Protective and pathologic functions of macrophages induced by helminths

摘要 土壤传播蠕虫感染的全球流行率估计有20亿人感染， 估计有8.7亿儿童面临感染风险。蠕虫感染可导致严重的 营养不良，生长迟缓，严重的免疫病理学，并对当地造成巨大的经济负担， 社区.蠕虫寄生虫在进入肠道之前，需要经过多个组织的复杂迁移周期。 宿主的内脏为了应对这些挑战，哺乳动物的免疫系统进化出了 在促进有益的炎症和减少寄生虫负担之间保持微妙的平衡， 并限制病理性炎症以维持组织完整性。保持这种平衡的重要性在于 通过表现出免疫应答失调的患者中出现的严重病理学来证明， 蠕虫尽管平衡保护性和病理性反应的重要性， 蠕虫感染，调节这些途径的细胞和分子事件仍然未知。它 已经确定，辅助性T细胞2型（TH 2）细胞因子反应，蠕虫诱导免疫的特征 在人类和小鼠中，促进蠕虫清除和限制感染诱导的组织损伤都需要。 一个新兴的文学机构现在已经表明，2型精氨酸激活的巨噬细胞作为关键的运作， 这些不同途径的调节器。此外，我们最近的工作还表明， 中性粒细胞和肺巨噬细胞之间的相互作用是巨噬细胞获得抗日本圆线虫抗体所必需的 在呼吸道中的巴西（Nb）效应器功能。此外，我们的初步数据表明， 嗜碱性粒细胞群体是巨噬细胞启动肺中伤口愈合反应所必需的。集体 这些研究提供了一种假设，即与Nb引发的先天免疫细胞的协调相互作用 群体是巨噬细胞获得宿主保护效应子功能所必需的。这将直接 该提案的目标1中测试的重点是询问促进所需的辅助细胞， Nb感染后肺中的巨噬细胞活化。已经确定，长寿命的组织来源的 巨噬细胞（TD-Macs）在胎儿发育期间聚集在肺部，而单核细胞衍生的巨噬细胞 （Mo-Mac）在持续炎症的背景下在组织环境中积累。此外， 证明了TD-Mac和Mo-Mac在蠕虫感染的情况下可以表现出不同的表型。 尽管有这些进展，TD-Mac和Mo-Mac对抗蠕虫免疫和抗寄生虫免疫的独特贡献仍然是有限的。 组织完整性仍然未知。这将在本提案的目标2中直接测试，重点是阐明 Nb感染后肺巨噬细胞群体的不同和共同效应子功能。这些目标将 利用锡拉库扎和高斯的集体智力和科学资源来解决 实验室和这些研究的结果将增加我们对肺巨噬细胞 是在急性炎症的背景下进行编程的。

ABSTRACT The global prevalence of soil transmitted helminth infections is estimated at two billion individuals infected, with an estimated 870 million children at risk of becoming infected. Helminth infections can lead to significant malnutrition, growth retardation, severe immunopathology, and exert enormous economic burdens on local communities. Helminth parasites take complex migratory cycles through multiple tissues before entering the intestine of their host. To combat these challenges, the mammalian immune system has evolved mechanisms to maintain a delicate balance between promoting beneficial inflammation needed to reduce parasitic burdens and limiting pathologic inflammation to maintain tissue integrity. The importance of maintaining this balance is evident by the severe pathology that presents in patients exhibiting dysregulated immune responses to helminths. Despite the importance of balancing protective and pathologic responses in the context of helminth infections, the cellular and molecular events that regulate these pathways remain unknown. It is well established that T helper type 2 (TH2) cytokine responses, characteristics of helminth-induced immunity in humans and mice, are required to both promote worm clearance and limit infection-induced tissue damage. An emerging body of literature has now shown that type 2 cytokine-activated macrophages operate as critical regulators of these distinct pathways. In addition, our recent work has also demonstrated that interactions between neutrophils and lung macrophages are required for macrophages to acquire anti-Nippostrongylus brasiliensis (Nb) effector functions in the airways. Moreover, our preliminary data suggest that interactions with basophil populations are required for macrophages to initiate wound healing responses in the lung. Collectively these studies provide the hypothesis that coordinated interactions with Nb-primed innate immune cell populations are necessary for macrophages to acquire host-protective effector functions. This will be directly tested in Aim 1 of this proposal focused on interrogating the accessory cells necessary to promote macrophage activation in the lung following Nb infection. It is well established that long-lived tissue-derived macrophages (TD-Macs) populate the lungs during fetal development, while monocyte-derived macrophages (Mo-Macs) accumulate in tissue environments in the context of ongoing inflammation. Further, it has been demonstrated that TD-Macs and Mo-Macs can exhibit distinct phenotypes in the context of helminth infections. Despite these advances the distinct contributions of TD-Macs and Mo-Macs to anti-helminth immunity and tissue integrity remain unknown. This will be directly tested in Aim 2 of this proposal focused on elucidating the distinct and common effector functions of lung macrophage populations following Nb infection. These aims will be addressed employing the collective intellectual and scientific resources of the Siracusa and Gause laboratories and the results of these studies will increase our understanding of how pulmonary macrophages are programed in the context of acute inflammation.