Brugia Infections in Mice: Role of Eosinophils

描述(申请人提供)：过去几年，使用 以马来丝虫为工作模型的小鼠腹腔感染模型 试图在这个模型系统中理解宿主-寄生虫的相互作用。一 在我们所面临的难题中，有一个是 哺乳动物的身体消除了大的、后生动物、细胞外、组织栖息地 寄生虫。我们在过去两三年中获得的数据， 强烈提示B淋巴细胞起着关键作用。我们的发现， 在C节中更详细地描述，还表明最终的 杀死寄生虫的效应器是先天免疫的组成部分。有能力 产生靶向突变，包括缺失(敲除小鼠)和插入突变 (转基因小鼠)，使功能的评估成为可能 先天免疫成分在迄今为止的重要性 难以想象。这项提议的目标是使用这些强大的工具，即 影响嗜酸性粒细胞的各种基因的转基因和敲除突变 功能和数量，以评估它们在抵抗布鲁贾病毒宿主保护中的作用 马来人。工作假说支持这一假设，即嗜酸性粒细胞。在……里面 存在合适的抗体和补体成分。主修 对小鼠腹膜腔内马来丝虫的清除作用。我们会 利用IL-S转基因和基因敲除小鼠，以及针对该病毒的抗体 趋化因子受体CCR3，以检测嗜酸性粒细胞在宿主抵抗中的作用 感染马来丝虫。我们将研究嗜酸性粒细胞的作用机制 利用体内和体外模型，完成它们的宿主保护功能。 我们相信，这里提出的研究将有助于我们理解 哺乳动物宿主对抗遥远的传染性病原体的机制 比它们自己的效应器细胞还大。

DESCRIPTION (provided by applicant): Over the past several years, using intraperitoneal infection of mice with Brugia malayi as our working model, we have sought to understand host-parasite interactions in this model system. One of the puzzles that we have been confronted with is the mechanism by which the mammalian body eliminates large, metazoan, extracellular, tissue dwelling parasites. Data that we have obtained over the last two or three years, strongly suggest that B lymphocytes play a critical role. Our findings, described in greater detail in section C, also suggest that the ultimate effectors of parasite killing are components of innate immunity. The ability to generate targeted mutations, both deletional (knockout mice) and insertional (transgenic mice), has made possible the evaluation of the functional importance of components of innate immunity in a manner hithertofore unimaginable. The goal of this proposal is to use these powerful tools, namely transgenic and knockout mutations in various genes affecting eosinophil function and number, to evaluate their role in host protection against Brugia malayi. The working hypothesis underlvinc this proposal that eosinophils. In the presence Qf the appropriate antibodies and complement components. Major role in the elimination Qf B. malayi from the murine peritoneal cavity. We will use IL-S transgenic and knockout mice, as well as antibodies against the chemokine receptor CCR3, to examine the role of eosinophils in host resistance to Brugia malayi infection. We will examine mechanism by which eosinophils accomplish their host protective function, using in vivo and in vitro models. We believe that the studies proposed herein will help us understand the mechanisms by which mammalian hosts combat infectious agents that are far larger than their own effector cells.