Regulation of Candida Dimorphism

Kink, Gerald

Abstract

Candida species are important agents of AIDS-related disease. Candida, like the related yeast Saccharomyces cerevisiae, is capable of switching between pseudohyphal and budding growth. In Candida, the ability to grow both in the yeast and pseudohyphal form has been strongly implicated in the ability to the organism to act as a pathogen. Work in the Timberlake and Fink laboratories has led to the identification of S. cerevisiae and Aspergillus nidulans genes that enhance pseudohyphal growth when overexpressed in S. cerevisiae. The high degree of conservation among genes from divergent fungal species suggests that homologous genes are involved in the control of dimorphism in Candida. The primary objective of this proposal is to test this hypothesis and to isolate and characterize the genes that regulate dimorphic switching in this human pathogen. Initially, we will test the S. cerevisiae and A. nidulans regulatory genes for their activities in Candida. Then, we will clone the homologous Candida genes and confirm that their overexpression has similar effects on growth form. Subsequently, we will construct strains containing null mutations of the genes to determine if the cells can be locked into one or the other growth form. If so, mutant strains will be tested for pathogenicity in a mouse model. Finally, as a prelude to future studies of the regulatory pathways(s) controlling dimorphism, we will determine patterns of gene expression for the known genes. The information obtained will be of basic value for understanding the biology of Candida pathogenesis. Moreover, the products of the regulatory genes we will identify may serve as targets for identification of novel antibiotics. Myco Pharmaceutical is in an excellent position to utilize the results from our studies to construct and utilize yeast strains for screening potential antibiotic compounds.