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

项目概述：这个由MRC资助的博士培训伙伴关系（DTP）将尖端的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，使学生能够解决以假设为主导的生物医学研究问题。这是一个为期4年的计划，其第一年涉及一系列教学模块和两个基于实验室的研究项目，导致跨学科生物医学研究硕士学位。前两个学期包括一系列教学模块，让学生在多学科科学中获得坚实的基础。学生还参加了一系列由学术和行业专家领导的大师班，这些专家在分子，细胞和组织动力学，微生物学和感染，应用生物医学技术以及人工智能和数据科学领域。在第三和夏季学期，学生在他们选择的实验室进行两个为期11周的研究项目。金黄色葡萄球菌是一种引起一系列疾病的细菌，但最广为人知的是医院获得性感染的原因。这些感染可能是严重的，难以治疗，由于抗生素耐药菌株的S。金黄色葡萄球菌，例如耐甲氧西林的S.金黄色葡萄球菌（MRSA）。S.金黄色葡萄球菌最初被认为在感染期间驻留在宿主细胞外，但现在被认为具有细胞内生活方式。细胞内的细菌与持续感染和逃避抗生素有关。认为S.与许多细菌一样，金黄色葡萄球菌通过分泌多种毒素来操纵宿主细胞。为了将毒素受控地输出到宿主中，细菌需要细胞膜中的分泌机器。S.金黄色葡萄球菌具有称为Esat-6分泌系统（Ess）的专门分泌机器。类似的Esat-6系统最初是在结核分枝杆菌中发现的，结核分枝杆菌是导致结核病的病原体。葡萄球菌Ess蛋白对于细菌的毒力是重要的，并且目前被认为是疫苗候选物。我们最近的工作表明，Ess蛋白干扰葡萄球菌感染过程中的细胞死亡。然而，潜在的人类细胞过程和持续感染的ESTA介导的调制的基本机制仍然不清楚。在这项工作中，我们将调查的作用，埃斯机的生命周期和复制的S。金黄色葡萄球菌在人类巨噬细胞，细胞参与宿主防御。我们将使用各种分子、细胞和高分辨率显微镜技术评估Ess系统对巨噬细胞信号传导途径和免疫反应的影响。此外，由于持续性感染很难研究，我们将开发敏感的技术来建模和可视化长期感染，使用基于物理和工程的方法。将在实验室中开发专门的人体器官模拟物，以研究S.金黄色葡萄球菌持续感染的生理相关条件。

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.