Innate type 2 immune mechanisms of resistance

描述（由申请人提供）：虽然宿主2型免疫反应可以介导对肠道线虫寄生虫的保护性免疫，但其机制仍不确定，迄今尚未开发出有效的疫苗。虽然宿主对微生物病原体（如许多病毒和细菌）抗性的1型先天免疫机制已经得到了很好的描述，但对多细胞寄生虫抗性的2型先天免疫机制却知之甚少。在自然感染中，蠕虫经常侵入皮肤，迁移到肺部，然后进入肠道。虽然以前的研究主要是研究肠道区域的蠕虫排出，但最近的研究表明，肺可能是促进蠕虫排出的一个重要的新靶点。在拟议的研究中，我们将检查先天性免疫细胞群介导二次接种后加速蠕虫在肺部排出。先前的研究表明，在继发性而非原发性接种后，肠道线虫寄生虫巴西乳杆菌（N. brasiliensis）通过肺部的免疫机制被迅速排出。这种反应独立于适应性免疫发生，持续存在的先天免疫细胞群可能介导快速驱逐。我们将利用我们实验室开发的一种新的过继性转移系统，从供体小鼠的肺部转移的巨噬细胞可以加速蠕虫在受体体内的排出。在互补的体外培养系统中，引物效应巨噬细胞粘附在巴西乳螨幼虫上，导致代谢受损和幼虫死亡率增加。这些体内和体外模型系统将用于研究巨噬细胞介导的蠕虫损伤和加速驱逐的机制。在第一个目的中，我们将探讨免疫环境在初次接种后支持巨噬细胞发育的效应。有趣的是，我们在初步结果中表明，中性粒细胞对这些效应巨噬细胞的发育至关重要。我们将描述这种相互作用，并研究其他潜在的免疫细胞相互作用。这种效应巨噬细胞群体保持了一种长寿命的持久表型，能够介导加速的蠕虫驱逐。我们将研究这一群体的可塑性及其在不同免疫微环境中维持这种表型的能力。在第二个目标中，我们将研究在二次反应期间促进蠕虫驱逐的实际先天免疫机制。使用体外和体内模型系统，我们将研究巨噬细胞如何介导加速蠕虫驱逐。我们将重点关注在巨噬细胞效应功能中可能重要的特定候选分子和代谢途径。我们将进一步研究特异性先天免疫细胞群是否与效应巨噬细胞相互作用，最终促进加速驱逐。因此，我们在实验室开发的模型系统为探索蠕虫抗性的2型先天免疫机制提供了必要的工具，提出的实验将为这个研究很少但非常重要的免疫和传染病领域提供重要的见解。

DESCRIPTION (provided by applicant): Although the host type-2 immune response can mediate protective immunity against intestinal nematode parasites, the mechanisms involved remain uncertain and as yet effective vaccines have not been developed. While type 1 innate immune mechanisms of host resistance against microbial pathogens, such as many viruses and bacteria, are well described, relatively little is know regarding type 2 innate immune mechanisms of resistance to multicellular parasites. In natural infections, helminths often invade the skin, migrate to the lung, and then enter the intestine. Although previous studies have primarily examined worm expulsion in the enteric region, recent studies suggest that the lung may be a significant and novel target for enhancing worm expulsion. In the proposed studies, we will examine the innate immune cell populations mediating accelerated worm expulsion in the lung after secondary inoculation. Previous studies indicate that the intestinal nematode parasite, N. brasiliensis, is rapidly expulsed through immune mechanisms in the lung after secondary but not primary inoculation. This response occurs independently of adaptive immunity, with persistent innate immune cell populations likely mediating the rapid expulsion. We will utilize a novel adoptive transfer system developed in our laboratory where macrophages transferred from lungs of primed donor mice mediate accelerated worm expulsion in na¿ve recipients. In complementary in vitro culture systems the primed effector macrophages adhere to N. brasiliensis larvae, causing impaired metabolism and increased larval mortality. These in vivo and in vitro model systems will be used to investigate mechanisms of macrophage-mediated worm damage and accelerated expulsion. In the first aim, we will interrogate the immune milieu supporting effector macrophage development after primary inoculation. Intriguingly, we show in the preliminary results that neutrophils are essential for development of these effector macrophages. We will characterize this interaction and also examine other potential immune cell interactions. This effector macrophage population retains a long- lived persistent phenotype capable of mediating accelerated worm expulsion. We will examine the plasticity of this population and its capacity to maintain this phenotype in different immune microenvironments. In the second aim, we will investigate the actual innate immune mechanisms that contribute to worm expulsion during the secondary response. Using in vitro and in vivo model systems, we will examine how macrophages mediate accelerated worm expulsion. We will focus on specific candidate molecules and metabolic pathways that may be important in this macrophage effector function. We will further examine whether specific innate immune cell populations interact with effector macrophages to ultimately contribute to accelerated expulsion. Thus, the model systems that we have developed in our laboratory provide the necessary tools to explore type 2 innate immune mechanisms of helminth resistance and the proposed experiments will provide important insights into this little studied yet highly significant area of immunity and infectious disease.