Mechanism of dysbiosis caused by AE Pathogens

 描述(由申请人提供)：附着和消除(AE)病原体是高收入和低收入国家腹泻疾病的重要原因。AE病原体使用一种外膜粘附素，称为内膜素，与一种名为移位内膜受体(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亲密附着为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了它们的生长。这导致肠道相关微生物群落的组成发生变化，其特征是以AE病原体为主。哪些机制对微生物区系组成的这些变化负责的问题是一个将在本申请中解决的影响很大的话题。我们的中心假设是，T3SS介导的与宿主上皮细胞的亲密附着为AE病原体提供了呼吸所需的氧气，从而提供了比发酵共生细菌和推动肠道生态失调更大的优势。我们将通过研究轮齿芽孢杆菌T3SS促进有氧呼吸的机制(目标1)并确定轮齿芽孢杆菌与肠道微生物群竞争期间有氧呼吸的后果(目标2)来检验我们假设的不同方面。这项拟议的工作具有创新性，因为它是第一批阐明控制AE病原体、宿主及其微生物群之间平衡的分子机制之一。我们期望拟议工作的圆满完成将迎来 一项重大的概念进步表明，与上皮细胞的亲密附着通过为AE病原体提供生长所需的氧气而提供了一种健康优势。

 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.