Candida albicans is the most frequently isolated invasive fungal pathogen of humans. Candida species are the fourth most common cause of bloodstream infections in hospitalized adults, and the third most common cause of such infections in children in the United States. 38 - 49% of adults, and 19.6% of children with such an infection die. Candida's morphogenetic switch from the oval yeast form to the filamentous hyphal form of growth is a subject of intense investigation. The opposite morphogenetic step, from the hyphal to the yeast form of growth, has received surprisingly little attention. Both in vitro and in human tissue the fungus constantly switches from hyphal to yeast-form growth. Five C. albicans genes required for the filament-to-yeast morphogenetic step have been tested in animal studies. All are required for Candida's virulence. Moreover, other fungal species which grow exclusively as yeast in the host are more virulent than C. albicans, while species which grow exclusively as hyphae in host tissue are less virulent. Here, the first systematic investigation of the hypha-to-yeast morphogenetic step of C. albicans is proposed. A forward genetic approach will be used, by performing a genome-wide screen for molecules that are required for this developmental step in C. albicans. This screen will be accomplished with two novel genetic tools adapted in preliminary experiments for use in C. albicans, a dominant selectable marker and a maximally random transposon system. In pilot experiments using these tools, mutants impaired in the hypha-to-yeast switch have already been isolated, and genetic elements disrupted by the transposon in these mutants have been identified. In addition to screening a mutant collection created with our novel tools, it is proposed to utilize available homozygous and heterozygous mutant collections. Studies of Candida morphogenesis have principally relied on investigation of homologs of relevant Saccharomyces cerevisiae genes. However, the demands on C. albicans and S. cerevisiae made by their respective environments are very different. Conserved regulatory modules have been found to control divergent outputs between the two organisms. With the forward genetic approach proposed here, previously unknown regulatory circuits in C. albicans are expected to be identified. This work will lay the foundation for in-depth studies of the mechanisms of hypha-to-yeast morphogenesis in C. albicans. It is hoped that a better understanding of this critical element of virulence will lead to new strategies for therapeutic intervention.
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