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的角度理解中枢神经系统(CNS)中隐球菌疾病的病理生理学的工作。新生隐球菌和加蒂氏隐球菌代表被包裹的担子菌酵母菌，每年产生100万例疾病，使用目前的治疗方法估计有60万人死亡。隐球菌是一种嗜神经性疾病，会导致隐球菌性脑膜脑炎，这是这种疾病感染的威胁生命的阶段。目的1不仅确定隐球菌临床分离株对人中枢神经系统的体内转录反应，而且还将鉴定对酵母在中枢神经系统中生长和存活有重要贡献的基因(S)和基因途径(S)。此外，我们将根据患者的结局(或多或少的毒力)、基因型和其他变量来表征这些反应，以确定可能有助于中枢神经系统菌株适应而产生疾病的保守基因。这些基因的影响将通过稳健的分析来评估，这些分析检查它们对人类脑脊液存活、毒力决定因素和动物模型存活的影响。目的2通过研究碳和氮代谢，继续我们关于核心代谢如何促进隐球菌在中枢神经系统中的生长和生存的重点分析。这一应用集成了先进的分子技术，通过我们之前的研究对真菌的洞察，以及与人类疾病和结果的密切联系。它的目标是解剖、识别和验证酵母在中枢神经系统的应激反应中的“弱点”，从而为抗真菌策略提供新的靶点(S)，这些策略在治疗这种威胁生命的真菌感染方面仍然基本上失败。

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.