Synergy of Host Defense Mechanisms in the Lung

新生隐球菌是一种比较常见的呼吸道病原体。 免疫力受损的人罹患危及生命的疾病的原因。巨噬细胞 关键细胞在控制和传播肺部感染中的作用。新生革兰氏菌是一种 一种兼性细胞内病原体，可在破坏巨噬细胞后在巨噬细胞中复制 吞噬体膜。真菌对吞噬体膜的损伤决定了 真菌-巨噬细胞相互作用的结果。对于新生葡萄球菌，以及其他土壤 病原真菌，毒力的能力已经被认为是通过与 环境中的吞噬捕食者，它们选择特征，然后可以促进毒力 哺乳动物。事实上，新生芽孢杆菌发病机制的一个显著方面是它是 在许多不同的动物宿主中具有毒力，并可以在哺乳动物的吞噬细胞中复制， 鱼、昆虫和原生动物。这提出了一个令人着迷的问题：没有 对动物宿主的需要能够颠覆如此多物种的免疫效应细胞。我们 假设这种非特定毒力的能力来自于它破坏 宿主细胞，其中包括细胞内分泌的 大量的效应器分子。我们有初步数据表明，新月芽孢杆菌释放出许多 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 我们提出的应用于鉴定人巨噬细胞和阿米巴内产生的蛋白质 破坏宿主细胞。然后对这些蛋白质的一个子集进行详细研究，以进行剖析 细胞内致病机制。提出了三个具体目标：目标1.确定 人巨噬细胞内产生的CN蛋白；目的2.鉴定关键CN 与阿米巴相互作用产生的化合物；目的3.确定阿米巴的作用机制 某些CN蛋白在吞噬细胞内致病策略中的作用 原生动物细胞。这项工作将阐明新生隐孢子菌的胞内机制。 发病机制和这些信息可能与设计改进的治疗方法、抗真菌药物有关 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.