Synergy of Host Defense Mechanisms in the Lung

描述（由申请人提供）：宿主对真菌病原体新型隐球菌的防御依赖于先天和获得性体液和细胞免疫机制。隐球菌感染是通过吸入获得的。因此，肺是宿主与微生物初次相遇的场所，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。最近的研究已经证实，肺泡巨噬细胞在隐球菌感染的结果中起着关键作用。新生C.是一种兼性细胞内病原体，可以在巨噬细胞内复制。隐球菌感染的成功控制包括肉芽肿的形成，酵母细胞可以在肉芽肿上停留很长一段时间。因此，巨噬细胞与新生C.之间的相互作用可能是新生C.感染结果的最重要决定因素，因为它既控制宿主防御，也控制新生C.的毒力和致病性。在过去的资助期内，Casadevall实验室发现了两项与巨噬细胞相互作用有关的发现。首先，我们观察到吞噬作用触发巨噬细胞复制，这种现象是对宿主有利还是有害，取决于随后发生的是一个感染细胞还是两个感染细胞。其次，研究显示新生C.从感染的巨噬细胞中退出的机制涉及同型吞噬体融合和吞噬体挤压与宿主细胞的存活。该应用程序旨在从真菌和宿主细胞的存活和损伤、细胞周期进展和吞噬体挤压等方面剖析新型C.吞噬的结果。提出了三个具体目标：1)确定FcR和/或补体受体对新生梭状菌吞噬的结果；2)研究巨噬细胞中新生巨噬球菌诱导的细胞周期进程的作用机制和结果；3)探讨巨噬细胞巨吞噬体胞吐的作用机制和结果。这些研究的完成有望对细胞复制和吞噬这两个基本的细胞过程提供新的认识，并为新形芽孢杆菌的细胞内发病机制提供新的见解。的相关性。该申请寻求资金，以探索致病性真菌C. neoformmans如何与肺部最重要的宿主防御细胞相互作用。这一信息对于了解真菌如何在肺部扎根并引起疾病非常重要。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。项目说明：该申请寻求资金，以探索致病真菌如何与肺中最重要的宿主防御细胞相互作用。这一信息对于了解真菌如何在肺部扎根并引起疾病非常重要。此外，这些研究将提供可用于设计基于免疫试剂（如抗体）的疫苗和新疗法的信息。

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.