Investigation of the role of the Type VII secretion systems in Staphylococcus aureus-macrophage interactions

金黄色葡萄球菌，一种经常在我们的皮肤和鼻孔上发现的细菌，是威胁生命的感染如肺炎和心内膜炎的主要原因之一。这种病原体经常与医疗保健系统和医院相关的S。金黄色葡萄球菌感染是全球医疗保健费用增加的原因。新的抗生素耐药菌株的出现一直是有效治疗链球菌的主要障碍。金黄色葡萄球菌感染与可用的药物治疗。针对耐药S.金黄色葡萄球菌感染可有效解决耐药性问题。已知金黄色葡萄球菌与我们的细胞密切相互作用。除了从细胞外活动外，这种细菌还可以进入我们的细胞内，利用它作为一个小生境进行繁殖。称为巨噬细胞的免疫细胞形成第一道防线，在病原体清除中很重要。然而，研究表明，这些细胞并不总是有效地杀死S。金黄色。S.金黄色葡萄球菌能够在巨噬细胞内存活和繁殖，巨噬细胞随后无意中帮助将细菌运送到身体的其他部位。我们目前对这种病原体用来操纵这些免疫细胞的细菌蛋白质和途径没有很好的了解。S.金黄色葡萄球菌在感染期间将几种蛋白质输出到外部环境。它有一个专门的蛋白质输出系统，称为VII型分泌系统（T7SS），分泌对细菌毒力重要的蛋白质。这些蛋白质也显示出良好的疫苗潜力。T7SS蛋白在感染过程中的确切生物学功能尚不清楚。我们最近的研究表明，T7SS蛋白可以控制巨噬细胞死亡。但是，我们不知道这些蛋白质如何干扰细胞内的通路或我们对这种病原体的免疫反应。该项目的主要目标是了解T7SS蛋白如何干扰宿主信号通路以及如何影响葡萄球菌感染结果。我们将使用细胞，生物化学和高通量分析的组合来研究与T7SS相互作用的蛋白质和途径。我们还将利用葡萄球菌肺炎的实验室模型探索这些蛋白在肺部感染中的作用模式。我们的研究将揭示宿主颠覆的新途径和对迷人的T7输出系统的新见解。重要的是，我们相信这些研究将为这些蛋白质的治疗和预防用途的开发提供信息。

Staphylococcus aureus, a bacterium often found on our skin and nares, is one of the major causes for life threatening infections such as pneumonia and endocarditis. This pathogen is frequently associated with healthcare systems and hospital-associated S. aureus infections have been responsible for increasing healthcare costs globally. The rise of new antibiotic resistant strains has been a major hurdle in effective treatment of S. aureus infections with the available drug therapies. A vaccine against resistant S. aureus infections could provide an effective solution to antimicrobial resistance.During infection, S. aureus is known to closely interact with our cells. In addition to acting from outside cells, this bacterium can enter inside our cells using it as a niche to multiply. Immune cells called macrophages, which form the first line of defence, are important in pathogen clearance. However, studies have indicated that these cells are not always effective in killing S. aureus. S. aureus is able to survive and multiply within macrophages, which then inadvertently aid in transporting bacteria to other body sites. We do not currently have a good understanding of the bacterial proteins and pathways that this pathogen uses to manipulate these immune cells. S. aureus exports several proteins to the external environment during infection. It has a specialised protein export system called the type VII secretion system (T7SS), which secretes proteins that are important for virulence of the bacterium. These proteins have also shown good vaccine potential. The precise biological functions of the T7SS proteins during infection are not known. Our recent research demonstrated that the T7SS proteins can control macrophage death. But, we do not understand how these proteins interfere with pathways inside cells or with our immune responses to this pathogen. The main goals of this project are to understand how the T7SS proteins interfere in host signalling pathways and how this impacts staphylococcal infection outcomes. We will use a combination of cellular, biochemical and high throughput assays to study proteins and pathways that interact with the T7SS. We will also explore the mode of action of these proteins during lung infections employing a laboratory model of staphylococcal pneumonia.Our studies will reveal novel pathways of host subversion and new insight into the fascinating T7 export systems. Importantly we believe these studies would inform the development of these proteins for therapeutic and prophylactic use.