Innate defenses against enterotoxigenic E. coli as potential therapeutic contributors

针对产肠毒素大肠杆菌的先天防御作为潜在的治疗贡献者

基本信息

批准号：
10686839
负责人：
Jennifer Foulke-Abel
金额：
$ 46.14万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686839
关键词：
Acute Adhesions Animals Apical Attention Bacteria Cancer cell line Cells Clinical Clinical Research Coculture Techniques Cyclic AMP Cyclic GMP Cyclic Nucleotides Diarrhea Disease Disease Outbreaks Drug Design Enabling Factors Enteral Enterotoxins Environment Epithelium Escherichia coli Escherichia coli Infections Functional disorder Goals Host Defense Human IL8 gene Image Immune Immune response Immunization Immunology Infection Inflammation Inflammatory Innate Immune Response Intention Interleukin-1 beta Intervention Intestines Investigation Knowledge Macrophage Methodology Modeling Molecular Multicenter Studies Oxygen Pathogenesis Pathogenicity Peptides Phase Phenotype Physiological Population Production Protein Subunits Reaction Regulation Research Role Second Messenger Systems Shigella Shigella Infections Signal Induction Signal Transduction Small Intestines Therapeutic Tissues Transcript Vaccine Design Vaccines Variant Work adaptive immunity antimicrobial peptide beta-Defensins burden of illness cell type cytokine design diarrheal disease enteroaggregative Escherichia coli enterotoxigenic Escherichia coli extracellular follow-up gut bacteria human model immune activation improved innovation insight intestinal epithelium intraepithelial microbiome model development monocyte monolayer neutrophil novel pathogen pathogenic bacteria peripheral blood pre-clinical response scaffold synergism targeted treatment therapeutic target therapy development tool vaccine strategy γδ T cells

项目摘要

PROJECT SUMMARY The bacterial pathogen enterotoxigenic E. coli (ETEC) contributes to the global burden of diarrheal disease because vaccine protection and therapy remain inadequate. A long-term goal is to improve knowledge of innate immune responses to ETEC infection, as they are likely important for initiating durable adaptive immunity. The objective of this project is to understand the innate immune defenses employed by human intestine to sense and eliminate ETEC, thus informing strategies for vaccine and/or drug design. We will (Aim 1) characterize the recognition and response mechanisms employed by tissue resident macrophages and neutrophils against ETEC infection. In a complementary inquiry, we will (Aim 2) assess antimicrobial peptides (AMPs) released by epithelial and immune cells in response to ETEC that could serve as potential treatment. These aims will be explored in primary co-culture models of human small intestinal epithelium (tissue-derived enteroids) and immune cell types from peripheral blood that are assembled on scaffolds to facilitate physiologically relevant crosstalk between bacteria, epithelia, and immune cell populations. Model development, application of anaerobic environment to mimic conditions in the intestinal lumen, and characterization will combine the expertise of the Enteroid and Immunology Cores that support this P01. The proposed studies are significant in that they will indicate the molecular signal transduction involved in reacting to and resolving ETEC infection without clinically overt inflammation, an understudied aspect of acute pathogenic diarrheal disease. Results from these studies will be compared to findings from enteroaggregative E. coli and Shigella pathogenesis proposals in this P01 to identify common effectors for therapeutic targeting. The projects of this P01 will cumulatively innovate human primary epithelial and immune cell co-culture strategies for host-pathogen research.

项目摘要细菌病原体肠毒素大肠杆菌（ETEC）有助于全球腹泻疾病负担因为疫苗保护和治疗仍然不足。一个长期目标是提高对对ETEC感染的先天免疫反应，因为它们对于启动耐用的适应性可能很重要免疫。该项目的目的是了解人类使用的先天免疫防御措施肠感知和消除ETEC，从而为疫苗和/或药物设计的策略提供了信息。我们将（目标 1）表征组织常驻巨噬细胞采用的识别和响应机制和中性粒细胞反对ETEC感染。在补充查询中，我们（AIM 2）评估抗菌肽（放大器）由上皮和免疫细胞释放，以响应ETEC，可以作为潜在治疗。这些目的将在人类小肠上皮的主要共培养模型中探索（组织衍生来自外周血中的肠todo虫和免疫细胞类型，这些细胞类型是在脚手架上组装的，以促进细菌，上皮和免疫细胞种群之间的生理相关串扰。模型开发，应用厌氧环境在模仿肠腔中的条件以及表征将结合支持该P01的肠托体和免疫学核心的专业知识。这拟议的研究很重要，因为它们将表明参与反应的分子信号转导进行和解决ETEC感染而没有临床明显的炎症，这是急性的研究致病性腹泻病。这些研究的结果将与肠肠系合的发现进行比较该P01中的大肠杆菌和志贺氏菌发病机理提案，以鉴定用于治疗靶向的常见效应子。该P01的项目将累积创新人类原发性上皮和免疫细胞共培养宿主病原体研究的策略。