Synergy of Host Defense Mechanisms in the Lung

描述(申请人提供)：宿主对真菌病原体新生隐球菌的防御依赖于先天和后天体液和细胞免疫机制。隐球菌感染是通过吸入获得的。因此，肺部是宿主与微生物最初接触的部位，感染的结局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。最近的研究表明，肺泡巨噬细胞在隐球菌感染的转归中起着关键作用。新生梭菌是一种兼性的细胞内病原体，可以在巨噬细胞内复制。隐球菌感染的成功遏制需要形成肉芽肿，酵母细胞可以在肉芽肿中长时间驻留。因此，巨噬细胞和新生弧菌之间的相互作用可能是决定新生弧菌感染结局的最重要的决定因素，因为它既控制宿主防御，又控制新生弧菌的毒力和致病性。在过去的资助期间，卡萨德瓦尔实验室发现了两项与新生葡萄球菌-巨噬细胞相互作用有关的发现。首先，观察到吞噬作用触发巨噬细胞复制，这一现象是有利于还是损害宿主，取决于随后分别是一个感染细胞还是两个感染细胞。其次，研究表明，新生葡萄球菌通过同型吞噬小体融合和吞噬小体挤出与宿主细胞存活相结合的机制从感染的巨噬细胞中排出。这项应用建议解剖结果的吞噬有关的真菌和宿主细胞的生存和损害，细胞周期进展和吞噬小体排出。我们提出了三个具体的目标：1)确定FCR和/或补体受体吞噬新生弧菌的结果；2)确定新生弧菌诱导巨噬细胞周期进展的作用机制和结果；3)确定巨噬细胞巨噬体胞吐的作用机制和结果。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，并为新生假单胞菌的细胞内致病机制提供新的见解。关联性。这项申请寻求资金，以探索致病真菌新生弧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自身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Abs)的新疗法的信息。项目说明：该申请寻求资金，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自身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抗体等免疫试剂的新疗法的信息。

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.