Targeted changes of the cell wall proteome influence Candida albicans ability to form single- and multi-strain biofilms

Vitor Cabral, Sadri Znaidi, Louise A Walker, Hélène Martin-Yken, Etienne Dague, Mélanie Legrand, Keunsook Lee, Murielle Chauvel, Arnaud Firon, Tristan Rossignol, Mathias L Richard, Carol A Munro, Sophie Bachellier-Bassi, Christophe d'Enfert

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Biofilm formation is an important virulence trait of the pathogenic yeast Candida albicans. We have combined gene overexpression, strain barcoding and microarray profiling to screen a library of 531 C. albicans conditional overexpression strains (∼10% of the genome) for genes affecting biofilm development in mixed-population experiments. The overexpression of 16 genes increased strain occupancy within a multi-strain biofilm, whereas overexpression of 4 genes decreased it. The set of 16 genes was significantly enriched for those encoding predicted glycosylphosphatidylinositol (GPI)-modified proteins, namely Ihd1/Pga36, Phr2, Pga15, Pga19, Pga22, Pga32, Pga37, Pga42 and Pga59; eight of which have been classified as pathogen-specific. Validation experiments using either individually- or competitively-grown overexpression strains revealed that the contribution of these genes to biofilm formation was variable and stage-specific. Deeper functional analysis of PGA59 and PGA22 at a single-cell resolution using atomic force microscopy showed that overexpression of either gene increased C. albicans ability to adhere to an abiotic substrate. However, unlike PGA59, PGA22 overexpression led to cell cluster formation that resulted in increased sensitivity to shear forces and decreased ability to form a single-strain biofilm. Within the multi-strain environment provided by the PGA22-non overexpressing cells, PGA22-overexpressing cells were protected from shear forces and fitter for biofilm development. Ultrastructural analysis, genome-wide transcript profiling and phenotypic analyses in a heterologous context suggested that PGA22 affects cell adherence through alteration of cell wall structure and/or function. Taken together, our findings reveal that several novel predicted GPI-modified proteins contribute to the cooperative behaviour between biofilm cells and are important participants during C. albicans biofilm formation. Moreover, they illustrate the power of using signature tagging in conjunction with gene overexpression for the identification of novel genes involved in processes pertaining to C. albicans virulence.

Original languageEnglish
Article numbere1004542
Number of pages21
JournalPLoS Pathogens
Issue number12
Publication statusPublished - 11 Dec 2014

Bibliographical note

Funding: This work has been supported by the European Commission (EURESFUN, LSHM-CT-2005-518199; Galar Fungail 2, MRTN-CT-2003-504148; FINSysB, PITN-GA-2008-214004) and Agence Nationale de la Recherche (KANJI, ANR-08-MIE-033-01) to CE and the Wellcome Trust (The Candida albicans ORFeome project, WT088858MA) to CM and Cd. Oligonucleotide synthesis and plasmid sequencing were supported by Pasteur-Génopole-Ile-de-France. VC was the recipient of a PhD fellowship of the European Commission (FINSysB, PITN-GA-2008-214004). SZ was the recipient from post-doctoral fellowships of the European Commission (FINSysB, PITN-GA-2008-214004) and Agence Nationale de la Recherche (KANJI, ANR-08-MIE-033-01). ML was the recipient of a post-doctoral fellowship of Institut Pasteur (Bourse Roux). TR was the recipient of a post-doctoral fellowship from the European Commission (EURESFUN, LSHM-CT-2005-518199). CM acknowledges financial support from a Medical Research Council New Investigator Award (G0400284). ED acknowledges financial support of a young scientist program of Agence Nationale de la Recherche (AFMYST project ANR-11-JSV5-001-01 n° SD 30024331). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


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