Synergy of Host Defense Mechanisms in the Lung

描述（由申请方提供）：宿主对真菌病原体新型隐球菌的防御依赖于先天性和获得性体液和细胞免疫机制。隐球菌感染通过吸入获得。因此，肺部是宿主与微生物最初接触的部位，感染的结果由局部免疫反应决定。在肺中，主要的宿主防御细胞类型是肺泡巨噬细胞。最近的研究已经确定肺泡巨噬细胞在隐球菌感染的结果中起着关键作用。C.新生儿是一种兼性细胞内病原体，可在巨噬细胞内复制。隐球菌感染的成功遏制涉及肉芽肿的形成，其中酵母细胞可以长时间驻留。因此，巨噬细胞与C. neoformans可能是C. neoformans感染，因为它控制宿主防御和C. neoforms毒力和致病性。在过去的资助期间，Casadevall实验室有两项与C。新生儿-巨噬细胞相互作用。首先，观察到吞噬作用触发巨噬细胞复制，这是一种对宿主有益或有害的现象，这取决于所捕获的是一个感染的细胞还是两个感染的细胞。第二，C.新形虫通过一种机制从感染的巨噬细胞中排出，该机制涉及同型吞噬体融合和吞噬体挤出，宿主细胞存活。本申请提出剖析C.关于真菌和宿主细胞存活和损伤、细胞周期进展和吞噬体挤出，新形线虫的吞噬作用。提出了三个具体目标：1）确定C.通过FcR和/或补体受体的吞噬作用; 2）确定C. 3）确定巨噬细胞中巨噬体胞吐作用的作用机制和结果。这些研究的完成有望为细胞复制和吞噬这两个基本的细胞过程提供新的线索，并为C。细胞内发病机制。本案无关本申请旨在寻求资金，以探索致病真菌C。新生儿与肺中最重要的宿主防御细胞相互作用。这些信息对于了解真菌如何在肺部建立并导致疾病非常重要。此外，这些研究将提供信息，可用于设计疫苗和新的疗法的基础上免疫试剂，如抗体。项目叙述：本申请寻求资金，以探索致病真菌如何与肺部最重要的宿主防御细胞相互作用。这些信息对于了解真菌如何在肺部建立并导致疾病非常重要。此外，这些研究将提供可用于设计疫苗和基于免疫试剂（如抗体）的新疗法的信息。

DESCRIPTION (provided by applicant): Host defense against the fungal pathogen Cryptococcus neoformans depends on both innate and acquired humoral and cellular immune mechanisms. Cryptococcal infection is acquired by inhalation. Therefore, the lung is the site of the initial encounter between host and microbe and the outcome of infection is decided by the local immune response. In the lung, the major host defense cell type is the alveolar macrophage. Recent studies have established that the alveolar macrophage plays a critical role in the outcome of cryptococcal infection. C. neoformans is a facultative intracellular pathogen that can replicate inside macrophages. Successful containment of cryptococcal infection involves the formation of granulomas where yeast cells can reside for long periods of time. Hence, the interaction between macrophages and C. neoformans is probably the most important determinant of the outcome of C. neoformans infection in that it governs both host defense and C. neoformans virulence and pathogenicity. In the past funding period the Casadevall laboratory made two discoveries related to C. neoformans-macrophage interactions. First, it was observed that phagocytosis triggers macrophage replication, a phenomenon that either benefits or harms the host depending on whether what ensues is one infected cell or two infected cells, respectively. Second, C. neoformans was shown to exit from infected macrophages through a mechanism that involves homotypic phagosome fusion and phagosome extrusion with survival of the host cell. This application proposes to dissect the outcome of C. neoformans phagocytosis with regards to fungal and host cell survival and damage, cell cycle progression and phagosome extrusion. Three specific aims are proposed: 1) To determine the outcome of C. neoformans phagocytosis by FcR and/or complement receptor; 2) To identify the mechanism of action and outcome of C. neoformans-induced cell cycle progression in macrophages; 3) To identify the mechanism of action and outcome of macro-phagosome exocytosis in macrophages. Completion of these studies is expected to shed new light on the two fundamental cellular processes of cell replication and phagocytosis and to provide new insights on the mechanisms of C. neoformans intracellular pathogenesis. Relevance. This application seeks funds to explore how the pathogenic fungus C. neoformans interacts with the most important host defense cell in the lungs. This information is important for understanding how the fungus establishes itself in the lungs and causes disease. Furthermore, these studies will provide information that could be used to design vaccines and new therapies based on immunological reagents such as Abs.Project Narrative: This application seeks funds to explore how the pathogenic fungus interacts with the most important host defense cell in the lungs. This information is important for understanding how the fungus establishes itself in the lungs and causes disease. Furthermore, these studies will provide information that could be used to design vaccines and new therapies based on immunological reagents such as antibodies.