The Role of the Staphyloccocal Ess in the modulation of host responses

课程概述：这个由MRC资助的博士培训伙伴关系(DTP)将尖端分子和分析科学与数据分析中的创新计算方法结合在一起，使学生能够解决假设引导的生物医学研究问题。这是一个为期4年的课程，第一年包括一系列的教学模块和两个基于实验室的研究项目，这些项目导致了跨学科生物医学研究的硕士学位。前两个学期包括精选的教学模块，使学生能够在多学科的科学中获得坚实的基础。学生们还参加了由学术和行业专家主持的一系列大师课程，这些专家涉及分子、细胞和组织动力学、微生物学和传染病、应用生物医学技术以及人工智能和数据科学等领域。在第三学期和暑期，学生们在他们选择的实验室里进行两个为期十一周的研究项目。项目：金黄色葡萄球菌是一种导致一系列疾病的细菌，但最广为人知的是导致医院获得性感染的原因。由于金黄色葡萄球菌抗药性菌株的增加，例如耐甲氧西林金黄色葡萄球菌(MRSA)，这些感染可能很严重，很难治疗。金黄色葡萄球菌最初被认为在感染期间居住在宿主细胞外，但现在被认为具有细胞内的生活方式。驻留在细胞内的细菌与持续感染和逃避抗生素有关。人们认为，金黄色葡萄球菌像许多细菌一样，通过分泌广泛的毒素来操纵宿主细胞。为了控制毒素向宿主的出口，细菌需要细胞膜上的分泌机。金黄色葡萄球菌有一种特殊的分泌机，称为ESAT-6分泌系统(Ess)。类似的ESAT-6系统最初在引起结核病的病原体结核分枝杆菌中发现。葡萄球菌Ess蛋白对细菌的毒力很重要，目前正被认为是疫苗候选。我们最近的工作证明，在葡萄球菌感染过程中，Ess蛋白干扰细胞死亡。然而，Ess介导的调节人类细胞过程和持续感染的基本机制仍不清楚。在这项工作中，我们将研究ESS机器在金黄色葡萄球菌在人巨噬细胞内的生命周期和复制中的作用，巨噬细胞是参与宿主防御的细胞。我们将使用各种分子、细胞和高分辨率显微镜技术来评估ESS系统对巨噬细胞信号通路和免疫反应的影响。此外，由于持续性感染很难研究，我们将开发敏感的技术，使用基于物理学和工程学的方法对长期感染进行建模和可视化。实验室将开发专门的人体器官模拟物，以研究Ess蛋白在生理相关条件下金黄色葡萄球菌持续感染中的作用机制。

Programme overview:This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address hypothesis-led biomedical research questions. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice. Project:Staphylococcus aureus is a bacterium responsible for a range of illnesses, but is most widely known as a cause of hospital acquired infections. These infections can be severe and difficult to treat due to the rise in antibiotic resistant strains of S. aureus, e.g. Methicillin Resistant S. aureus (MRSA). S. aureus is primarily thought to reside outside host cells during infection, but is now recognized to have an intracellular lifestyle. Bacteria residing within cells have been associated with persistent infections and evasion of antibiotics. It is thought that S. aureus manipulates host cells by the secretion of a wide range of toxins, as many bacteria do. For controlled export of the toxins into the host, bacteria require secretory machines in their cell membrane. S. aureus has a specialised secretion machine known as the Esat-6 secretion system (Ess). Similar Esat-6 systems were originally discovered in Mycobacterium tuberculosis, the pathogen that causes tuberculosis. The staphylococcal Ess proteins are important for bacterial virulence, and are currently being considered as vaccine candidates. Our recent work demonstrated that an Ess protein interferes with cell death during staphylococcal infection. However, the basic mechanisms underlying Ess-mediated modulation of human cell processes and persistent infections remain unclear. In this work, we will investigate the role of the Ess machine in the lifecycle and replication of S. aureus inside human macrophages, cells involved in host defence. We will assess the impact of the Ess system on macrophage cell signalling pathways and immune responses using a variety of molecular, cellular and high-resolution microscopy techniques. Moreover, as persistent infections are hard to study, we will develop sensitive techniques to model and visualise long term infections, using physics and engineering based approaches. Specialised human organ mimics will be developed in the laboratory to investigate the mechanism of action of the Ess proteins in S. aureus persistent infections in physiologically relevant conditions.