The proposed research will continue to use Wangiella dermatitides as a model to study cell-wall related virulence factors among dematiaceous (melanized) fungal pathogens of humans. Previous results suggest that this polymorphic fungus is a model for phaeohyphomycosis infections. The emphasis of this application is on the cell wall given that: it is the boundary between the pathogen and host; it is the determinant for morphology; contains virulence factors; and is an attractive potential target for antifungal agent design. The focus of these studies are systems leading to chitin localization and melanin enrichment of cell walls in the polarized and non-polarized vegative phenotypes expressed under conditions associated with human infection. The proposed research is designed to provide information about four chitin synthase (WdCHS) genes of W. dermatitides and in particular it unique Class III-type gene, WdCHS3 which has no homolog in S. cerevisiae or C. albicans contribute to pathogenicity. WdCHS3 is significantly overexpressed at 37 C and loss of its product's function results in decreased virulence and does inhibition of melanization.
The specific aims of this proposal are: 1) to study the WdCHS genes, establish how their expression is regulated and identify factors that control the time, place and function of their products with a focus on the mechanisms involve in the temperature-induced overexpression of WdCHS3 (a Class III-type gene) at 37 C and by other conditions hypothesized to influence the growth, development, and differentiation of W. dermatitidis during these infections; 2) to establish the individual and collective importance of the four WdCHs isozymes and their chitin products to yeast, isotropic and huphal growth and their contributions to pathogenicity and virulence and augmented by melanin and by transient or prolonged periods of isotropic enlargement and with a focus on the potential for WdChs3p (a class III-type isozyme) to be a particularly vulnerable antifungal target.
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