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

金黄色葡萄球菌是一种经常在我们的皮肤和鼻孔中发现的细菌，是肺炎和心内膜炎等威胁生命的感染的主要原因之一。这种病原体经常与医疗系统有关，医院相关的金黄色葡萄球菌感染是全球医疗成本增加的原因。新的耐药菌株的出现一直是利用现有药物疗法有效治疗金黄色葡萄球菌感染的主要障碍。一种针对耐药金黄色葡萄球菌感染的疫苗可以有效地解决抗菌素耐药性问题。在感染期间，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部，利用它作为繁殖的利基。被称为巨噬细胞的免疫细胞构成了第一道防线，在清除病原体方面非常重要。然而，研究表明，这些细胞并不总是有效地杀死金黄色葡萄球菌。金黄色葡萄球菌能够在巨噬细胞内存活和繁殖，然后巨噬细胞无意中帮助将细菌运送到身体的其他部位。我们目前还没有很好地了解这种病原体用来操纵这些免疫细胞的细菌蛋白质和途径。金黄色葡萄球菌在感染期间向外部环境输出几种蛋白质。它有一个专门的蛋白质输出系统，称为VII型分泌系统(T7SS)，它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的死亡。但是，我们不知道这些蛋白质是如何干扰细胞内的途径或我们对这种病原体的免疫反应的。该项目的主要目标是了解T7SS蛋白如何干扰宿主信号通路，以及这如何影响葡萄球菌感染结果。我们将使用细胞、生化和高通量分析相结合的方法来研究与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来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，并对迷人的T7输出系统进行新的洞察。重要的是，我们相信这些研究将为这些用于治疗和预防的蛋白质的开发提供信息。

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.