title: Critical role of Bcr1-dependent adhesins in C. albicans biofilm formation in vitro and in vivo.
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.
authors.affiliation: Department of Microbiology, Columbia University, New York, New York, USA.
authors.forename: Clarissa J
authors.initials: CJ
authors.lastname: Nobile
authors.forename: David R
authors.initials: DR
authors.lastname: Andes
authors.forename: Jeniel E
authors.initials: JE
authors.lastname: Nett
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Smith
authors.forename: Fu
authors.initials: F
authors.lastname: Yue
authors.forename: Quynh-Trang
authors.initials: QT
authors.lastname: Phan
authors.forename: John E
authors.initials: JE
authors.lastname: Edwards
authors.forename: Scott G
authors.initials: SG
authors.lastname: Filler
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D018441:Biofilms / Q000254:growth & development*; D002176:Candida albicans / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D002177:Candidiasis / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D002404:Catheterization / Q000009:adverse effects; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000502:physiology*; D005656:Fungal Proteins / Q000235:genetics / Q000502:physiology*; D015966:Gene Expression Regulation, Fungal; D005800:Genes, Fungal / Q000502:physiology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C109455:ALA1 protein, Candida albicans; C093538:ALS1 protein, Candida albicans; C113620:ALS3 protein, Candida albicans; D015815:Cell Adhesion Molecules; C082909:ECE1 protein, Candida albicans; D005656:Fungal Proteins; C118102:HWP1 protein, Candida albicans; D008562:Membrane Glycoproteins; D051562:Proto-Oncogene Proteins c-bcr