Candida albicans is a major human fungal pathogen, causing both mucosal and deep tissue infections. A significant risk factor for C. albicans infection is the presence of an implanted medical device, which provides a surface for biofilm formation. The biofilm creates a protected microenvironment for survival of the pathogen. The immediate goal of studies here proposed is to define the key C. albicans genes and regulatory pathways that govern biofilm formation, with the long-term objective of developing new treatment strategies based upon this understanding. We have implemented a new strategy for analysis of unique C. albicans traits: a transcription factor function survey. With this strategy, we create strains with defects in each transcription factor gene and test the strains for phenotypic defects. We then use microarray analysis to identify target genes that have a direct role in phenotype under study. We have thus far tested homozygous insertion mutants in each of 84 transcription factor genes for biofilm defects. Zinc-finger protein Bcr1 p is required for biofilm formation and for expression of a group of surface protein genes and adhesins. We will analyze single and multiple target gene mutants as well as overexpressing strains in assays for biofilm formation. In addition, we will identify target genes for additional biofilm regulators that we define in our screen. Target genes will be subjected to functional analysis. Finally, we will test our in vitro results with a rat central venous catheter model for biofilm formation in vivo. Attributes including viable burden, biofilm architecture, and gene expression profiles will be monitored.
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