Sensing of helminths by tuft cells

哺乳动物的免疫系统会遇到各种各样的外源激动剂，包括 病毒、细菌、原生动物、寄生虫（蠕虫）和过敏性颗粒。确定如何 免疫系统首先感知并区分这些激动剂是我们理解 免疫反应和相应的治疗干预。发现Toll样的 受体结合细菌脂多糖建立了免疫传感的基础范例， 所述微生物配体由同源免疫受体检测。许多配体-受体对 自从被鉴定以来，我们对细菌和病毒“1型”检测的理解是相当先进的。 相比之下，人们对免疫系统如何首先感知蠕虫并 过敏原，所有这些都会引起相同的“2型”免疫反应。我们最近发现 在肠道蠕虫感染期间，2型免疫应答需要上皮细胞类型， 以前未知的功能：簇细胞。这一发现不仅“去细胞化”了神秘的簇状细胞， 但也可能提供2型免疫感应中病原体和宿主之间缺失的环节。 毛簇细胞直接接触寄生蠕虫的肠腔， 上皮细胞，它们编码以Ca 2+门控阳离子通道为中心的化学传感途径 TRPM 5. Trpm 5缺陷型小鼠的2型免疫应答是有缺陷的，暗示了一种感觉， 对簇细胞的功能。在这项提议中，我们的目标是了解肠簇细胞如何感知 蠕虫感染，从而采用一个全新的和创新的切入点， 了解2型免疫感应。首先，我们结合联合收割机在体内和体外筛选方法 鉴定一种与蠕虫感染相关的配体，该配体激活簇细胞并驱动2型 炎症接下来，我们试图鉴定簇状细胞上的一种受体，该受体产生细胞生长所需的Ca 2+通量， 打开TRPM 5，随后控制蠕虫感染。我们还寻求开发新技术， 在体外培养的簇细胞，一个进步，将支持我们自己的研究和新兴的 一般对簇细胞感兴趣。虽然重点是蠕虫感染，如果成功，这项工作将 建立一个新的模式，为启动2型免疫反应，并应提供 对过敏原和其他2型激动剂检测的见解。我们的研究结果可能 因此发现了治疗蠕虫感染和过敏性炎症的新的治疗靶点。

The mammalian immune system encounters an enormous diversity of foreign agonists, including viruses, bacteria, protozoa, parasitic worms (helminths), and allergenic particles. Determining how the immune system first senses and distinguishes these agonists is fundamental to our understanding of the immune response and accordingly to our therapeutic interventions. The discovery that Toll-like receptors bind bacterial lipopolysaccharide established a foundational paradigm in immune sensing in which microbial ligands are detected by cognate immune receptors. Many ligand-receptor pairs have since been identified and our understanding of bacterial and viral “type 1” detection is quite advanced. By contrast, very little is known about how the immune system first senses helminths and allergens, all of which give rise to the same “type 2” immune response. We recently discovered that during intestinal helminth infection, the type 2 immune response requires an epithelial cell type with previously unknown function: the tuft cell. This finding not only “de-orphanized” the enigmatic tuft cell lineage but may also provide the missing link between pathogen and host in type 2 immune sensing. Tuft cells directly contact the intestinal lumen where helminths reside, and uniquely among intestinal epithelial cells, they encode a chemosensing pathway that centers on the Ca2+-gated cation channel TRPM5. Type 2 immune responses are defective in Trpm5-deficient mice, implicating a sensing function for tuft cells. In this proposal we aim to understand how intestinal tuft cells sense helminth infection, thereby employing an entirely new and innovative entry point to understanding type 2 immune sensing. First, we combine in vivo and in vitro screening approaches to identify a ligand associated with helminth infection that activates tuft cells and drives type 2 inflammation. Next, we seek to identify a receptor on tuft cells that generates the Ca2+ flux required to open TRPM5 and subsequently control helminth infection. We also seek to develop new techniques for in vitro culture of tuft cells, an advance that would support both our own research and the emerging interest in tuft cells generally. Although focused on helminth infection, if successful this work would establish a novel paradigm for the initiation of type 2 immune responses and should provide insights into the detection of allergens and other type 2 agonists as well. Our findings may therefore uncover novel therapeutic targets for treating both helminth infection and allergic inflammation.