Saturday, September 7, 2024
9/7/2024
PROJECT SUMMARY/ABSTRACT Candida albicans is the number one cause of life-threatening fungal infections in hospitals. A key virulence attribute of C. albicans is the ability to switch between multiple distinct cellular forms that are adapted to unique environmental niches. Heritable yet reversible differentiation between “white” and “opaque” cell types generates two distinct pathogenic forms of C. albicans derived from a single genome, with differential expression of nearly one in five genes in the organism. Most virulence studies in C. albicans have focused on the white cell type since most strains were believed to be incapable of switching to the opaque state without first undergoing chromosomal rearrangements; however, this assumption has recently been shown to be untrue. Although opaque cells have long been known to be far more adept at infecting skin than white cells, very little is known about the unique virulence attributes of the opaque cell type, or how stochastic switching between the white and opaque cell types contributes to the progression of an infection. Instead, our understanding of the white-opaque switch has largely focused on the transcriptional regulatory network that controls the heritable differentiation between these two cell types. This network bears a striking resemblance to similar networks that control cellular differentiation in higher eukaryotes; however, equivalent programs are not found in other model yeasts like Saccharomyces cerevisiae or Schizosaccharomyces pombe, making C. albicans an attractive “simple” eukaryotic organism to study how complex transcriptional programs are established and inherited from one generation to the next. We propose to use a recently developed planarian model of infection, which reveals similar opaque-specific virulence characteristics as the mouse skin model, to identify opaque-specific virulence genes. Combined with our recently developed fluorescent switch-reporter strains, we will also investigate the yet unexplored contribution of stochastic white-opaque switching to C. albicans virulence. These approaches are tailored to enable undergraduate researchers to easily gain hands-on experience with animal models of fungal pathogenesis and contribute to our understanding of an understudied aspect of C. albicans virulence while simultaneously avoiding the high cost and added complications of vertebrate animal models. We have also found that Wor1, the master regulator of the opaque cell type, forms large macromolecular condensates in the nuclei of opaque cells, and we propose to use ultra-high resolution fluorescence imaging combined with molecular genetics approaches to characterize these protein condensates and determine their role in the establishment and heritable maintenance of the opaque cell type. Together these approaches will provide novel insights into the transcriptional regulatory control of stochastic white-opaque switching, identify opaque-specific virulence genes, and inform how switching between these two differentiated cell types contributes to epithelial adhesion and damage, and progression to invasive candidiasis.
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