Human Gastrointestinal Biomimetics for Enteric Bacterial Infections

用于肠道细菌感染的人体胃肠道仿生学

• 批准号: 10462793
• 负责人: ANTHONY W MARESSO
• 金额: $ 34.72万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462793
• 关键词: Ablation; Address; Adherence; Affect; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Apical; Bacterial Infections; Bacteriophages; Binding; Biological Models; Biology; Biomedical Engineering; Biomimetics; Biota; Cell physiology; Cells; Child; Coculture Techniques; Collection; Colon; Communicable Diseases; Complex; Cues; Data; Diarrhea; Disease; Duodenum; Ecosystem; Elements; Enteral; Environment; Epithelial Cells; Equilibrium; Escherichia coli; Escherichia coli Infections; Etiology; Extracellular Matrix; Funding; Gastrointestinal tract structure; Growth; Heparan Sulfate Proteoglycan; Human; Hybrids; Immune; Immune response; Immunocompromised Host; Immunologics; Infection; Infection prevention; Inflammation; Inflammatory; Integration Host Factors; Intestinal Mucosa; Intestines; Knowledge; Measures; Mediating; Medicine; Modeling; Molecular; Molecular Profiling; Mucous Membrane; Multi-Drug Resistance; National Institute of Allergy and Infectious Disease; Nature; Organoids; Pathogenesis; Patients; Physiological; Physiology; Polysaccharides; Predisposition; Property; Recording of previous events; Reporting; Research; Seminal; Surface; System; Therapeutic; Tissues; Tropism; Vaccines; Virulent; Work; antagonist; base; cytotoxicity; enteric pathogen; enteroaggregative Escherichia coli; gastrointestinal; gastrointestinal infection; gut microbiota; heparin proteoglycan; ileum; intestinal epithelium; jejunum; microbiota; novel; pathogen; programs; receptor; response; shear stress

Project Summary – Project 3 The intestinal mucosal surface is a complex mechano-physiologic environment comprised of pathogen, commensal, and host. Because this complexity may affect our understanding of the etiology of disease, it is critical to develop model systems that accurately capture their physiology. Human intestinal organoids (HIOs) have been proposed as a mucosal biomimetic to study infectious diseases caused by enteric pathogens. Our previously funded project (part of the NIAID U19 NAMSED initiative) established the use of HIOs to understand the pathogenesis of Enteroaggregative E. coli (EAEC), a common cause of persistent diarrhea in children, the immunocompromised, and travelers. There is no vaccine for EAEC and antibiotic treatment is complicated by multi-drug resistance, the ablation of protective commensals, and reported ineffectiveness at reducing diarrheal duration. A seminal finding from our study was the unexpected observation that the susceptibility to EAEC infection was substantially dependent on the host donor, especially in the context of new data that suggests the mucosal receptor for EAEC is heparan-sulfated proteoglycan (HSPG). The work in this renewal builds upon this observation by now hypothesizing that EAEC donor-specific adherence drives the local delivery of secreted cytopathic effectors to the intestinal epithelium. In Aim 1, a large collection of HIOs are characterized for their sensitivity to EAEC infection and hallmark signatures of molecular pathogenesis correlated to the status of donor HSPGs. In Aim 2, key intestinal mechano-physiologic properties, including luminal flow, basolateral stiffness, the presence of immune cells, and segmental connectivity, are assessed for their effect on HSPG-dependent EAEC infection. Finally, human intestinal microbiota (commensals and phage) that antagonize EAEC by competing for a glycan-based intestinal niche will be identified. This work will reveal the host factors that govern EAEC susceptibility to infection, the mechano-physiologic cues that drive them, and targeted biota-based approaches that are antagonistic and therapeutic.

项目总结 – 项目 3 肠粘膜表面是一个复杂的机械生理环境，由病原体组成， 因为这种复杂性可能会影响我们对疾病病因的理解，所以它是。 对于开发准确捕捉人类肠道类器官（HIO）生理学的模型系统至关重要。 已被提议作为粘膜仿生剂来研究肠道病原体引起的传染病。 先前资助的项目（NIAID U19 NAMSED 计划的一部分）建立了使用 HIO 来理解 肠聚集性大肠杆菌（EAEC）的发病机制，这是儿童持续性腹泻的常见原因， 免疫功能低下和旅行者 没有针对 EAEC 的疫苗，抗生素治疗也很复杂。 多重耐药性、保护性共生体的消除以及据报道在减少腹泻方面无效 我们的研究的一个重要发现是意外的观察结果，即对 EAEC 的易感性。 感染在很大程度上取决于宿主供体，特别是在新数据表明 EAEC 的粘膜受体是硫酸乙酰肝素蛋白聚糖 (HSPG)，本次更新的工作以此为基础。 现在观察假设 EAEC 供体特异性依从性驱动分泌的局部递送 在目标 1 中，大量 HIO 的特征在于其对肠上皮的细胞病变效应。 对 EAEC 感染的敏感性以及与供体状态相关的分子发病机制的标志特征 在目标 2 中，关键的肠道机械生理特性，包括腔内流量、基底外侧硬度、 评估免疫细胞的存在和节段连接对 HSPG 依赖性 EAEC 的影响 最后，人类肠道微生物群（共生菌和噬菌体）通过竞争来拮抗 EAEC。 这项工作将确定基于聚糖的肠道生态位，揭示控制 EAEC 的宿主因素。 对感染的易感性、驱动感染的机械生理线索以及基于生物群的针对性方法 是对抗性的和治疗性的。