Stromal cells in immunity to infection

基质细胞对感染具有免疫力

基本信息

批准号：
10711890
负责人：
EDWARD J. PEARCE
金额：
$ 57.7万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-26 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10711890
关键词：
ATAC-seq Address Adipocytes Adipose tissue Affect Amphiregulin Antigens Applications Grants Biology Cell Communication Cells Cellular Metabolic Process Cellular biology Complex Connective Tissue Cells Data Development Disease Encapsulated Epidermal Growth Factor Receptor Extracellular Matrix Fibroblasts Fibrosis Flow Cytometry Gene Expression Profile Genetic Transcription Grant Granuloma Granulomatous Health Helminths Homeostasis Host resistance Human Hypersensitivity Immune Immune response Immunity Impaired wound healing Infection Interleukin-13 Interleukin-4 Interleukin-5 Intervention Intestines Invaded Lead Malignant Neoplasms Measurement Mediating Mesenchymal Stem Cells Mesentery Metabolic Modeling Morbidity - disease rate Multipotent Stem Cells Mus Nematoda Nematospiroides dubius Organ Outcome Paper Parasites Parasitology Pathway interactions Perforation Play Population Predisposition Primary Infection Process Production Property Publishing Reporting Resistance Resistance to infection Role Shapes Signal Transduction Small Intestines Soil Source Specificity Stromal Cells Structure System T-Lymphocyte TSLP gene Techniques Th2 Cells Therapeutic Intervention Tissues Training Transforming Growth Factor beta Work atopy cell motility cell type cellular imaging curative treatments cytokine enteric infection enteric pathogen healing helminth infection human disease in vivo insight interest interstitial lipid metabolism loss of function multipotent stromal progenitor neglected tropical diseases novel parasite invasion pathogen prevent protective effect receptor repaired resilience resistance mechanism response single-cell RNA sequencing soft tissue stem stem cells tissue repair tissue resident memory T cell transcriptome sequencing transmission process

项目摘要

Project Summary The objective of our work is to decipher how stromal cells interact with immune cells to alter tissue biology to support resistance to an intestinal infection. Our work will use mice infected with the intestinal helminth parasite Heligmosomoides polygyrus bakeri (Hp), which is a recognized inducer of type 2 immunity. In this system, mice are resistant to reinfection following curative treatment of primary infection, and resistance is Th2 cell-dependent. We recently reported that during Hp infection mesenteric adipose tissue (mAT) becomes populated by long-lived Th2RM cells which make Amphiregulin and TGFβ1 in addition to the signature Th2 cytokines IL-4, IL-5 and IL-13, and that deletion of the Amphiregulin receptor on stromal cells is associated with increased susceptibility to Hp. Further, stromal cells within mAT, and especially a subset of stromal cells with multipotent potential (multipotent progenitor cells, MPC) to differentiate into fibroblasts or adipocytes, become activated and makes the alarmins IL-33 and TSLP that are able to promote Th2 RM cell activation. We have localized both Th2RM cells and MPC to interstitial spaces in mAT. We propose that mAT interacts with the intestine to participate in the protective response against Hp. This involves the production of alarmins to support Th2RM cell activity, and to produce extracellular matrix (ECM), which we postulate is important for trapping invading parasites in granulomas, and supporting soft tissue integrity and repair during infection. Based on our published findings and new preliminary data, we hypothesize that Th2RM cells and stromal cells work as a team to mutually facilitate each other’s activation and exert host protective effects during Hp infection. On the basis of our recently published findings and new preliminary data on innate training in MPC, and lipid metabolism and motility of Th2RM cells, we have developed two Specific Aims: 1, To understand the role of MPC in shaping host resistance to Hp; and 2, To determine the function, antigen specificity, and cell- intrinsic metabolic and migratory features of mAT-resident Th2 cells. To address these Aims we will use RNA seq, ATACseq, flow cytometry, parasitological techniques, advanced imaging of cell movement ex-vivo, measurements of tissue stiffness, ex-vivo studies of the functional properties of Th2RM cells and stromal cells, and in vivo loss of function models to probe the roles of Amphiregulin, TGFβ, IL-33 and TSLP. Our work has the potential to reveal novel features of stromal cell biology that are integral to underlying effector mechanisms of resistance and immunity to intestinal pathogens, and to highlight potential points of intervention for manipulating stromal cell biology as it relates to type 2 immunity in health and disease. Our findings may have relevance to understanding human conditions such as atopy/allergy, impaired wound healing, fibrosis and cancer, in which dysregulated stromal cell biology and ECM production are implicated.

项目摘要我们工作的目的是破译基质细胞如何与免疫细胞相互作用，以改变组织生物学支持对肠道感染的抗性。我们的工作将使用感染肠蠕虫的小鼠寄生虫Heligmosomoides Polygyrus Bakeri（HP），它是公认的2型免疫诱导剂。在这个系统，小鼠对原发性感染的治疗治疗后具有抗性，耐药性为Th2 细胞依赖性。我们最近报告说，在HP感染期间，肠系膜脂肪组织（MAT）变成由长寿命的Th2RM细胞填充，除了特征TH2之外，这些细胞还产生了两次两次凝胶蛋白和TGFβ1 细胞因子IL-4，IL-5和IL-13，以及在基质细胞上的两极分裂蛋白受体的缺失与增加了对HP的敏感性。此外，MAT内的基质细胞，尤其是基质细胞的子集多能电位（多能祖细胞，MPC）分化为成纤维细胞或脂肪细胞，变成激活并使Alarmins IL-33和TSLP能够促进Th2 RM细胞激活。我们有将Th2RM细胞和MPC局部定位于MAT中的间隙空间。我们建议垫子与肠子参与针对HP的受保护反应。这涉及到警报的产生支持Th2RM细胞活性并产生细胞外基质（ECM），我们假设这对于捕获入侵颗粒中的寄生虫，并在感染过程中支持软组织完整性和修复。根据我们已发表的发现和新的初步数据，我们假设Th2RM细胞和基质细胞作为一个团队的工作，以相互促进彼此的激活并在惠普期间执行主机保护效果感染。根据我们最近发表的发现和有关MPC先天培训的新初步数据，以及Th2RM细胞的脂质代谢和运动能力，我们开发了两个具体的目的：1，以了解 MPC在塑造宿主对HP的抗性中的作用；和2，确定功能，抗原特异性和细胞 - MAT居民Th2细胞的内在代谢和迁移特征。为了解决这些目标，我们将使用RNA Seq，Atacseq，流式细胞术，寄生学技术，细胞运动的先进成像，即体内，测量组织刚度的测量，对Th2RM细胞和基质细胞的功能特性的离体研究，并在体内丧失功能模型，以探测两次凝血蛋白，TGFβ，IL-33和TSLP的作用。我们的工作有揭示基质细胞生物学新颖特征的潜力，这些特征是潜在效应机制不可或缺的对肠道病原体的抗药性和免疫力，并突出显示干预的潜在干预点操纵基质细胞生物学与健康和疾病中的2型免疫培养有关。我们的发现可能有与了解人类状况的相关性，例如特应性/过敏，伤口愈合受损，纤维化和癌症，其中涉及基质细胞生物学和ECM产生的失调。