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性健康问题。虽然这些感染 寄生虫通常不会致命，但它们与高发病率有关，慢性感染通常 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，在包括小鼠和人类在内的物种中观察到，其特征在于 先天性淋巴样细胞（ILC 2）、嗜酸性粒细胞和肥大细胞募集和组织损伤。小鼠感染模型 与肠道寄生虫已经建立了研究的细胞和分子机制的2型免疫 更详细的反应：蠕虫，如巴西日本圆线虫和多脑Heligmosomoides polygyrus， 和某些原生生物的目的毛滴虫诱导急性宿主2型免疫防御反应， 小肠感染后。2型免疫应答由寄生虫感应白细胞介素-25（IL-25）启动 产生上皮簇细胞，导致产生ILC 2的IL-13的激活，ILC 2反过来又发出信号， 上皮细胞这种前馈IL-25-ILC 2-IL-13回路放大2型免疫应答并启动 大量的组织重塑，包括簇状细胞和杯状细胞增生，以及粘液产生，导致 控制肠道寄生虫。尽管我们对免疫组织的理解最近取得了进展， 在2型介导的炎症中的串扰，我们缺乏对详细过程的完整理解 潜在的寄生虫诱导的肠道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型介导的肠道炎症，我们 筛选与肠道2型炎症有关的新参与者。我们发现了一组高度同源的 这些基因在体内和体内2型诱导寄生虫感染时在肠中显著上调， 体外IL-13刺激条件下的小肠类器官培养物。因此，本提案的目的是 研究这些新鉴定的2型诱导基因在保护性2型免疫中的作用， 蠕虫及其在肠上皮细胞中的功能。我们制造了基因敲除小鼠， 在小肠类器官培养物中的表达系统。在aim 1中，我们将研究这些候选基因的作用 在体内宿主对原生生物和蠕虫的2型免疫应答中，以及在目标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.