Hypha-to-yeast morphogenetic step in C. albicans

描述（由申请人提供）：白色念珠菌是人类最常分离的侵袭性真菌病原体。在美国，念珠菌是住院成人血液感染的第四大常见原因，也是儿童血液感染的第三大常见原因。38 - 49%的成人和19.6%的儿童死于这种感染。念珠菌的形态发生从卵形酵母形式到丝状菌丝形式的生长转变是一个深入研究的课题。相反的形态发生步骤，从菌丝到酵母的生长形式，却很少受到关注。无论是在体外还是在人体组织中，这种真菌都在不断地从菌丝形态转变为酵母形态。五种白色念珠菌基因需要的细丝到酵母的形态发生步骤已经在动物研究中进行了测试。这些都是念珠菌的毒力所必需的。此外，在宿主中以酵母菌形式生长的其他真菌比白色念珠菌的毒性更强，而在宿主组织中以菌丝形式生长的真菌的毒性较小。

DESCRIPTION (provided by applicant): 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.