Mechanism of dysbiosis caused by AE Pathogens

AE病原体引起生态失调的机制

• 批准号: 8895812
• 负责人: Andreas J Baumler
• 金额: $ 23.48万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8895812
• 关键词: Address; Automobile Driving; Bacteria; Bacterial Adhesins; Binding; Cell Respiration; Citrobacter rodentium; Communities; Country; Development; Disease; Epithelial Cells; Equilibrium; Funding Mechanisms; Goals; Growth; Income; Infection; Laboratories; Large Intestine; Low income; Mediating; Membrane; Microbe; Modeling; Molecular; Mus; Oxygen; Research; Respiration; Science; Testing; Type III Secretion System Pathway; Virulence Factors; Work; expectation; fitness; gut microbiota; innovation; microbial community; mouse model; pathogen; public health relevance; receptor; tissue/cell culture

 DESCRIPTION (provided by applicant): Attaching and effacing (AE) pathogens are an important cause of diarrheal disease in both high-income and low-income countries. AE pathogens use an outer membrane adhesin, termed intimin, to bind to a receptor protein, termed translocated intimin receptor (Tir), which the pathogen injects into epithelial cells using type III secretion system (T3SS). The resulting intimate attachment to epithelial cells provides AE pathogens access to a microenvironment that boosts their growth through unknown mechanisms. This results in changes in the composition of gut associated microbial communities that are characterized by a dominance of the AE pathogen. The question of which mechanisms are responsible for these changes in the microbiota composition represents a high-impact topic that will be addressed in this application. Our central hypothesis is that T3SS-mediated intimate attachment to host epithelial cells provides AE pathogens with access to oxygen for respiration, thus providing a substantial advantage over fermenting commensal bacterial and driving dysbiosis in the gut. We will test different aspects of our hypothesis by investigating the mechanism by which the C. rodentium T3SS promotes aerobic respiration (Aim 1) and determining the consequences of aerobic respiration during competition of C. rodentium with the gut microbiota (Aim 2). The proposed work is innovative because it is among the first to elucidate molecular mechanisms that control the balance between AE pathogens, the host and its microbiota. It is our expectation that successful completion of the proposed work will usher in a major conceptual advance by demonstrating that intimate attachment to epithelial cells confers a fitness advantage by providing AE pathogens with access to oxygen for growth.

 描述（由申请人提供）：附着和消失（AE）病原体是高收入和低收入国家中疟疾疾病的重要原因。AE病原体使用称为内膜素的外膜粘附素与称为易位内膜素受体（Tir）的受体蛋白结合，病原体使用III型分泌系统（T3SS）将其注入上皮细胞。由此产生的与上皮细胞的紧密附着为AE病原体提供了进入微环境的途径，该微环境通过未知的机制促进它们的生长。这导致肠道相关微生物群落的组成发生变化，其特征在于AE病原体占优势。哪些机制负责微生物群组成的这些变化的问题代表了将在本申请中解决的高影响主题。我们的中心假设是T3SS介导的与宿主上皮细胞的紧密附着为AE病原体提供了呼吸氧气的途径，从而提供了比发酵肠道细菌和驱动肠道生态失调的实质性优势。我们将通过研究C.啮齿类T3SS促进好氧呼吸（Aim 1），并决定好氧呼吸在竞争过程中的后果。啮齿动物与肠道微生物群（目标2）。这项工作具有创新性，因为它是第一个阐明控制AE病原体，宿主及其微生物群之间平衡的分子机制的研究。我们期望，拟议工作的圆满完成将带来 这是一个重大的概念性进展，证明了与上皮细胞的紧密附着通过为AE病原体提供生长所需的氧气而赋予了适应性优势。