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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.

项目总结