AIDS OPPORTUNISTIC INFECTIONS--VIRULENCE OF C GLABRATA

描述（改编自申请人摘要）：在HIV阳性人群中，阴道和食管念珠菌病的第二常见原因是光滑念珠菌。这在一定程度上是由于光棘球蚴对唑类药物的相对抗性。在重症监护室中也普遍存在光滑锥虫。光叶蛾与寄主的相互作用尚不清楚。本研究的目的是分析光棘球蚴与寄主的分子相互作用，并确定其毒力因子。分子和遗传操作是可能的，并使其更容易的事实是单倍体的光棘。研究者产生了随机插入突变体，并制定了一种策略，以筛选多达96个突变体并行在一个单一的池。利用这种策略，他已经确定了EPA1基因，这是一种介导与宿主细胞表面碳水化合物结合的粘附素。在本提案中，他将描述这种粘附素的配体特异性、结构域结构和亚细胞定位。遗传和分子方法将用于鉴定其他粘附素，最终目的是表征大多数与宿主-细胞相互作用相关的光棘粘附素。在EPA1分析中开发的遗传工具允许对毒性进行广泛的遗传分析。研究者将在小鼠粘膜和全身念珠菌病模型中直接筛选无毒突变体。一些次级筛选将识别那些与特定宿主分子离散相互作用的突变体。

DESCRIPTION (Adapted from the Applicant's Abstract): In the HIV- positive population, the second most frequent cause of vaginal and esophageal candidiasis is Candida glabrata. This is in part due to the relative resistance of C. glabrata to azole therapeutics. C. glabrata is also prevalent in ICUs. The interaction of C. glabrata with the host is not well understood. The objective of this proposal is to analyze the molecular interactions of C. glabrata with its host and to identify virulence factors in C. glabrata. Molecular and genetic manipulation is possible in C. glabrata, and is made easier by the fact that C. glabrata is haploid. The investigator has generated random insertion mutants and developed a strategy to screen up to 96 mutants in parallel in a single pool. Using this strategy, he has identified the EPA1 gene, an adhesin mediating binding to carbohydrates on the cell surface of the host. In this proposal, he will characterize this adhesin's ligand specificity, domain structure and sub-cellular localization. Genetic and molecular approaches will be used to identify other adhesins, with the eventual aim to characterize the majority of C. glabrata adhesins relevant to the host-cell interaction. The genetic tools developed in the analysis of EPA1 allow for a broad genetic analysis of virulence. The investigator will screen directly for avirulent mutants in murine models of mucosal and systemic candidiasis. A number of secondary screens will identify those mutants involved in discrete interactions with specific host molecules.