–271 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Filler, S. G. & Sheppard, D. C. Fungal invasion of normally non-phagocytic host cells. PLoS Pathog. 2, e129 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Phan, Q. T. et al. Als3 is a Candida albicans invasin that binds to cadherins and induces endocytosis by host cells. PLoS Biol. 5, e64 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Zhu, W. D. & Filler, S. G. Interactions of Candida albicans with epithelial cells. Cell. Microbiol. 12, 273–282 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Scherwitz, C. Ultrastructure of human cutaneous candidosis. J. Invest. Dermatol. 78, 200–205 (1982).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Lorenz, M. C., Bender, J. A. & Fink, G. R. Transcriptional response of Candida albicans upon internalization by macrophages. Eukaryot. Cell 3, 1076–1087 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Noble, S. M. & Johnson, A. D. Genetics of Candida albicans, a diploid human fungal pathogen. Annu. Rev. Genet. 41, 193–211 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Taschdjian, C. L., Burchill, J. J. & Kozinn, P. J. Rapid identification of Candida albicans by filamentation on serum and serum substitutes. AMA J. Dis. Child. 99, 212 (1960).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Buffo, J., Herman, N. & Soll, D. R. A characterization of pH regulated dimorphism in Candida albicans. Mycopathologia 85, 21–30 (1985).

    Article  Google Scholar 

  20. 20

    Mardon, D., Balish, E. & Phillips, A. W. Control of dimorphism in a biochemical variant of Candida albicans. J. Bacteriol. 100, 701–707 (1969).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Simonneti, N., Stripolli, V. & Cassone, E. A. Yeast-mycelial conversion induced by N-acetyl-D-glucosamine in Candida albicans. Nature 250, 344–346 (1974).

    Article  Google Scholar 

  22. 22

    Brown, D. H. Jr, Giusani, A. D., Chen, X. & Kumamoto, C. A. Filamentous growth of Candida albicans in response to physical environmental cues and its regulation by the unique CZF1 gene. Mol. Microbiol. 34, 651–662 (1999).

    CAS  Article  Google Scholar 

  23. 23

    Sonneborn, A., Bockmuhl, D. P. & Ernst, J. F. Chlamydospore formation in Candida albicans requires the Efg1p morphogenetic regulator. Infect. Immun. 67, 5514–5517 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Lee, K. L., Buckley, H. R. & Cambell, C. C. An amino acid liquid synthetic medium for the development of mycelial and yeast forms of Candida albicans. Sabouraudia 13, 148–153 (1975).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Shareck, J. & Belhumeur, P. Modulation of morphogenesis in Candida albicans by various small molecules. Euk Cell 3 Jun 2011 (doi:10.1128/EC.05030-11).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Hornby, J. M. et al. Quorum sensing in the dimorphic fungus Candida albicans is mediated by farnesol. Appl. Environ. Microbiol. 67, 2982–2992 (2001). The first identification of a quorum sensing compound, farnesol. This opened up a new field studying intercellular communication between C. albicans cells and with bacterial cells.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

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

    CAS  Article  Google Scholar 

  29. 29

    De Sordi, L. & Muhlschlegel, F. A. Quorum sensing and fungal-bacterial interactions in Candida albicans: a communicative network regulating microbial coexistence and virulence. FEMS Yeast Res. 9, 990–999 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

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

    CAS  Article  Google Scholar 

  31. 31

    Hogan, D. A. & Kolter, R. Pseudomonas candida interactions: an ecological role for virulence factors. Science 296, 2229–2232 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Hogan, D. A. Talking to themselves: autoregulation and quorum sensing in fungi. Eukaryot. Cell 5, 613–619 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Shapiro, R. S., Robbins, N. & Cowen, L. E. Regulatory circuitry governing fungal development, drug resistance, and disease. Microbiol. Mol. Biol. Rev. 75, 213–267 (2011). This review provides a recent, exhaustive and detailed description of the complex network of pathways that regulate the transcription of hypha-specific genes.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Braun, B. R. & Johnson, A. D. Control of filament formation in Candida albicans by the transcriptional repressor TUP1. Science 277, 105–109 (1997). The first identification of a protein that negatively controls hyphal growth and hypha-specific gene expression.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Kadosh, D. & Johnson, A. D. Induction of the Candida albicans filamentous growth program by relief of transcriptional repression: a genome-wide analysis. Mol. Biol. Cell 16, 2903–2912 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Braun, B. R., Kadosh, D. & Johnson, A. D. NRG1, a repressor of filamentous growth in C.albicans, is down-regulated during filament induction. EMBO J. 20, 4753–4761 (2001). The identification of Nrg1as a co-repressor of hypha-specific gene transcription.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37

    Murad, A. M. A. et al. Nrg1 represses yeast–hypha morphogenesis and hypha–specific gene expression in Candida albicans. EMBO J. 20, 4742–4752 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Kadosh, D. & Johnson, A. D. Rfg1, a protein related to the Saccharomyces cerevisiae hypoxic regulator Rox1, controls filamentous growth and virulence in Candida albicans. Mol. Cell Biol. 21, 2496–2505 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Stoldt, V. R., Sonneborn, A., Leuker, C. E. & Ernst, J. F. Efg1p, an essential regulator of morphogenesis of the human pathogen Candida albicans, is a member of a conserved class of bHLH proteins regulating morphogenetic processes in fungi. EMBO J. 16, 1982–1991 (1997). The first identification of the Efg1 transcription factor, which is required for hypha-specific gene expression.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Leberer, E. et al. Signal transduction through homologs of the Ste20p and Ste7p protein kinases can trigger hyphal formation in the pathogenic fungus Candida albicans. Proc. Natl Acad. Sci. USA 93, 13217–13222 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Lane, S., Zhou, S., Pan, T., Dai, Q. & Liu, H. The basic helix–loop–helix transcription factor Cph2 regulates hyphal development in Candida albicans partly via Tec1. Mol. Cell Biol. 21, 6418–6428 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Lane, S., Birse, C., Zhou, S., Matson, R. & Liu, H. P. DNA array studies demonstrate convergent regulation of virulence factors by Cph1, Cph2, and Efg1 in Candida albicans. J. Biol. Chem. 276, 48988–48996 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Cao, F. et al. The Flo8 transcription factor is essential for hyphal development and virulence in Candida albicans. Mol. Biol. Cell 17, 295–307 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Davis, D., Wilson, R. B. & Mitchell, A. P. RIM101 dependent and independent pathways govern pH responses in Candida albicans. Mol. Cell Biol. 20, 971–978 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45

    Davis, D. Adaptation to environmental pH in Candida albicans and its relation to pathogenesis. Curr. Genet. 44, 1–7 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    El Barkani, A. et al. Dominant active alleles of RIM101 (PRR2) bypass the pH restriction on filamentation of Candida albicans. Mol. Cell Biol. 20, 4635–4647 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    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  Article  PubMed  PubMed Central  Google Scholar 

  48. 48

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

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

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

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

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Leberer, E. et al. Ras links cellular morphogenesis to virulence by regulation of the MAP kinase and cAMP signalling pathways in the pathogenic fungus Candida albicans. Mol. Microbiol. 42, 673–687 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52

    Rocha, C. R. C. et al. Signaling through adenylyl cyclase is essential for hyphal growth and virulence in the pathogenic fungus Candida albicans. Mol. Biol. Cell 12, 3631–3643 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Fang, H. M. & Wang, Y. RA domain-mediated interaction of Cdc35 with Ras1 is essential for increasing cellular cAMP level for Candida albicans hyphal development. Mol. Microbiol. 61, 484–496 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Xu, X. L. et al. Bacterial peptidoglycan triggers Candida albicans hyphal growth by directly activating the adenylyl cyclase Cyr1p. Cell Host Microbe 4, 28–39 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55

    Klengel, T. et al. Fungal adenylyl cyclase integrates CO2 sensing with cAMP signaling and virulence. Curr. Biol. 15, 2021–2026 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56

    Zou, H., Fang, H. M., Zhu, Y. & Wang, Y. Candida albicans Cyr1, Cap1 and G-actin form a sensor/effector apparatus for activating cAMP synthesis in hyphal growth. Mol. Microbiol. 75, 579–591 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Davis-Hanna, A., Piispanen, A. E., Stateva, L. I. & Hogan, D. A. Farnesol and dodecanol effects on the Candida albicans Ras1-cAMP signalling pathway and the regulation of morphogenesis. Mol. Microbiol. 67, 47–62 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58

    Hall, R. A. et al. The quorum sensing molecules farnesol/homoserine lactone and dodecanol operate via distinct modes of action in Candida albicans. Eukaryot. Cell 10 Jun 2011 (doi: 10.1128/EC.05060-11).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59

    Kebaara, B. W. et al. Candida albicans Tup1 is involved in farnesol-mediated inhibition of filamentous growth induction. Eukaryot. Cell 7, 980–987 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    Nantel, A. et al. Transcription profiling of Candida albicans cells undergoing the yeast-to-hyphal transition. Mol. Biol. Cell 13, 3452–3465 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Martin, R. et al. The Candida albicans specific gene EED1 encodes a key regulator of hyphal extension. PLoS ONE 6, e18394 (2011). The identification of a hypha-specific gene ( EED1 ) that is required for hyphal growth. Epistasis analysis places it downstream of EFG1 but upstream of UME6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63

    Banerjee, M. et al. UME6, a novel filament-specific regulator of Candida albicans hyphal extension and virulence. Mol. Biol. Cell 19, 1354–1365 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. 64

    Carlisle, P. L. et al. Expression levels of a filament-specific transcriptional regulator are sufficient to determine Candida albicans morphology and virulence. Proc. Natl Acad. Sci. USA 106, 599–604 (2009). A desciption of UME6 , a hypha-specific gene that is required for hyphal growth. Importantly, this reference shows that overexpression of UME6 is sufficient for hyphal growth, suggesting that UME6 expression is a critical limiting step for hyphal growth.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65

    Carlisle, P. L. & Kadosh, D. Candida albicans Ume6, a filament-specific transcriptional regulator, directs hyphal growth via a pathway involving Hgc1 cyclin-related protein. Eukaryot. Cell 9, 1320–1328 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66

    Zeidler, U. et al. UME6 is a crucial downstream target of other transcriptional regulators of true hyphal development in Candida albicans. FEMS Yeast Res. 9, 126–142 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67

    Zheng, X., Wang, Y. & Wang, Y. Hgc1, a novel hypha-specific G1 cyclin-related protein regulates Candida albicans hyphal morphogenesis. EMBO J. 23, 1845–1856 (2004). A key paper that, for the first time, identifies a gene that is only expressed in hyphae and is also required for hyphal development.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68

    Sudbery, P. E. The germ tubes of Candida albicans hyphae and pseudohyphae show different patterns of septin ring localisation. Mol. Microbiol. 41, 19–31 (2001). This study shows that although pseudohyphae may superficially resemble hyphae, there are fundamental differences in the underlying cellular organization. The article describes a qualitative test to distinguish between hyphae and pseudohyphae.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69

    Warenda, A. J. & Konopka, J. B. Septin function in Candida albicans morphogenesis. Mol. Biol. Cell 13, 2732–2746 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Soll, D. R., Herman, M. A. & Staebell, M. A. The involvement of cell wall expansion in the two modes of mycelium formation of Candida albicans. J. Gen. Microbiol. 131, 2367–2375 (1985). A classic paper that demonstrates that hyphal growth is polarized to the tip.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Finley, K. R. & Berman, J. Microtubules in Candida albicans hyphae drive nuclear dynamics and connect cell cycle progression to morphogenesis. Eukaryot. Cell 4, 1697–1711 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72

    Hazan, I., Sepulveda-Becerra, M. & Liu, H. P. Hyphal elongation is regulated independently of cell cycle in Candida albicans. Mol. Biol. Cell 13, 134–145 (2002). A meticulous analysis that shows that cell cycle events occur with the same kinetics in yeast and hyphae, so that changes in cell cycle organization are not responsible for hyphal morphology. Furthermore, this analysis shows that germ tube evagination can occur before the start of the cell cycle, and thus a germ tube is not a modified bud.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    Crampin, H. et al. Candida albicans hyphae have a Spitzenkörper that is distinct from the polarisome found in yeast and pseudohyphae. J. Cell Sci. 118, 2935–2947 (2005). This investigation shows that hyphal growth is driven by a Spitzenkörper; therefore, the mechanism of polarized growth is different in hyphae and in yeast and pseudohyphae. The article illustrates the power of high-resolution imaging of fluorescently tagged proteins.

    CAS  Article  Google Scholar 

  74. 74

    Crampin, H. The identification of the Spitzenkörper in Candida albicans and the partial characterization of the contractile ring components. Thesis, Univ. Sheffield (2006).

  75. 75

    Lenardon, M. D. et al. Phosphorylation regulates polarisation of chitin synthesis in Candida albicans. J. Cell Sci. 123, 2199–2206 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76

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

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Odds, F. C. Morphogenesis in Candida albicans. Crit. Rev. Microbiol. 12, 45–93 (1985).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78

    Gow, N. A. R. & Gooday, G. W. A model for the germ tube formation and mycelial growth form of Candida albicans. Sabouraudia 22, 137–143 (1984).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    Gow, N. A. R. & Gooday, G. W. Vacuolation, branch production and linear growth of germ tubes of Candida albicans. J. Gen. Microbiol. 128, 2195–2198 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Soll, D. R., Stasi, M. & Bedell, G. The regulation of nuclear migration and division during pseudo-mycelium outgrowth in the dimorphic yeast Candida albicans. Exp. Cell Res. 116, 207–215 (1978).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81

    Martin, R., Walther, A. & Wendland, J. Ras1-induced hyphal development in Candida albicans requires the formin Bni1. Eukaryot. Cell 4, 1712–1724 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82

    Bishop, A. et al. Hyphal growth in Candida albicans requires the phosphorylation of Sec2 by the Cdc28–Ccn1/Hgc1 kinase. EMBO J. 29, 2930–2942 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83

    Jones, L. A. & Sudbery, P. E. Spitzenkörper, exocyst and polarisome components in Candida albicans hyphae show different patterns of localization and have distinct dynamic properties. Eukaryot. Cell 9, 1455–1465 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    Virag, A. & Harris, S. D. The Spitzenkörper: a molecular perspective. Mycol. Res. 110, 4–13 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85

    Bartnicki-Garcia, S., Hergert, F. & Gierz, G. Computer-simulation of fungal morphogenesis and the mathematical basis for hyphal (tip) growth. Protoplasma 153, 46–57 (1989).

    Article  Google Scholar 

  86. 86

    Akashi, T., Kanbe, T. & Tanaka, K. The role of the cytoskeleton in the polarized growth of the germ tube in Candida albicans. Microbiology 140, 271–280 (1994).

    Article  PubMed  PubMed Central  Google Scholar 

  87. 87

    Hazan, I. & Liu, H. P. Hyphal tip-associated localization of Cdc42 is F-actin dependent in Candida albicans. Eukaryot. Cell 1, 856–864 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. 88

    Barton, R. & Gull, K. Variation in cytoplasmic microtubular organisation and spindle length between the two forms of the dimorphic fungus Candida albicans. J. Cell Sci. 91, 211–220 (1988).

    PubMed  PubMed Central  Google Scholar 

  89. 89

    Rida, P. C. G., Nishikawa, A., Won, G. Y. & Dean, N. Yeast-to-hyphal transition triggers formin-dependent golgi localization to the growing tip in Candida albicans. Mol. Biol. Cell 17, 4364–4378 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90

    Yokoyama, K., Kaji, H., Nishimura, K. & Miyaji, M. The role of microfilaments and microtubules in apical growth and dimorphism of Candida albicans. J. Gen. Microbiol. 136, 1067–1075 (1990).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. 91

    Reijnst, P., Walther, A. & Wendland, J. Functional analysis of Candida albicans genes encoding SH3-domain-containing proteins. FEMS Yeast Res. 10, 452–461 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. 92

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  93. 93

    Martin, R. et al. Functional analysis of Candida albicans genes whose Saccharomyces cerevisiae homologues are involved in endocytosis. Yeast 24, 511–522 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94

    Walther, A. & Wendland, J. Polarized hyphal growth in Candida albicans requires the Wiskott–Aldrich syndrome protein homolog Wal1p. Eukaryot. Cell 3, 471–482 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 95

    Borth, N. et al. Candida albicans Vrp1 is required for polarized morphogenesis and interacts with Wal1 and Myo5. Microbiology 156, 2962–2969 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. 96

    Oberholzer, U., Marcil, A., Leberer, E., Thomas, D. Y. & Whiteway, M. Myosin I is required for hypha formation in Candida albicans. Eukaryot. Cell 1, 213–228 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97

    Robertson, A. S., Smythe, E. & Ayscough, K. R. Functions of actin in endocytosis. Cell. Mol. Life Sci. 66, 2049–2065 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. 98

    Epp, E. et al. Forward genetics in Candida albicans that reveals the Arp2/3 complex is required for hyphal formation, but not endocytosis. Mol. Microbiol. 75, 1182–1198 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99

    Park, H. O. & Bi, E. F. Central roles of small GTPases in the development of cell polarity in yeast and beyond. Microbiol. Mol. Biol. Rev. 71, 48–96 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. 100

    Leberer, E., Thomas, D. Y. & Whiteway, M. Pheromone signalling and polarized morphogenesis in yeast. Curr. Opin. Genet. Dev. 7, 59–66 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. 101

    Bassilana, M., Hopkins, J. & Arkowitz, R. A. Regulation of the Cdc42/Cdc24 GTPase module during Candida albicans hyphal growth. Eukaryot. Cell 4, 588–603 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. 102

    Bassilana, M., Blyth, J. & Arkowitz, R. A. Cdc24, the GDP–-GTP exchange factor for Cdc42, is required for invasive hyphal growth of Candida albicans. Eukaryot. Cell 2, 9–18 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. 103

    Ushinsky, S. C. et al. CDC42 is required for polarized growth in the human pathogen Candida albicans. Eukaryot. Cell 1, 95–104 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. 104

    Court, H. & Sudbery, P. Regulation of Cdc42 GTPase activity in the formation of hyphae in Candida albicans. Mol. Biol. Cell 18, 265–281 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 105

    Zheng, X. D., Lee, R. T. H., Wang, Y. M., Lin, Q. S. & Wang, Y. Phosphorylation of Rga2, a Cdc42 GAP, by CDK/Hgc1 is crucial for Candida albicans hyphal growth. EMBO J. 26, 3760–3769 (2007). This paper provides the first example of a molecular mechanism in which a protein that is only expressed in hyphae promotes hyphal growth.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. 106

    Hausauer, D. L., Gerami-Nejad, M., Kistler-Anderson, C. & Gale, C. A. Hyphal guidance and invasive growth in Candida albicans require the Ras-like GTPase Rsr1p and its GTPase-activating protein Bud2p. Eukaryot. Cell 4, 1273–1286 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107

    Brand, A. et al. An internal polarity landmark is important for externally induced hyphal behaviors in Candida albicans. Eukaryot. Cell 7, 712–720 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. 108

    Dunkler, A. & Wendland, J. Candida albicans Rho-type GTPase-encoding genes required for polarized cell growth and cell separation. Eukaryot. Cell 6, 844–854 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Bassilana, M. & Arkowitz, R. A. Rac1 and Cdc42 have different roles in Candida albicans development. Eukaryot. Cell 5, 321–329 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. 110

    Hope, H., Bogliolo, S., Arkowitz, R. A. & Bassilana, M. Activation of Rac1 by the guanine nucleotide exchange factor Dck1 is required for invasive filamentous growth in the pathogen Candida albicans. Mol. Biol. Cell 19, 3638–3651 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. 111

    Brace, J., Hsu, J. & Weiss, E. L. Mitotic exit Control of the Saccharomyces cerevisiae Ndr/LATS kinase Cbk1 regulates daughter cell separation after cytokinesis. Mol. Cell Biol. 31, 721–735 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. 112

    Clemente-Blanco, A. et al. The Cdc14p phosphatase affects late cell-cycle events and morphogenesis in Candida albicans. J. Cell Sci. 119, 1130–1143 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. 113

    Gonzalez-Novo, A. et al. Sep7 is essential to modify septin ring dynamics and inhibit cell separation during Candida albicans hyphal growth. Mol. Biol. Cell 19, 1509–1518 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. 114

    Wang, A., Raniga, P. P., Lane, S., Lu, Y. & Liu, H. P. Hyphal chain formation in Candida albicans: Cdc28–Hgc1 phosphorylation of Efg1 represses cell separation genes. Mol. Cell Biol. 29, 4406–4416 (2009). This paper, together with reference 113, describes molecular mechanisms for the suppression of cell separation in hyphae

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. 115

    Anderson, J. & Soll, D. R. Differences in actin localization during bud and hypha formation in the yeast Candida albicans. J. Gen. Microbiol. 132, 2035–2047 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Kron, S. J., Styles, C. A. & Fink, G. R. Symmetrical cell-division in pseudohyphae of the yeast Saccharomyces cerevisiae. Mol. Biol. Cell 5, 1003–1022 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. 117

    Wightman, R., Bates, S., Amnorrattapan, P. & Sudbery, P. E. In Candida albicans, the Nim1 kinases Gin4 and Hsl1 negatively regulate pseudohypha formation and Gin4 also controls septin organization. J. Cell Biol. 164, 581–591 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. 118

    Berman, J. Morphogenesis and cell cycle progression in Candida albicans. Curr. Opin. Microbiol. 9, 595–601 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  119. 119

    Bachewich, C., Nantel, A. & Whiteway, M. Cell cycle arrest during S or M phase generates polarized growth via distinct signals in Candida albicans. Mol. Microbiol. 57, 942–959 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. 120

    Chapa y Lazo, B., Bates, S. & Sudbery, P. E. CLN3 regulates hyphal morphogenesis in Candida albicans. Eukaryot. Cell 4, 90–94 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  121. 121

    Atir-Lande, A., Gildor, T. & Kornitzer, D. Role for the SCFCDC4 ubiquitin ligase in Candida albicans morphogenesis. Mol. Biol. Cell 16, 2772–2785 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. 122

    Bachewich, C. & Whiteway, M. Cyclin Cln3p links G1 progression to hyphal and pseudohyphal development in Candida albicans. Eukaryot. Cell 4, 95–102 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  123. 123

    Bensen, E. S., Clemente-Blanco, A., Finley, K. R., Correa-Bordes, J. & Berman, J. The mitotic cyclins Clb2p and Clb4p affect morphogenesis in Candida albicans. Mol. Biol. Cell 16, 3387–3400 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  124. 124

    Chou, H., Glory, A. & Bachewich, C. Orthologues of the APC/C coactivators Cdc20p and Cdh1p are important for mitotic progression and morphogenesis in Candida albicans. Eukaryot. Cell 10, 696–709 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. 125

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  126. 126

    Umeyama, T. et al. Candida albicans protein kinase CaHsl1p regulates cell elongation and virulence. Mol. Microbiol. 55, 381–395 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. 127

    Wang, Y. CDKs and the yeast-hyphal decision. Curr. Opin. Microbiol. 12, 644–649 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  128. 128

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. 129

    Gutiérrez-Escribano, P. et al. Cdk-dependent phosphorylation of Mob2 is essential for hyphal development in Candida albicans. Mol. Biol. Cell 22, 2458–2469 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  130. 130

    Sinha, I. et al. Cyclin-dependent kinases control septin phosphorylation in Candida albicans hyphal development. Dev. Cell 13, 421–432 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. 131

    Li, C. R., Lee, R. T.-H., Wang, Y. M., Zheng, X. D. & Wang, Y. Candida albicans hyphal morphogenesis occurs in Sec3p-independent and Sec3p-dependent phases separated by septin ring formation. J. Cell Sci. 120, 1898–1907 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  132. 132

    McNemar, M. D. & Fonzi, W. A. Conserved serine/threonine kinase encoded by CBK1 regulates expression of several hypha-associated transcripts and genes encoding cell wall proteins in Candida albicans. J. Bacteriol. 184, 2058–2061 (2002). This paper is the first to demonstrate that Cbk1 is absolutely required for hyphal growth. The role of this kinase remains mysterious, but its action clearly critical for hyphal formation.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  133. 133

    Song, Y. et al. Role of the RAM network in cell polarity and hyphal morphogenesis in Candida albicans. Mol. Biol. Cell 19, 5456–5477 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  134. 134

    Nelson, B. et al. RAM: A conserved signaling network that regulates Ace2p transcriptional activity and polarized morphogenesis. Mol. Biol. Cell 14, 3782–3803 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. 135

    Jansen, J. M., Barry, M. F., Yoo, C. K. & Weiss, E. L. Phosphoregulation of Cbk1 is critical for RAM network control of transcription and morphogenesis. J. Cell Biol. 175, 755–766 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  136. 136

    Moyes, D. L. et al. A biphasic innate immune MAPK response discriminates between the yeast and hyphal forms of Candida albicans in epithelial cells. Cell Host Microbe 8, 225–235 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  137. 137

    Nucci, M. & Anaissie, E. Revisiting the source of candidemia: skin or gut? Clin. Infect. Dis. 33, 1959–1967 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  138. 138

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

    CAS  Article  Google Scholar 

  139. 139

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  140. 140

    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  Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    Drago, L. et al. Candida albicans cellular internalization: a new pathogenic factor? Int. J. Antimicrob. Agents 16, 545–547 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  142. 142

    Saville, S. P., Lazzell, A. L., Monteagudo, C. & Lopez-Ribot, J. L. Engineered control of cell morphology in vivo reveals distinct roles for yeast and filamentous forms of Candida albicans during infection. Eukaryot. Cell 2, 1053–1060 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  143. 143

    Noble, S. M., French, S., Kohn, L. A., Chen, V. & Johnson, A. D. Systematic screens of a Candida albicans homozygous deletion library decouple morphogenetic switching and pathogenicity. Nature Genet. 42, 590–598 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  144. 144

    Gladfelter, A. S. & Sudbery, P. E. in The Septins (eds. Hall, P. A., Russell, S. E. & Pringle, J. R.) 125–146 (Wiley-Blackwell, Chichester, 2008).

    Google Scholar 

  145. 145

    Evangelista, M., Pruyne, D., Amberg, D. C., Boone, C. & Bretscher, A. Formins direct Arp2/3-independent actin filament assembly to polarize cell growth in yeast. Nature Cell Biol. 4, 32–41 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  146. 146

    Pruyne, D. Role of formins in actin assembly: nucleation and barbed-end association. Science 297, 612–615 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  147. 147

    Sagot, I., Klee, S. K. & Pellman, D. Yeast formins regulate cell polarity by controlling the assembly of actin cables. Nature Cell Biol. 4, 42–50 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  148. 148

    Sheu, Y. J., Santos, B., Fortin, N., Costigan, C. & Snyder, M. Spa2p interacts with cell polarity proteins and signaling components involved in yeast cell morphogenesis. Mol. Cell Biol. 18, 4053–4069 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  149. 149

    Riedl, J. et al. Lifeact: a versatile marker to visualize F-actin. Nature Methods 5, 605–607 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Work in the author's laboratory is supported by the UK Biotechnology and Biological Sciences Research Council grant BB-F007892.

Author information

Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Supplementary information

Supplementary information S1 (table)

List of hyphal induced genes. (PDF 107 kb)

Supplementary information S2 (movie)

Continuous presence of the Spitzenkörper at the hyphal tip. (MPG 12901 kb)

Supplementary information S3 (movie)

Secretory vesicles stream towards the tip. (AVI 294 kb)

Supplementary information S4 (movie)

Enlargement of the Spitzenkörper. (MPG 1195 kb)

Related links

Related links

FURTHER INFORMATION

Peter E. Sudbery's homepage

Glossary

Genetic toolbox

Describing methods that can be used to investigate Candida albicans. As C. albicans is an obligate diploid, to generate null strains it is necessary to delete both copies of a gene, designated −/− in this Review. Strains with multiple auxotrophic markers have facilitated the generation of null strains. Other advances include using gene fusion to generate fluorescent and epitope-tagged proteins, and regulatable promoters.

Germ tube

In this Review, a narrow, tube-like projection from a mother yeast cell that forms up to the end of the first cell cycle when an unbudded yeast cell is placed in hypha-inducing conditions.

Septins

A family of related proteins that form structures consisting of heteromeric filaments; first identified in Saccharomyces cerevisiae, in which they form a ring at the bud neck. Just before cytokinesis, the ring splits in two and this organizes the formation of the septum. The septin ring also acts as a diffusion barrier to the movement of proteins along the inner side of the plasma membrane.

v-SNAREs

(Vesicle-membrane soluble N-ethyl-maleimide-sensitive attachment protein receptors). Highly α-helical proteins that mediate the specific fusion of vesicles with target membranes. SNAREs have been classified into two complementary classes that are referred to as vesicle-membrane SNAREs (v-SNAREs) and target-membrane SNAREs (t-SNAREs).

Thigomotropism

The ability of hyphae to sense and grow along topographical cues in the environment such as cracks and ridges. This ability may help growth towards entry points in epithelia and endothelia.

Galvanotropism

The ability to sense and orientate along an electric field; Candidia albicans hyphae grow towards the cathode.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sudbery, P. Growth of Candida albicans hyphae. Nat Rev Microbiol 9, 737–748 (2011). https://doi.org/10.1038/nrmicro2636

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

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