Candida albicans is a leading fungal pathogen, causing over 10,000 lethal invasive infections per year in the US. This organism can grow in several morphological forms, notably budding yeast and hyphae. Hyphae are prominent in infected tissue, and many lines of evidence indicate that the program of hyphal formation is required for pathogenicity during invasive infection. C. albicans is surrounded by a cell wall that is the target of echinocandin antifungals, which are used clinically, as well as several other therapeutic strategies under development. The organism's response to stress caused by cell wall inhibitors enables it to survive echinocandin treatment. Defects in known cell wall stress response regulators, such as the conserved Cell Wall Integrity MAP Kinase pathway components, cause C. albicans to become hypersensitive to echinocandins. The yeast and hyphal growth forms differ considerably in cell wall constituents. For example, the highly expressed yeast-specific gene YWP1 encodes a cell wall protein; the highly expressed hyphal-specific genes ALS3, HWP1, and HYR1 encode cell wall proteins. On this basis we suspected that the cell wall stress response may differ between yeast and hyphae. To date, the response to cell wall stress has been characterized primarily in yeast-form C. albicans cells. Because of the role of hyphae in pathogenesis, we hypothesize that the cell wall stress response in hyphal cells may be significant for its relevance to drug therapy and, potentially, for enabling resistance to arise. Our preliminary results have revealed unique features of the cell wall stress response in hyphae. First, RNASeq data show that the hyphal gene expression response to echinocandin treatment is distinct from that observed in yeast-form cells. Second, we have found that the transcription factor Cup9 is required for echinocandin tolerance in hyphae, but not in yeast. A cup9?/? mutant fails to express ~10% of the hyphal echinocandin-inducible genes, thus suggesting that additional transcription factors mediate the hyphal cell wall stress gene expression response. We propose to extend our studies through three specific aims. First, we will determine the functional role of the hyphal cell wall stress transcriptional response. Second, we will determine which regulators govern the hyphal cell wall stress transcriptional response. Third, we will determine which hyphal cell wall proteins influence functional aspects of the hyphal cell wall stress response.
Candida albicans is a major invasive fungal pathogen. It is encased in a cell wall that is the target of antifungal drugs in the clinic and in development. The organism can grow as hyphae, which are long tubular cells attached end-to-end, and are prominent in infected tissue. Our studies seek to define how hyphae respond to cell wall inhibition.
