Mechanisms of Host Adaptation for Candida albicans

描述（由申请人提供）：专性寄生生物白色念珠菌定植于其人类宿主的肠道，通常不会引起疾病。然而，免疫功能低下的个体有可能获得源自该微生物群落的机会性感染。因此，清楚地了解从细菌到病原体的转变是公共卫生的当务之急。在真菌病原体如新型隐球菌和烟曲霉中，膜结合固醇调节元件结合蛋白（SREBP）是宿主适应和毒力所需的关键低氧转录因子。在哺乳动物细胞中，SREBP调节脂质稳态。C.白色念珠菌具有称为Cph 2的SREBP同源物，但已知的SREBP功能如毒力、缺氧反应和固醇稳态调节不需要CPH 2。然而，C.白色念珠菌宿主肠道定植需要Cph 2，表明Cph 2控制着一个不确定的转录程序，这对念珠菌病至关重要。 在哺乳动物细胞和担子菌C. SREBP蛋白水解需要高尔基体位点-1和位点-2蛋白酶。然而，子囊菌如C.白色念珠菌缺乏位点2蛋白酶。我们最近在粟酒裂殖酵母中的工作鉴定了SREBP激活所需的高尔基体E3连接酶复合物。C.白色念珠菌含有该SREBP切割缺陷（Dsc）E3连接酶复合物中所有亚基的同系物。 在这里，我们将我们对SREBP和Dsc E3连接酶复合物的研究带到了C。白色念珠菌由于宿主环境的性质，产生了一个生态位，为这个专性寄生虫是未知的，我们将重点放在C。白色念珠菌宿主肠道定植。了解定殖的特定要求将允许在肠道和致病环境之间进行比较，阐明治疗和治疗C的潜在靶点。白色念珠菌感染 我们假设C.白色念珠菌SREBP Cph 2是宿主肠道定殖过程中基因表达所需的主要转录因子，并且保守的Dsc E3连接酶复合物通过介导Cph 2活化而在肠道定殖中起作用。我们的具体目标是：目标1。确定Cph 2在肠道定植过程中的转录靶点。AIM 2.测试Cph 2在肠道定植中的功能是否需要切割和DNA结合。 宿主肠道中Cph 2转录靶点的鉴定是了解白色念珠菌栖息的宿主环境的第一步。我们的研究将产生用于识别小鼠肠道中真菌基因表达程序的协议，为其他转录网络的研究提供蓝图。

DESCRIPTION (provided by applicant): The obligate commensal organism Candida albicans colonizes the intestinal tract of its human host, and normally causes no disease. However, immunocompromised individuals risk acquiring opportunistic infections originating from this commensal population of microflora. Thus, a clear understanding of the transition from commensal to pathogen is a public health imperative. In fungal pathogens such as Cryptococcus neoformans and Aspergillus fumigatus, the membrane-bound sterol regulatory element binding protein (SREBP) is a key hypoxic transcription factor required for host adaptation and virulence. In mammalian cells, SREBPs regulate lipid homeostasis. C. albicans has an SREBP homolog called Cph2, but known SREBP functions such as virulence, the hypoxic response, and regulation of sterol homeostasis do not require CPH2. However, C. albicans host intestinal colonization requires Cph2, suggesting that Cph2 controls an undefined transcriptional program essential for commensalism. In mammalian cells and the basidiomycete C. neoformans, SREBP proteolysis requires the Golgi Site-1 and Site-2 proteases. However, ascomycetous fungi like C. albicans lack the Site-2 protease. Our recent work in Schizosaccharomyces pombe identified a Golgi E3 ligase complex required for SREBP activation. C. albicans contains homologs of all subunits in this Defective for SREBP Cleavage (Dsc) E3 ligase complex. Here, we bring our studies of SREBP and the Dsc E3 ligase complex to C. albicans. Because the qualities of the host environment that generate a niche for this obligate commensal are unknown, we will focus on C. albicans host intestinal colonization. Knowing specific requirements for colonization will allow comparison between the commensal and the pathogenic environments, elucidating potential targets for therapeutics and treatment of C. albicans infections. We hypothesize that the C. albicans SREBP Cph2 is a principal transcription factor required for gene expression during host intestinal colonization and that the conserved Dsc E3 ligase complex functions in intestinal colonization by mediating Cph2 activation. Our specific aims are: AIM 1. To determine the transcriptional targets of Cph2 during intestinal colonization. AIM 2. To test whether Cph2 function in intestinal colonization requires cleavage and DNA binding. Identification of Cph2 transcriptional targets in the host intestine represents the first step toward understanding the host environment that Candida albicans inhabits. Our studies will yield protocols for the identification of fungal gene expression programs in the mouse intestine, providing a blueprint for studies of other transcriptional networks.