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Genetic control of Candida albicans biofilm development

Key Points

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

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

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

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

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

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

Abstract

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

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

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Acknowledgements

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

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

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Glossary

Pseudohypha

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

Quorum sensing

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

Ergosterol

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

Azole

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

Polyene

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

Persister

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

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

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