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

VII 型分泌系统在金黄色葡萄球菌-巨噬细胞相互作用中的作用的研究

基本信息

批准号：
MR/X00161X/1
负责人：
Meera Unnikrishnan
金额：
$ 88.36万
依托单位：
University of Warwick
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2023
资助国家：
英国
起止时间：
2023 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FX00161X%2F1
关键词：
Investigation role Type VII secretion

项目摘要

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.

金黄色葡萄球菌是一种经常在我们的皮肤和鼻孔上发现的细菌，是威胁生命感染的主要原因之一，例如肺炎和心内膜炎。该病原体经常与医疗保健系统和与医院相关的金黄色链球菌感染有关，负责全球增加医疗费用。新的抗生素抗性菌株的兴起一直是有效治疗金黄色葡萄球菌感染的主要障碍。抗抗性金黄色葡萄球菌感染的疫苗可以为抗菌耐药性提供有效的解决方案。据说感染，金黄色葡萄球菌已知与我们的细胞紧密相互作用。除了从外部细胞起作用外，该细菌还可以使用它作为繁殖的细分市场进入我们的细胞内。称为巨噬细胞的免疫细胞形成第一道防线，在病原体清除率中很重要。但是，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中生存和繁殖，然后无意中有助于将细菌运输到其他身体部位。目前，我们对这种病原体用来操纵这些免疫细胞的细菌蛋白和途径尚未充分了解。 S. Aureus在感染过程中将几种蛋白质导出到外部环境。它具有一个名为VII型分泌系统（T7SS）的专门蛋白质输出系统，该系统分泌对细菌毒力很重要的蛋白质。这些蛋白质也显示出良好的疫苗电位。感染过程中T7SS蛋白的精确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，我们不了解这些蛋白如何干扰细胞内部的途径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传导途径，以及这如何影响葡萄球菌感染结果。我们将使用细胞，生化和高通量测定的结合来研究与T7SS相互作用的蛋白质和途径。我们还将采用葡萄球菌肺炎实验室模型探索这些蛋白质在肺部感染过程中的作用方式。重要的是，我们认为这些研究将为这些蛋白质的发展提供治疗和预防性使用。