The role of the tuft cell inflammasome in infection

簇细胞炎症小体在感染中的作用

• 批准号: 10418402
• 负责人: Isabella Rauch
• 金额: $ 39.4万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-20 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10418402
• 关键词: Actins; Address; Affect; Anti-Bacterial Agents; Antiparasitic Agents; Attenuated; Bacterial Gastroenteritis; Bacterial Infections; Biology; CASP1 gene; Cell Communication; Cell model; Cells; Cellular biology; Complement; Data; Detection; Dinoprostone; Disease; Dopamine D2 Receptor; Eicosanoids; Enterocytes; Epithelial; Epithelial Cells; Evolution; Exposure to; Foundations; Gastroenteritis; Genes; Health Sciences; Hormones; Immune; Immune response; Immune signaling; Immune system; Immunity; In Vitro; Individual; Infection; Inflammasome; Inflammatory; Inflammatory Response; Interleukin-13; Interleukin-18; Interleukin-5; Intestines; Laboratories; Lamina Propria; Lead; Lymphocyte; Lymphoid; Lymphoid Cell; Mediating; Modeling; Mucous body substance; Mus; Nippostrongylus; Nutrient; Oregon; Parasites; Parasitic infection; Pathway interactions; Peptide Hydrolases; Prostaglandin D2; Prostaglandins; Publishing; Reaction; Reporting; Resistance; Role; Salmonella; Salmonella typhimurium; Sentinel; Shigella Infections; Signal Transduction; Small Intestines; Source; Systemic infection; Testing; Tissues; Universities; Washington; Water; antimicrobial; base; cell type; co-infection; cysteinyl-leukotriene; cytokine; enteric infection; experimental study; gastrointestinal; gastrointestinal infection; gut inflammation; helminth infection; immunological status; immunoreaction; in vivo; in vivo Model; innate immune sensing; interleukin-22; intestinal epithelium; lipid mediator; microorganism; mouse Cre recombinase; mouse model; pathogen; pathogenic bacteria; prevent; receptor expression; response; sensor; single-cell RNA sequencing

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.

项目概要 肠上皮暴露于不同类别的病原体，不仅起到一线作用 防御宿主入侵，而且在以下情况下也向底层固有层中的免疫细胞发出信号 检测到病原体。 NAIP/NLRC4 炎性体已成为重要的先天免疫 细菌性胃肠道感染中肠上皮细胞（IEC）中的传感器，导致快速排出 感染细胞并在病原体识别后释放细胞因子和类二十烷酸。先天免疫的作用 IEC 各个亚型水平上的传感和 NAIP/NLRC4 炎性体尚不清楚。 最近，我们发现 IEC 中簇状细胞独特地释放类二十烷酸前列腺素 D2 (PGD2) 炎症小体激活后。簇细胞是 IEC 的一种罕见亚型，主要因其在抗- 寄生免疫。簇细胞在一般细菌感染过程中的作用以及释放的作用 PGD​​2在肠道免疫中的作用尚不清楚。 我们的初步数据表明，簇细胞炎症小体激活导致组织中 IL-22 水平增加，IL-22 是一种 TH17 细胞或先天性淋巴细胞 (ILC) 产生的抗菌细胞因子，以及簇状细胞 炎症小体的表达可防止小肠细菌定植。根据我们的初步数据 并发表了有关 PGD2 受体表达的数据，我们提出了通过 PGD2 的簇细胞-ILC3 通讯轴。 我们假设簇细胞是小肠感染状态的中枢哨兵，并且能够 改变肠道免疫反应的极化。 我们的目标是利用体内方法确定簇细胞炎症小体激活后导致 IL-22 增加的途径 簇细胞特异性炎性体激活和条件上皮 PGD2 合酶和 ILC3 PGD2 模型 受体缺乏。此外，我们将定义簇细胞感染和炎性小体激活的重要性 在细菌性胃肠炎期间，使用沙门氏菌减毒株清除感染模型 不会导致全身感染。我们还将探讨簇细胞炎性体影响的能力 与巴西尼波圆线虫共同感染期间持续的 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 感知和肠道免疫系统对不同类型感染做出反应的能力。 该提案汇集了俄勒冈健康与科学大学 Rauch 实验室和 华盛顿大学 Tait Wojno 实验室的专业知识。 Tait Wojno 的独特专业知识 使用蠕虫感染小鼠模型的实验室将用于合作开展令人兴奋的研究 补充 Rauch 实验室在上皮细胞生物学、炎性体生物学和 肠道细菌感染。