Synergy of Host Defense Mechanisms in the Lung

真菌新型隐球菌是一种呼吸道病原体， 导致免疫力受损的个体发生危及生命的疾病。巨噬细胞是 控制和传播肺部感染的关键细胞。C. neoformans是一个 一种兼性细胞内病原体，在破坏巨噬细胞后可以在巨噬细胞中复制， 吞噬溶酶体膜真菌对吞噬溶酶体膜的破坏决定了 真菌-巨噬细胞相互作用的结果。梭以及其他的土壤 致病真菌，毒力的能力已被提出，从相互作用出现与 环境中的吞噬性捕食者选择的特征，然后可以提高毒力， 哺乳动物事实上，C.新形式的发病机制是，它是 在许多不同的动物宿主中具有毒性并且可以在哺乳动物的吞噬细胞中复制， 鱼类昆虫和原生动物这就提出了一个有趣的问题：一个没有 需要动物宿主能够破坏来自如此多物种的免疫效应细胞。我们 假设这种非特异性毒力的能力来自于它破坏 宿主细胞与“细胞内发病机制试剂盒”，包括细胞内分泌的 许多效应分子。我们有初步的数据表明C。新形式释放出许多 小鼠巨噬细胞内的蛋白质，包括几个众所周知的毒力因子。在这 应用我们提出鉴定人类巨噬细胞和变形虫内产生的蛋白质， 破坏宿主细胞。然后将详细研究这些蛋白质的一个子集， 细胞内发病机制。提出了三个具体目标：目标1。以识别 CN蛋白在人巨噬细胞内产生;目的2。识别关键CN 在与阿米巴相互作用过程中产生的化合物;目的3.为了弄清 某些CN蛋白在吞噬细胞中的细胞内致病策略中的作用 原生动物细胞本工作将阐明C.细胞内新生菌 发病机制，这一信息可以相关的设计改进的治疗，抗真菌 治疗和疫苗。

The fungus Cryptococcus neoformans is a respiratory pathogen that is a relatively frequent cause of life-threatening disease in individuals with impaired immunity. Macrophages are critical cells in the control and dissemination of infection in the lung. C. neoformans is a facultative intracellular pathogen that can replicate in macrophage after damaging the phagolysosomal membrane. Fungal damage to the phagolysosomal membrane determines the outcome of the fungal-macrophage interaction. For C. neoformans, as well as other soil pathogenic fungi, the capacity for virulence has been proposed to emerge from interactions with phagocytic predators in the environment that select for traits that can then promote virulence in mammals. In fact, one of the remarkable aspects of C. neoformans pathogenesis is that it is virulent in many different animal hosts and can replicate in phagocytic cells from mammals, fish, insects and protozoa. This poses the fascinating question of how a soil organism with no need for an animal host is able to subvert immune effector cells from so many species. We hypothesize that this capacity for non-specific virulence comes from its ability to undermine host cells with an ‘intracellular pathogenesis kit’ that includes the intracellular secretion of numerous effector molecules. We have preliminary data that C. neoformans releases many proteins inside murine macrophages that include several well-known virulence factors. In this application we propose to identify proteins made inside human macrophages and amoeba that undermine host cells. A subset of these proteins will then be studied in detail to dissect mechanisms of intracellular pathogenesis. Three specific aims are proposed: Aim 1. To identify CN proteins produced intracellularly in human macrophages; Aim 2. To identify key CN compounds produced during its interaction with amoeba; Aim 3. To ascertain the mechanism of action of certain CN proteins in the intracellular pathogenic strategy in phagocytic human and protozoan cells. This work will illuminate the mechanisms of C. neoformans intracellular pathogenesis and this information can be relevant to designing improved therapies, antifungal therapies and vaccines.