Innate type 2 immune mechanisms of resistance

描述（由申请方提供）：尽管宿主2型免疫应答可介导针对肠道线虫寄生虫的保护性免疫，但涉及的机制仍不确定，并且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）的抗性的1型先天免疫机制已得到很好的描述，但关于对多细胞寄生虫的抗性的2型先天免疫机制知之甚少。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检查肠道区域的蠕虫驱逐，最近的研究表明，肺可能是一个重要的和新的目标，以提高蠕虫驱逐。在拟议的研究中，我们将检查二次接种后介导肺中加速蠕虫排出的先天免疫细胞群。以往的研究表明，肠道线虫N.巴西杆菌在二次接种后通过肺部免疫机制迅速排出，但初次接种后不会。这种反应独立于适应性免疫发生，持续的先天免疫细胞群可能介导快速排出。我们将利用我们实验室开发的一种新的过继转移系统，其中从致敏供体小鼠的肺转移的巨噬细胞介导幼稚受体的加速蠕虫排出。在补充的体外培养系统中，致敏的效应巨噬细胞粘附于N。brasiliensis幼虫，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。 在第一个目标中，我们将询问免疫环境支持初次接种后的效应巨噬细胞的发展。有趣的是，我们的初步结果表明，中性粒细胞是必不可少的发展这些效应巨噬细胞。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留了能够介导加速蠕虫驱逐的长寿命持久表型。我们将研究该群体的可塑性及其在不同免疫微环境中维持该表型的能力。在第二个目标中，我们将研究实际的先天免疫机制，有助于蠕虫驱逐在二级反应。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。我们将集中在特定的候选分子和代谢途径，这可能是重要的巨噬细胞效应功能。我们将进一步研究特定的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，我们在实验室中开发的模型系统提供了必要的工具来探索蠕虫抗性的2型先天免疫机制，并且所提出的实验将为免疫和传染病的这一很少研究但非常重要的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.