Critical Role of Bcr1-Dependent Adhesins in C. albicans Biofilm Formation In Vitro and In Vivo

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Abstract
The fungal pathogen Candida albicans is frequently associated with catheter-based infections because of its ability to form resilient biofilms. Prior studies have shown that the transcription factor Bcr1 governs biofilm formation in an in vitro catheter model. However, the mechanistic role of the Bcr1 pathway and its relationship to biofilm formation in vivo are unknown. Our studies of biofilm formation in vitro indicate that the surface protein Als3, a known adhesin, is a key target under Bcr1 control. We show that an als3/als3 mutant is biofilm-defective in vitro, and that ALS3 overexpression rescues the biofilm defect of the bcr1/bcr1 mutant. We extend these findings with an in vivo venous catheter model. The bcr1/bcr1 mutant is unable to populate the catheter surface, though its virulence suggests that it has no growth defect in vivo. ALS3 overexpression rescues the bcr1/bcr1 biofilm defect in vivo, thus arguing that Als3 is a pivotal Bcr1 target in this setting. Surprisingly, the als3/als3 mutant forms a biofilm in vivo, and we suggest that additional Bcr1 targets compensate for the Als3 defect in vivo. Indeed, overexpression of Bcr1 targets ALS1, ECE1, and HWP1 partially restores biofilm formation in a bcr1/bcr1 mutant background in vitro, though these genes are not required for biofilm formation in vitro. Our findings demonstrate that the Bcr1 pathway functions in vivo to promote biofilm formation, and that Als3-mediated adherence is a fundamental property under Bcr1 control. Known adhesins Als1 and Hwp1 also contribute to biofilm formation, as does the novel protein Ece1. The formation of biofilms (surface-attached microbial communities) on implanted medical devices such as catheters is a major cause of fungal and bacterial infections. Prior studies of the fungal pathogen Candida albicans have shown that the regulator Bcr1 is required for biofilm formation in vitro, but the mechanism through which it promotes biofilm formation and its significance for biofilm formation in vivo was uncertain. The authors demonstrate that Bcr1 is required for biofilm formation in vivo in a rat model of catheter-based infection. Manipulation of Bcr1 target genes through mutation and gene overexpression shows that the known surface adhesin Als3 has a pivotal role in biofilm formation and that adhesins Als1 and Hwp1 also contribute to biofilm formation. The results thus indicate that adherence is the key property regulated by Bcr1 and highlight a group of adhesins as potential therapeutic targets.