The role of the tuft cell inflammasome in infection

项目摘要 肠上皮细胞暴露于不同种类的病原体，不仅是作为第一线的工具， 免疫系统不仅是抵抗宿主入侵的防御系统， 检测到病原体。NAIP/NLRC 4炎性体已成为重要的先天性免疫调节因子。 在细菌性胃肠道感染中，肠上皮细胞（IEC）中的传感器，导致快速挤出 感染的细胞和病原体识别后释放细胞因子和类花生酸。先天免疫的作用 在IEC的各个亚型的水平上，NAIP/NLRC 4炎性体的敏感性和特异性尚不清楚。 最近，我们发现在IEC中，簇状细胞唯一地释放类花生酸前列腺素D2（PGD2）。 炎性小体激活后。簇状细胞是IEC的一种罕见亚型，主要以其在抗肿瘤中的作用而闻名。 寄生免疫毛丛细胞在细菌感染过程中的作用以及释放的 PGD2在肠道免疫中的作用尚不清楚。 我们的初步数据显示，簇状细胞炎性小体激活导致组织中IL-22水平升高， 可由TH17细胞或先天淋巴样细胞（ILC）产生的抗菌细胞因子，且所述簇状细胞 炎性体表达保护小肠免受细菌定植。根据我们的初步数据 和已发表的关于PGD2受体表达的数据，我们提出了通过PGD2的簇细胞-ILC3通讯轴。 我们假设，簇状细胞是小肠感染状态的中心哨兵， 改变肠道免疫反应的极化。 我们的目的是确定导致IL-22增加的途径后，簇状细胞炎性小体激活，使用在体内 簇状细胞特异性炎性小体激活和条件性上皮PGD2合酶和ILC3 PGD2的模型 受体缺陷进一步，我们将确定的重要性，簇细胞感染和炎性小体激活 在细菌性胃肠炎期间，使用沙门氏菌减毒株的感染清除模型， 不会导致全身性感染。我们还将探讨毛簇细胞炎性小体影响 在与寄生虫巴西日本圆线虫共感染期间持续的2型免疫反应，以及 沙门氏菌。这些研究将极大地有助于我们了解上皮细胞类型特异性病原体 肠道免疫系统对不同类型感染的反应能力。 这项提案汇集了俄勒冈州健康与科学大学劳赫实验室的研究和 这是华盛顿大学Tait Wojno实验室的专业知识。Tait Wojno的独特专业知识 将利用使用蠕虫感染小鼠模型的实验室来合作进行令人兴奋的研究 补充了Rauch实验室在上皮细胞生物学，炎性体生物学， 肠道细菌感染

Project summary The intestinal epithelium is exposed to different classes of pathogens and is not only instrumental as a first line of defense against invasion of the host, but also signals to immune cells in the underlying lamina propria when pathogens are detected. The NAIP/NLRC4 inflammasome has emerged as an important innate immune sensor in intestinal epithelial cells (IECs) in bacterial gastrointestinal infection, leading to rapid extrusion of infected cells and release of cytokines and eicosanoids upon pathogen recognition. The role of innate immune sensing and the NAIP/NLRC4 inflammasome at the level of individual subtypes of IEC is not well understood. Recently, we discovered that tuft cells uniquely among IECs release the eicosanoid prostaglandin D2 (PGD2) after inflammasome activation. Tuft cells are a rare subtype of IECs primarily known for their role in anti- parasitic immunity. The role of tuft cells during bacterial infection in general as well as the role of released PGD2 in intestinal immunity is unclear. Our preliminary data show that tuft cell inflammasome activation leads to increased tissue levels of IL-22, an antibacterial cytokine that can be produced by TH17 cells or innate lymphoid cells (ILCs), and that tuft cell inflammasome expression protects from small intestinal bacterial colonization. Based on our preliminary data and published data on PGD2 receptor expression we propose a tuft cell- ILC3 communication axis via PGD2. We hypothesize that tuft cells are central sentinels of infection status of the small intestine and capable of shifting the polarization of the intestinal immune response. We aim to define the pathway leading to IL-22 increase after tuft cell inflammasome activation using in vivo models of tuft cell specific inflammasome activation and conditional epithelial PGD2 synthase and ILC3 PGD2 receptor deficiency. Further we will define the importance of tuft cell infection and inflammasome activation during bacterial gastroenteritis, using a model of infection clearance with an attenuated strain of Salmonella that does not lead to systemic infection. We will also explore the capacity of the tuft cell inflammasome to affect an ongoing type 2 immune response during co-infection with a parasite, Nippostrongylus brasiliensis, and Salmonella. These studies will greatly contribute to our understanding of epithelial cell type specific pathogen sensing and the intestinal immune systems capacity to react to different types of infection. This proposal brings together studies in the Rauch laboratory at Oregon Health and Science University and the expertise of the Tait Wojno laboratory at the University of Washington. Unique expertise in the Tait Wojno laboratory in the use of murine models of helminth infection will be leveraged to collaborate on exciting studies that complement expertise in the Rauch laboratory in epithelial cell biology, inflammasome biology, and intestinal bacterial infection.