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：
10190304
负责人：
Jennifer Foulke-Abel
金额：
$ 35.19万
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/10190304
关键词：
Acute Adhesions Anaerobic Bacteria 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 Enteral Enterotoxins Environment Epithelial 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 Methodology Modeling Molecular Multicenter Studies Oxygen Pathogenesis Pathogenicity Peptides Phase Phenotype Physiological Population Production Protein Subunits Regulation Research Role Second Messenger Systems Shigella Shigella Infections Signal Transduction Small Intestines Therapeutic Time Tissues Transcript Vaccine Design Vaccines Variant Work adaptive immunity antimicrobial peptide base 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 macrophage microbiome model development monocyte monolayer neutrophil novel pathogen pathogenic bacteria peripheral blood pre-clinical response scaffold targeted treatment therapeutic target therapy development tool 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.

项目概要细菌病原体产肠毒素大肠杆菌 (ETEC) 加重了全球腹泻疾病的负担因为疫苗保护和治疗仍然不足。长期目标是提高知识水平对 ETEC 感染的先天免疫反应，因为它们可能对于启动持久适应性很重要免疫。该项目的目的是了解人类采用的先天免疫防御肠道来感知和消除 ETEC，从而为疫苗和/或药物设计策略提供信息。我们将（目标 1) 表征组织驻留巨噬细胞所采用的识别和反应机制中性粒细胞对抗 ETEC 感染。在补充调查中，我们将（目标 2）评估抗菌肽（AMP）由上皮细胞和免疫细胞响应 ETEC 释放，可作为潜在的治疗方法。这些目标将在人类小肠上皮（组织来源的肠类）和来自外周血的免疫细胞类型，它们组装在支架上以促进细菌、上皮细胞和免疫细胞群之间的生理相关串扰。模型开发、应用厌氧环境来模拟肠腔内的条件，以及表征将结合支持该 P01 的肠类和免疫学核心的专业知识。这拟议的研究具有重要意义，因为它们将表明反应中涉及的分子信号转导在没有临床明显炎症的情况下解决 ETEC 感染，这是急性感染的一个尚未得到充分研究的方面致病性腹泻病。这些研究的结果将与肠道聚合的结果进行比较本 P01 中的大肠杆菌和志贺氏菌发病机制建议旨在确定治疗靶向的常见效应器。本次P01项目将累积创新人类原代上皮与免疫细胞共培养宿主病原体研究策略。