Investigating biological functions of the staphylococcal type VII secretion systems

研究葡萄球菌 VII 型分泌系统的生物学功能

• 批准号: 2097375
• 金额: --
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2097375
• 关键词: Investigating; biological; functions; staphylococcal; type

Staphylococcus aureus is a leading cause of infections in animals and humans. Staphylococcal infections ranging from skin abscesses to septic shock have placed a huge financial burden on healthcare systems around the world. Antibiotic-resistant strains such as methicillin-resistant S.aureus (MRSA) and recurrent infections have made treatment of staphylococcal infections challenging. In animals, S.aureus causes mastitis, a severe infection of the mammary glands in dairy cows and is responsible for 10%-20% of the clinical and subclinical mastitis cases studied. Clinical mastitis impacts the health and welfare of dairy animals, and can cause death in worst cases. Persistent sub clinical infections are hard to eradicate. S.aureus encodes a specialised type VII Esat-6 secretion system (Ess), a system that was originally described in the intracellular pathogen, Mycobacterium tuberculosis. The staphylococcal Ess encodes virulence factors required for staphylococcal virulence and persistence in murine staphylococcal infection models. The Ess proteins are considered excellent vaccine and drug targets. The molecular mechanisms underlying Ess functions and its role in mediating persistent staphylococcal infection remain unclear. The goal of this project is to understand mechanisms by which Ess proteins mediate host and inter-bacterial interactions during staphylococcal infection. Employing isogenic mutants, the roles of individual Ess components will be investigated using global transcriptomic, proteomic and lipidomic approaches. In vitro cell infection assays will be used to study host cellular pathways that are modulated by Ess proteins. To understand the functions of Ess during staphylococcal infection, Ess-associated local immune and cellular responses will be studied in murine models of acute and chronic infection. Deciphering the biological roles of the Ess proteins will contribute to our understanding of staphylococcal mechanisms of persistence during infection.

金黄色葡萄球菌是动物和人类感染的主要原因。从皮肤脓肿到感染性休克的葡萄球菌感染给世界各地的卫生保健系统带来了巨大的经济负担。耐甲氧西林金黄色葡萄球菌（MRSA）等耐抗生素菌株和复发性感染使得葡萄球菌感染的治疗具有挑战性。在动物中，金黄色葡萄球菌引起乳腺炎，这是奶牛乳腺的一种严重感染，所研究的临床和亚临床乳腺炎病例中有10%-20%是由金黄色葡萄球菌引起的。临床乳腺炎影响奶牛的健康和福利，在最严重的情况下可导致死亡。持续的亚临床感染很难根除。金黄色葡萄球菌编码一种特殊的VII型Esat-6分泌系统（Ess），该系统最初在细胞内病原体结核分枝杆菌中被描述。在小鼠葡萄球菌感染模型中，葡萄球菌Ess编码葡萄球菌毒力和持久性所需的毒力因子。Ess蛋白被认为是极好的疫苗和药物靶点。Ess功能的分子机制及其在介导持续性葡萄球菌感染中的作用尚不清楚。该项目的目的是了解在葡萄球菌感染过程中，Ess蛋白介导宿主和细菌间相互作用的机制。采用等基因突变体，将使用全局转录组学、蛋白质组学和脂质组学方法研究单个Ess成分的作用。体外细胞感染试验将用于研究由Ess蛋白调节的宿主细胞通路。为了了解Ess在葡萄球菌感染中的功能，将在小鼠急性和慢性感染模型中研究Ess相关的局部免疫和细胞反应。破译Ess蛋白的生物学作用将有助于我们理解葡萄球菌在感染期间的持续机制。