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

Key Points

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

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

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

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

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

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

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

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

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

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

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

Abstract

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

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

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Acknowledgements

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

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Correspondence to Judith Berman.

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DATABASES

European Candida Database

Abp1

arg4

Cph1

Czf1

efg1

his1

HWP1

ICL1

INT1

MAD2

Mig1

MLS1

Nrg1

RBT1

Rim101

SAP4

SAP5

SAP6

spt3

Tup1

URA3

Saccharomyces Genome Database

Cdc28

Clb2

Cln1

Cln2

Fkh1

Fkh2

MATa1

MATα1

MATα2

Ste12

URA3

FURTHER INFORMATION

Candida albicans Genome Information

Candida Genome Sequencing Project

European Candida Database

MicroArray Lab, National Research Council of Canada

Stanford Genome Technology Center

Glossary

OPPORTUNIST

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

COMMENSAL

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

CANDIDIASIS

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

FUNGISTATIC

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

FUNGICIDAL

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

CHLAMYDOSPORES

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

SEPTIN

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

GERM TUBE

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

AUXOTROPHIC

Requiring a nutritional supplement to grow.

PROTOTROPH

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

FLP/FRT SYSTEM

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

PHAGOLYSOSOME

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

GLYOXYLATE CYCLE

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

PHENOTYPIC SWITCHING

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

CRENULATED

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

ISOTROPIC

Growth in all directions (opposite of polarized growth).

SPINDLE POLE BODY

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

CHECKPOINT PROTEIN

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

ASCOMYCETE

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

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

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