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

• 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
• 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

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.

项目总结 产肠毒素大肠杆菌(ETEC)是造成全球腹泻疾病负担的主要原因。 因为疫苗保护和治疗仍然不够。一个长期的目标是提高对 对ETEC感染的先天免疫反应，因为它们可能对启动持久适应很重要 豁免权。这个项目的目标是了解人类使用的先天免疫防御系统。 肠道中检测和消除ETEC，从而为疫苗和/或药物设计策略提供信息。我们会(瞄准) 1)描述组织驻留巨噬细胞所采用的识别和反应机制 中性粒细胞抗ETEC感染。在一个补充调查中，我们将(目标2)评估抗菌肽 (AMPS)由上皮细胞和免疫细胞对ETEC的反应而释放，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)的原代共培养模型中进行探索 肠样)和来自外周血的免疫细胞类型，组装在支架上以促进 细菌、上皮细胞和免疫细胞种群之间的生理上相关的串扰。型号 发展和应用厌氧环境来模拟肠腔内的条件，以及 定性将结合支持这一P01的肠道和免疫学核心的专业知识。这个 提出的研究具有重要意义，因为它们将表明参与反应的分子信号转导。 在没有临床明显炎症的情况下治疗和解决ETEC感染，这是急性肺炎研究不足的一个方面 致病性腹泻病。这些研究的结果将与肠聚集试验的结果进行比较。 在本P01中提出了大肠杆菌和志贺氏菌的致病机制建议，以确定治疗靶向的常见效应物。 P01的项目将累积创新人类原代上皮细胞和免疫细胞共培养 寄主-病原体研究的策略。