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（由适用提供）：在高收入和低收入国家中，附着和eSFAC（AE）病原体是腹泻疾病的重要原因。 AE病原体使用称为内膜蛋白的外膜粘合剂与受体蛋白结合，称为易位性内膜素受体（TIR），该病原体使用III型分泌系统（T3SS）将病原体注入上皮细胞。由此产生的对上皮细胞的亲密依恋为AE病原体提供了对微环境通过未知机制增强其生长的机会。这导致肠道相关的微生物群落的组成变化，其特征是AE病原体的优势。哪些机制导致微生物群组成中这些变化的问题代表了本应用程序中将解决的一个高影响主题。我们的中心假设是，T3SS介导的对宿主上皮细胞的亲密依恋提供了AE病原体，可以访问氧气以进行呼吸，从而比发酵的共生细菌具有很大的优势，并在肠道中驱动了营养不良。我们将通过研究啮齿动物C. t3ss促进有氧呼吸的机制来检验假设的不同方面（AIM 1），并确定在啮齿动物C. rodentium与肠道微生物群竞争期间有氧呼吸的后果（AIM 2）。提出的工作具有创新性，因为它是最早阐明分子机制来控制AE病原体，宿主及其微生物群之间平衡的人之一。我们期望成功完成拟议的工作将迎来 通过证明对上皮细胞的亲密依恋通过提供AE病原体并获得氧气的生长，这是一个重大的概念前进。