Gut mucosal type-2 immunity to parasitic infections

项目摘要 肠道蠕虫和原生生物感染仍然是一个重大的全球卫生问题。尽管由这些病毒感染 寄生虫通常不是致命的，它们与高发病率有关，通常伴有慢性感染。 导致贫血和营养不良。感染与保护性2型免疫密切相关 介导的肠道炎症，跨物种观察，包括小鼠和人类，其特征是 先天性淋巴样细胞(ILC2)、嗜酸性粒细胞和肥大细胞募集与组织损伤。感染的小鼠模型 肠道寄生虫已被建立来研究2型免疫的细胞和分子机制 更详细的答复：蠕虫，如巴西尼波斯特罗线虫和多回螺旋线虫， 和某些滴虫目的原生生物在小鼠体内诱导急性宿主2型免疫防御反应 感染后的小肠。寄生虫感应白介素25(IL-25)启动2型免疫反应 产生上皮绒毛细胞，导致IL-13激活，产生ILC2，进而重新发出信号 上皮细胞。这个前馈IL-25-ILC2-IL-13回路放大2型免疫反应并启动 大量组织重塑，包括簇状和杯状细胞增生，以及粘液产生，导致 遏制肠道寄生虫。尽管我们对免疫组织的了解最近取得了进展 在2型相声介导的炎症中，我们缺乏对详细过程的完整了解 寄生虫在肠道中诱导的2型免疫反应；这些限制了有效的治疗选择 肠道寄生虫感染。为了更详细地描述2型肠道炎症的特征，我们 筛选与肠道2型炎症有关的新成员。我们发现了一组高度同源的 2型在体内和体内诱导寄生虫感染时在肠道中显著上调的基因 体外IL-13刺激条件下的小肠器官培养。因此，这项提议的目标是 为了研究这些新发现的2型诱导基因在保护性2型免疫中的作用 肠道上皮细胞中的蠕虫及其功能。我们产生了基因敲除的小鼠，并使用了逆转录病毒 小肠器官培养中的表达系统。在目标1中，我们将研究这些候选基因的作用 在宿主对活体原生生物和蠕虫的2型免疫反应中，在目标2中，我们将评估它们在 肠上皮细胞在2型免疫刺激条件下的体外培养。这些发现可能会提供合理的 调节人类肠道寄生虫感染的2型炎症的方法。

Project Summary Enteric helminth and protist infections remain a significant global health problem. Although infections by these parasites are generally not fatal, they are associated with high rates of morbidity, with chronic infection often leading to anemia and malnourishment. Infections are strongly associated with protective type-2 immune mediated intestinal inflammation, observed across species, including mice and humans, and characterized by innate lymphoid cell (ILC2), eosinophil, and mast cell recruitment and tissue injury. Mouse models of infection with intestinal parasites have been established to study the cellular and molecular mechanisms of type-2 immune responses in greater detail: Helminths, such as Nippostrongylus brasiliensis and Heligmosomoides polygyrus, and certain protists of the order Trichomonadida induce acute host type-2 immune defense responses in the small intestine upon infection. Type-2 immune responses are initiated by parasite sensing interleukin-25 (IL-25) producing epithelial tuft cells, resulting in the activation of IL-13 producing ILC2 that in turn signal back on epithelial cells. This feedforward IL-25-ILC2-IL-13 circuit amplifies type-2 immune responses and initiates massive tissue remodeling including tuft- and goblet cell hyperplasia, and mucus production resulting in the containment of intestinal parasites. Despite the recent advancement in our understanding in immune-tissue crosstalk in type-2 mediated inflammation, we lack a complete understanding of the detailed processes underlying parasite-induced type-2 immune responses in the gut; these limits effective treatment options to enteric parasitic infections. To characterize type-2 mediated inflammation in the intestine in greater detail we screened for novel players implicated in intestinal type-2 inflammation. We identified a set of highly homologous genes that were significantly upregulated in the intestine upon type-2 inducing parasitic infections in vivo and in small intestinal organoid cultures upon IL-13 stimulating conditions in vitro. The goal of this proposal is therefore to study the role of these newly identified type-2 inducible genes in the protective type-2 immunity to protists and helminths and their function in intestinal epithelial cells. We generated knock-out mice and use a retroviral expression system in small intestinal organoid cultures. In aim 1, we will study the role of these candidate genes in host type-2 immune responses to protists and helminths in vivo and in aim 2 we will assess their function in intestinal epithelial cells under type-2 immune stimulating conditions in vitro. These findings may provide rational approaches to modulate type-2 inflammation to enteric parasite infections in humans.