The role of the tuft cell inflammasome in infection

簇细胞炎症小体在感染中的作用

基本信息

批准号：
10553185
负责人：
Isabella Rauch
金额：
$ 38.98万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10553185
关键词：
Actins Address Affect Anti-Bacterial Agents Antiparasitic Agents Attenuated Bacterial Gastroenteritis Bacterial Infections Biology CASP1 gene Cell Communication Cell Line Cell model Cells Cellular biology Collaborations Communicable Diseases Communication Complement Data Detection Dinoprostone Disease Dopamine D2 Receptor Eicosanoids Enterocytes Epithelial Cells Epithelium Evolution Exposure to Foundations Gastroenteritis Genes Health Hormones IL18 gene Immune Immune response Immune signaling Immune system Immunity In Vitro Individual Infection Inflammasome Inflammatory Inflammatory Response Interleukin-13 Interleukin-5 Intestines Invaded Laboratories Lamina Propria Lymphocyte Lymphoid Lymphoid Cell Mediating Modeling Mucous body substance Mus Nippostrongylus Oregon Parasites Parasitic infection Pathogen detection Pathway interactions Peptide Hydrolases Prostaglandin D2 Prostaglandins Publishing Reaction Regenerating islet derived protein 3-Gamma Reporting Resistance Role Salmonella Salmonella typhimurium Science Sentinel Shapes Shigella Infections Signal Transduction Small Intestines Sorting Source Systemic infection Testing Tissues Universities Washington Water antimicrobial cell type co-infection cysteinyl-leukotriene cytokine enteric infection experimental study gastrointestinal gastrointestinal infection gut inflammation helminth infection immunological status immunoreaction immunoregulation in vivo in vivo Model innate immune sensing interleukin-22 intestinal epithelium lipid mediator microorganism mouse Cre recombinase mouse model nutrient absorption pathogen pathogenic bacteria prevent receptor expression response sensor single-cell RNA sequencing

项目摘要

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.

项目摘要肠上皮暴露于不同类别的病原体，不仅是第一行防御侵入宿主的防御，但同时也向基础层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胃肠道感染中肠上皮细胞（IEC）中的传感器，导致快速挤出病原体识别后，感染细胞和细胞因子和类花生素的释放。先天免疫的作用在IEC的单个亚型水平上的传感和NAIP/NLRC4炎症体不太了解。最近，我们发现IEC中独特的簇细胞释放了eicosanoid Prostaglandin D2（PGD2）激活后。簇细胞是IEC的罕见亚型，主要以它们在抗 - 寄生虫免疫。簇细胞在细菌感染中的作用一般以及释放的作用肠道免疫中的PGD2尚不清楚。我们的初步数据表明，簇细胞炎性体激活导致组织水平升高IL-22，一种 Th17细胞或先天淋巴样细胞（ILC）可以产生的抗菌细胞因子，该簇细胞炎性体表达可保护小肠细菌定植。根据我们的初步数据并发表了有关PGD2受体表达的数据，我们通过PGD2提出了一个Tuft细胞ILC3通信轴。我们假设簇细胞是小肠的感染状态的中央哨兵，能够转移肠道免疫反应的极化。我们的目的是定义导致Tuft细胞炎症体激活后IL-22增加的途径，使用体内特异性细胞特异性炎性体激活和条件上皮PGD2合酶和ILC3 PGD2的模型受体缺乏。此外，我们将定义簇细胞感染和炎性体激活的重要性在细菌性胃肠炎期间，使用与沙门氏菌减毒的感染清除模型这不会导致全身感染。我们还将探索簇菌细胞炎症体的能力影响与寄生虫，nippostrongylus brasiliensis和沙门氏菌。这些研究将极大地有助于我们对上皮细胞类型特异性病原体的理解感应和肠道免疫系统对不同类型的感染有反应的能力。该提案汇集了俄勒冈州健康与科学大学劳奇实验室的研究以及华盛顿大学的Tait Wojno实验室的专业知识。 Tait Wojno的独特专业知识实验室在使用蠕虫感染的鼠模型中将利用令人兴奋的研究合作这种补充了上皮细胞生物学，炎症体生物学和肠道细菌感染。