Pathobiology of C. neoformans in the Central Nervous System

描述（由申请人提供）：本次竞争性更新将继续我们从酵母菌的角度了解中枢神经系统（CNS）隐球菌病的病理生理学的工作。新型隐球菌和格特隐球菌代表包囊化的担子菌酵母，它们每年产生一百万例疾病，估计目前的治疗导致60万人死亡。隐球菌是嗜神经性的，引起隐球菌脑膜脑炎，这是这种疾病感染的危及生命的阶段。目的1将不仅定义隐球菌临床分离株对人CNS的体内转录应答，而且还将鉴定对酵母在CNS中生长和存活能力有显著贡献的基因和基因途径。此外，我们将根据患者结局（或多或少的毒性）、基因型和其他变量来表征这些反应，以鉴定可能有助于CNS中菌株适应以产生疾病的保守基因。将使用稳健的试验评估这些基因的影响，这些试验检查了它们对人CSF中存活率、毒力决定因素和动物模型中存活率的影响。目标2继续我们的重点分析如何核心代谢促进隐球菌生长和生存在中枢神经系统通过调查碳和氮代谢。该应用整合了先进的分子技术，通过我们先前的研究对真菌的见解，以及与人类疾病和结果的密切联系。其目标是解剖，识别和验证CNS中酵母应激反应中的“薄弱”点，从而为抗真菌策略提供新的靶标，这些策略在治疗这种危及生命的真菌感染方面仍然基本失败。

DESCRIPTION (provided by applicant): This competitive renewal will continue our work on understanding the pathophysiology of cryptococcal disease in the central nervous system (CNS) from the yeast's perspective. Cryptococcus neoformans and Cryptococcus gattii represent encapsulated basidiomycetous yeasts that produce a million cases of disease per year and an estimated 600, 000 deaths with present treatment. Cryptococcus is neurotropic causing cryptococcal meningoencephalitis, the life-threatening stage of infection for this disease. Aim 1 will not only define the in vivo transcriptional response of Cryptococcus clinical isolates to human CNS, but it will also identify gene(s) and gene pathway(s) that contribute significantly to the yeasts ability to grow and survive in the CNS. Furthermore, we will characterize these responses based on patient outcome (more or less virulent), genotype, and additional variables to identify conserved genes that may contribute to strain adaptation in the CNS to produce disease. The impact of these genes will be assessed using robust assays that examine their impact on survival in human CSF, virulence determinants, survival in animal models. Aim 2 continues our focused analysis on how core metabolism promotes cryptococcal growth and survival in the CNS by investigating carbon and nitrogen metabolism. This application integrates advanced molecular techniques, insights of the fungus through our prior studies, and close linkage to human disease and outcome. Its goal is to dissect, identify, and validate "weak" spots in the yeast's stress response in the CNS and thus provides new target (s) for antifungal strategies, which continue to substantially fail in the treatment of this life-threatening fungal infection.