Elucidating functions of a specialised staphylococcal secretion system during infection

金黄色葡萄球菌是一种高度通用的细菌病原体，可导致人和动物的严重感染。医院相关的耐药金黄色葡萄球菌感染，从皮肤感染到败血症休克，是全球医疗成本增加的原因。新的抗药性菌株的出现是有效治疗金黄色葡萄球菌感染的主要障碍。反复发作的皮肤和软组织感染是非常常见的，很难消除。虽然金黄色葡萄球菌通常从真核细胞外发挥作用，但它可以进入宿主细胞内部并在内部繁殖，将其用作逃避抗生素和宿主反应的利基。我们还不完全了解金黄色葡萄球菌在恶劣的宿主细胞环境中生存所使用的蛋白质和途径。细胞内细菌可能在慢性葡萄球菌感染中起重要作用。然而，细胞内细菌引起持续或慢性感染的确切机制仍不清楚。金黄色葡萄球菌在感染期间向外部环境输出几种因子。它包含一个名为Ess的特殊蛋白质输出系统，该系统分泌对细菌毒力和良好疫苗候选至关重要的蛋白质。在其他重要的细胞内病原体中也发现了这种输出系统，比如结核杆菌。虽然我们对结核病系统了解很多，但金黄色葡萄球菌的功能尚不清楚。我们最近的研究表明，其中一种Ess蛋白EsxA可以使感染金黄色葡萄球菌的宿主细胞存活更长时间。我们不知道这些Ess蛋白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在分子和细胞水平上了解Ess蛋白在持续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蛋白来阻止细胞蛋白质和途径。我们将使用疾病的体内模型来探索这些蛋白在慢性葡萄球菌疾病中的作用模式。我们的研究将揭示持续葡萄球菌感染期间宿主颠覆的新途径，并有助于更好地理解迷人的Ess系统的生物学。

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.