Innate type 2 immune mechanisms of resistance

描述(申请人提供)：虽然宿主的2型免疫反应可以调节对肠道线虫寄生虫的保护性免疫，但所涉及的机制仍不确定，到目前为止还没有开发出有效的疫苗。虽然宿主抵抗微生物病原体(如许多病毒和细菌)的1型先天免疫机制已被很好地描述，但对2型先天免疫机制抵抗多细胞寄生虫的了解相对较少。在自然感染中，蠕虫通常侵入皮肤，迁移到肺部，然后进入肠道。虽然以前的研究主要研究肠道区域的蠕虫排泄，但最近的研究表明，肺可能是增强蠕虫排泄的重要和新的靶点。在拟议的研究中，我们将检查在二次接种后介导肺内加速驱虫的先天免疫细胞群。以往的研究表明，肠道线虫巴西线虫在二次接种后可通过免疫机制在肺内迅速排出，而不是一次接种。这种反应独立于获得性免疫而发生，持续的先天免疫细胞群可能参与快速排泄。我们将利用我们实验室开发的一种新的过继转移系统，在该系统中，从预置供体小鼠的肺中转移的巨噬细胞介导了初治受者加速的蠕虫排出。在互补的体外培养系统中，启动的效应巨噬细胞附着在巴西新陈代谢障碍的幼虫上，增加了幼虫的死亡率。这些体内和体外模型系统将被用来研究巨噬细胞介导的蠕虫损伤和加速排出的机制。在第一个目的中，我们将询问一次接种后支持效应巨噬细胞发育的免疫环境。有趣的是，我们在初步结果中显示，中性粒细胞对于这些效应巨噬细胞的发育是必不可少的。我们将描述这种相互作用的特征，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一种能够调节加速驱虫的长期持续表型。我们将检查这一群体的可塑性及其在不同免疫微环境中保持这一表型的能力。在第二个目标中，我们将调查在二次反应过程中导致蠕虫排出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调节加速的蠕虫驱逐。我们将专注于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定的先天免疫细胞群体是否与效应器巨噬细胞相互作用，最终促进加速排泄。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，拟议的实验将为这一免疫和传染病领域研究较少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.