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.

项目概要我们工作的目标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我们的工作将使用感染肠道蠕虫的小鼠来支持对肠道感染的抵抗力。寄生虫Heligmosomoides polygyrus Bakeri (Hp)，是公认的 2 型免疫诱导剂。系统中，小鼠在原发感染治愈后对再感染具有抵抗力，并且抵抗力是Th2 我们最近报道，在 Hp 感染期间，肠系膜脂肪组织 (mAT) 变得细胞依赖性。由长寿的 Th2RM 细胞组成，除了标志性 Th2 之外，还产生双调蛋白和 TGFβ1 细胞因子 IL-4、IL-5 和 IL-13，基质细胞上双调蛋白受体的缺失与此外，mAT 内的基质细胞，特别是具有 Hp 的基质细胞子集，对 Hp 的易感性增加。多能祖细胞（MPC）分化为成纤维细胞或脂肪细胞，成为激活并产生能够促进 Th2 RM 细胞激活的警报素 IL-33 和 TSLP。将 Th2RM 细胞和 MPC 定位于 mAT 的间隙空间，我们认为 mAT 与 mAT 相互作用。肠道参与针对 Hp 的保护性反应，这涉及到警报素的产生。支持 Th2RM 细胞活性，并产生细胞外基质 (ECM)，我们认为这对于将入侵的寄生虫捕获在肉芽肿中，并在感染期间支持软组织的完整性和修复。根据我们发表的研究结果和新的初步数据，我们发现 Th2RM 细胞和基质细胞 Hp期间，团队合作，相互促进激活，发挥宿主保护作用根据我们最近发表的关于 MPC 先天训练的研究结果和新的初步数据，以及 Th2RM 细胞的脂质代谢和运动性，我们制定了两个具体目标： 1、了解 MPC 在形成宿主对 Hp 的抵抗力中的作用；以及 2、确定其功能、抗原特异性和细胞- mAT 驻留 Th2 细胞的内在代谢和迁移特征为了实现这些目标，我们将使用 RNA。 seq、ATACseq、流式细胞术、寄生虫学技术、离体细胞运动的高级成像、组织硬度测量、Th2RM 细胞和基质细胞功能特性的体外研究，我们的工作包括体内功能丧失模型，以探讨双调蛋白、TGFβ、IL-33 和 TSLP 的作用。有可能揭示基质细胞生物学的新特征，这些特征是潜在效应机制的组成部分对肠道病原体的抵抗力和免疫力，并强调潜在的干预点操纵基质细胞生物学，因为它与健康和疾病中的 2 型免疫有关。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。