Elucidating functions of a specialised staphylococcal secretion system during infection

阐明感染期间特殊葡萄球菌分泌系统的功能

基本信息

批准号：
MR/N010140/1
负责人：
Meera Unnikrishnan
金额：
$ 50.11万
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：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FN010140%2F1
关键词：
Elucidating functions specialised staphylococcal secretion

项目摘要

Staphylococcus aureus is a highly versatile bacterial pathogen responsible for serious infections in humans and animals. Hospital associated antibiotic resistant S. aureus infections ranging from skin infections to septic shock are responsible for increasing healthcare costs globally. The rise of new antibiotic resistant strains is major hurdle in effective treatment of S. aureus infections. Recurring episodes of skin and soft tissue infections are extremely common and difficult to eliminate. While S. aureus usually acts from outside the eukaryotic cells, it can enter inside host cells and multiply inside, using it as a niche to evade antibiotics and host responses. We do not completely understand the proteins and pathways that S. aureus uses to survive in the hostile host cell environment. Intracellular bacteria may play an important role in chronic staphylococcal infections. However, precise mechanisms by which intracellular bacteria cause persistent or chronic infections remain unclear.S. aureus exports several factors to the external environment during infection. It contains a specialised protein export system called Ess, which secretes proteins that are important for virulence of the bacterium and good vaccine candidates. This export system is also found in other important intracellular pathogens like the tuberculosis bacillus. While we know much about the TB systems, the functions of the staphylococcal apparatus are not known. Our recent research demonstrated that one of these Ess proteins, EsxA allow host cells infected with S. aureus to survive longer. We do not understand how these Ess proteins interfere with pathways inside cells or with our immune responses to this pathogen. The main goals of this project are to understand, at a molecular and cellular level, the biological role of the Ess proteins during persistent staphylococcal infections. Using genetic, cellular and immunological techniques we will determine how the bacterium uses the Esx proteins to block cell proteins and pathways. We will explore the mode of action of these proteins during chronic staphylococcal disease using in vivo models of disease.Our studies will reveal novel pathways of host subversion during persistent staphylococcal infections and contribute to better understanding of the biology of the fascinating Ess systems.

金黄色葡萄球菌是一种高度用途的细菌病原体，负责人类和动物的严重感染。医院相关的抗生素抗生素S.金黄色葡萄球菌感染，从皮肤感染到败血性休克，造成全球医疗费用增加。新型抗生素抗性菌株的兴起是有效治疗金黄色葡萄球菌感染的主要障碍。皮肤和软组织感染的反复发作非常普遍，难以消除。金黄色葡萄球菌通常从真核细胞外作用，但它可以进入宿主细胞内部并在内部繁殖，以逃避抗生素和宿主反应的利基市场。我们不完全理解金黄色葡萄球菌用来在敌对宿主细胞环境中生存的蛋白质和途径。细胞内细菌可能在慢性葡萄球菌感染中起重要作用。但是，细胞内细菌引起持续或慢性感染的精确机制尚不清楚。金黄色在感染期间将几个因素导出到外部环境。它包含一个称为ESS的专门蛋白质输出系统，该系统分泌对细菌和良好疫苗候选物的毒力很重要的蛋白质。该输出系统也存在于其他重要的细胞内病原体中，例如结核菌芽孢杆菌。虽然我们对结核病系统了解很多，但葡萄球菌设备的功能尚不清楚。我们最近的研究表明，其中一种ESS蛋白ESXA允许感染金黄色葡萄球菌的宿主细胞生存更长的时间。我们不了解这些ESS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在分子和细胞水平上了解ESS蛋白在持续性葡萄球菌感染过程中的生物学作用。使用遗传，细胞和免疫学技术，我们将确定细菌如何使用ESX蛋白来阻断细胞蛋白和途径。我们将使用体内疾病模型探索这些蛋白质在慢性葡萄球菌疾病期间的作用方式。