Eosinophils support nematode infection

描述（由申请人提供）：嗜酸性粒细胞增多是针对蠕虫感染的免疫反应的标志。我们的目标是挑战的范式，嗜酸性粒细胞的功能仅限于作为效应细胞攻击寄生虫。旋毛虫在新生的第一阶段幼虫感染骨骼肌细胞时开始慢性感染。我们发现嗜酸性粒细胞有助于随后的肌炎，同时保护幼虫免受免疫介导的破坏。具体地说，我们发现在两种嗜酸性细胞谱系被切除的小鼠中，幼虫不能正常生长，然后被大量杀死。当这些小鼠恢复嗜酸性粒细胞时，寄生虫的存活率提高。我们的目标是阐明嗜酸性粒细胞的特性和作用，使它们能够支持生长和防止杀死线虫。我们假设嗜酸性粒细胞通过STAT6依赖机制影响宿主细胞的代谢来支持幼虫生长，并通过激活IL-10+CD4+CD25- T细胞来防止幼虫死亡。在强有力的初步数据和已发表的工作的支持下，我们的具体目标是：1。确定嗜酸性粒细胞在促进幼虫生长的局部先天反应中的作用。2. 定义嗜酸性粒细胞如何促进T细胞的激活和招募，从而阻止寄生虫的杀死。3. 阐明嗜酸性粒细胞如何直接保护免疫对抗再感染。我们的实验方法是高度机械的，几乎完全是在体内进行的，旨在揭示宿主免疫反应、螺旋体幼虫的细胞栖息地和幼虫本身之间的相互作用。在抗再感染的研究中，我们将测试一种新的小鼠品系，它可以被诱导去消耗嗜酸性粒细胞。我们的研究特别有价值，因为螺旋体是啮齿动物的天然病原体，占据肠道外部位；很少有组织寄生线虫感染的自然动物模型。拟议调查的结果将提供新的见解，可用于设计疫苗和治疗寄生虫引起的疾病，这些疾病继续困扰全世界的人们。最后，我们的研究也与其他嗜酸性粒细胞也存在于微环境中的慢性疾病相关，包括肥胖、癌症和过敏。

DESCRIPTION (provided by applicant): Eosinophilia is a hallmark of immune responses mounted against helminth infections. Our objective is to challenge the paradigm that eosinophils function exclusively as effector cells that attack parasitic worms. Trichinella spiralis initiates he chronic phase of infection when newborn, first-stage larvae infect skeletal muscle cells. We have discovered that eosinophils contribute to the ensuing myositis while simultaneously protecting larvae against immune-mediated destruction. Specifically, we find that larvae fail to grow normally, and then are killed in large numbers, in two strains of mice in which the eosinophil lineage has been ablated. Parasite survival improves when eosinophils are restored to such mice. Our goal is to elucidate the properties and actions of eosinophils that enable them to support growth and prevent killing of the nematode. We hypothesize that eosinophils support larval growth by influencing metabolism in the host cell by a STAT6- dependent mechanism, and that they prevent larval killing by activating IL-10+CD4+CD25- T cells. Supported by strong preliminary data and published work, our specific aims are to: 1. Determine the role of eosinophils in local innate responses that promote larval growth. 2. Define how eosinophils promote T cell activation and recruitment that prevents parasite killing. 3. Elucidate how eosinophils direct protective immunity against reinfection. Our experimental approaches are highly mechanistic, are conducted almost exclusively in vivo, and are designed to reveal the interplay among the host immune response, the cellular habitat of the T. spiralis larva, and the larva itself. In studies of resistance to re-infection, we will be testing a new mouse strain that an be induced to deplete eosinophils. Our studies are particularly valuable because T. spiralis is a natural pathogen of rodents that occupies an extra-intestinal site; there are very few natural animal models of tissue-dwelling nematode infection. Findings from the proposed investigations will provide new insights that can be applied to the design of vaccines and therapies for diseases caused by parasitic worms that continue to plague people worldwide. Finally, our studies have relevance to other chronic diseases in which eosinophils also populate the microenvironment, including obesity, cancer, and allergy.