Candida albicans is the main etiologic agent of oral candidiasis. Individuals most at risk for developing this mucosal infection are those with compromised immune systems or people with other predisposing factors. Symptoms of oral candidiasis can be severe, leading to a poor quality of life for these patients. Drug resistant strains of C. albicans are also emerging, making this oral fungal pathogen even more difficult to treat. One of the essential virulence properties that allows C. albicans to cause disease is its ability to reversibly switch morphology from budding yeast cells to pseudohyphal and hyphal filaments. The long term goal of our research is to gain a better understanding of the C. albicans virulence property, morphological switching, in order to develop new antifungal therapies to treat oral fungal infections. Currently, it is thought that the pseudohyphal and hyphal morphologies are determined by distinetgene sets, however direct evidence is lacking. The molecular mechanisms that control hyphal growth are not well defined. We have now generated a strain that allows us to explore these questions. Recently, our lab identified a novel filament-specific transcriptional regulator, Ume6, which is important for hyphal extension and filament-specific gene expression. We found that when UME6 is expressed at high constitutive levels, C. albicans grows as a nearly complete hyphal population. During an infection, we observed that high-level constitutive UME6 expression is sufficient to promote virulence. Interestingly, we observed that lower levels of UME6 expression resulted in a majority pseudohyphal population. We found that UME6 levels differentially regulated the expression of several known filament-specific genes. Our hypothesis is that UME6 levels determine C. albicans morphology in a dosage-dependent manner by up-regulating overlapping subset of filament-specific genes, including genes required for proper hyphal formation. In order to test this hypothesis, we will carry out experiments designed to accomplish the following aims: 1) determine the gene expression profile of C. albicans growing as pseudohyphal and hyphal morphologies specified by UME6 expression levels, 2) determine the role of UME6 in the regulation of the molecular mechanisms that specify proper hyphal growth. Public Health Relevance: At the completion of our studies, we expect to have a more in-depth knowledge of C. albicans morphological switching, which may lead to the development of more effective antifungal therapies to treat oral disease. Candida albicans causes severe oral disease, leading to a poor quality of life. The proposed study will increase our understanding of a property that is essential to the ability of C. albicans to cause disease.
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|Thompson, Delma S; Carlisle, Patricia L; Kadosh, David (2011) Coevolution of morphology and virulence in Candida species. Eukaryot Cell 10:1173-82|
|Carlisle, Patricia L; Kadosh, David (2010) Candida albicans Ume6, a filament-specific transcriptional regulator, directs hyphal growth via a pathway involving Hgc1 cyclin-related protein. Eukaryot Cell 9:1320-8|