Eosinophils support nematode infection

描述（由申请方提供）：嗜酸性粒细胞增多是对抗蠕虫感染的免疫应答的标志。我们的目标是挑战的范式，嗜酸性粒细胞的功能只作为效应细胞攻击寄生蠕虫。当旋毛虫新生的第一阶段幼虫感染骨骼肌细胞时，旋毛虫开始慢性感染期。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。具体来说，我们发现，幼虫不能正常生长，然后被大量杀死，在两个品系的小鼠，其中嗜酸性粒细胞谱系已被消融。当嗜酸性粒细胞恢复到这样的小鼠时，寄生虫存活率提高。我们的目标是阐明嗜酸性粒细胞的性质和作用，使他们能够支持生长，防止杀死线虫。我们假设嗜酸性粒细胞通过STAT 6依赖性机制影响宿主细胞的代谢来支持幼虫生长，并且它们通过激活IL-10+ CD 4 + CD 25- 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细胞活化和募集，防止寄生虫杀死。3.阐明嗜酸性粒细胞如何指导保护性免疫对抗再感染。我们的实验方法是高度机械化的，几乎完全在体内进行，旨在揭示宿主免疫反应、T。spiralis幼虫和幼虫本身。在抵抗再感染的研究中，我们将测试一种新的小鼠品系，它可以被诱导消耗嗜酸性粒细胞。我们的研究是特别有价值的，因为T。旋毛虫是啮齿类动物的一种天然病原体，占据肠外部位;很少有组织寄生线虫感染的天然动物模型。拟议调查的结果将提供新的见解，可用于设计由寄生蠕虫引起的疾病的疫苗和疗法，这些疾病继续困扰着世界各地的人们。最后，我们的研究与嗜酸性粒细胞也存在于微环境中的其他慢性疾病有关，包括肥胖症，癌症和过敏症。

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.