Protective and pathologic functions of macrophages induced by helminths

摘要 全球土壤传播蠕虫感染的流行率估计为20亿人感染， 据估计，有8.7亿儿童面临感染的风险。蠕虫感染可导致显著的 营养不良、生长迟缓、严重的免疫病理，并给当地造成巨大的经济负担 社区。蠕虫寄生虫经历复杂的迁移周期，穿过多个组织，然后进入 寄主的肠道。为了应对这些挑战，哺乳动物的免疫系统进化了各种机制 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 以及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 表现为免疫反应失调的患者的严重病理明显 蠕虫。尽管在以下情况下平衡保护性反应和病理反应的重要性 蠕虫感染，调节这些途径的细胞和分子事件仍然未知。它 众所周知，T辅助细胞2型(TH2)细胞因子反应的特点是蠕虫诱导的免疫 在人类和小鼠中，既需要促进蠕虫清除，也需要限制感染引起的组织损伤。 一组新兴的文献现在表明，2型细胞因子激活的巨噬细胞起关键作用。 这些不同途径的调节者。此外，我们最近的工作还表明，相互作用 在中性粒细胞和肺巨噬细胞之间，巨噬细胞需要获得抗尼氏杆菌 巴西里安(NB)效应器在呼吸道中起作用。此外，我们的初步数据表明，与 巨噬细胞需要嗜碱性粒细胞群才能在肺内启动伤口愈合反应。集体地 这些研究提供了一个假设，即与NB启动的先天免疫细胞的协调相互作用 巨噬细胞获得宿主保护性效应器功能所必需的群体。这将是直接 在本提案的目标1中进行了测试，重点是询问促进 肺炎支原体感染后肺内巨噬细胞活化。众所周知，长寿组织起源于 巨噬细胞(TD-MACs)在胎儿发育期间分布在肺内，而单核细胞来源的巨噬细胞 (Mo-MACs)在持续炎症的背景下在组织环境中积累。此外，它一直是 证明了TD-MACs和Mo-MACs在蠕虫感染的背景下可以表现出不同的表型。 尽管取得了这些进展，但TD-MACs和Mo-MACs在抗蠕虫免疫和 组织的完整性仍不清楚。这将在本提案的目标2中进行直接测试，重点是澄清 NB感染后肺巨噬细胞群的不同和共同的效应功能。这些目标将 利用锡拉库萨和古斯的集体智力和科学资源加以解决 实验室和这些研究的结果将增加我们对肺巨噬细胞如何 都是在急性炎症的背景下编程的。

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.