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: 10642951
• 负责人: ANTHONY W MARESSO
• 金额: $ 55.42万
• 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/10642951
• 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; Inpatients; 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; Program Description; Property; Recording of previous events; Reporting; Research; Seminal; Surface; System; Therapeutic; Tissues; Tropism; Vaccines; Virulent; Work; antagonist; cytotoxicity; enteric pathogen; enteroaggregative Escherichia coli; gastrointestinal; gastrointestinal infection; gut microbiota; heparin proteoglycan; ileum; intestinal epithelium; jejunum; microbiota; novel; pathogen; 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.

项目摘要 - 项目3 肠粘膜表面是一个复杂的机械生理环境，该环境完善了病原体， 共生和主持人。因为这种复杂性可能会影响我们对疾病病因的理解，所以 开发准确捕获其生理的模型系统至关重要。人肠癌（HIO） 已提出作为粘膜仿生的研究，以研究由肠道病原体引起的传染病。我们的 以前资助的项目（NIAID U19 NAMSED计划的一部分）建立了使用HIO来理解的 肠道大肠杆菌（EAEC）的发病机理，这是儿童持续性腹泻的常见原因， 免疫功能低下和旅行者。没有用于EAEC的疫苗，抗生素治疗很复杂 多药的抵抗力，受保护的共生的消融，并报道了减少腹泻的无效性 期间。我们研究的第二个发现是意外的观察，即对EAEC的敏感性 感染基本上取决于宿主供体，尤其是在新数据的背景下表明 EAEC的粘膜受体是乙酰硫酸化的蛋白聚糖（HSPG）。此续签的工作以此为基础 到目前 对肠上皮的细胞病毒作用。在AIM 1中，大量HIO的特征是 对EAEC感染的敏感性和分子发病机理的标志性特征与供体状态相关 HSPG。在AIM 2中，关键的肠道机械生理特性，包括腔流，基体刚度， 评估了免疫细胞的存在和节段连通性的对HSPG依赖性EAC的影响 感染。最后，通过竞争与EAEC拮抗的人类肠道菌群（共生和噬菌体） 将确定一个基于聚糖的肠道小裂。这项工作将揭示主管EAEC的主机因素 感染的敏感性，驱动它们的机械生理线索以及基于生物群的方法 具有拮抗和治疗性。