Mechanisms of cell death induction by Staphylococcus aureus in leucocytes and endothelial cells

金黄色葡萄球菌是一种常见的人类病原体，可诱发心内膜炎、肺炎、软组织感染、感染性休克等多种严重疾病。葡萄球菌的感染过程由多种毒力因素决定，包括毒素的释放、细菌的粘附和宿主细胞的侵袭。直到最近，不同的研究小组应用小鼠疾病模型，发表了关于金黄色葡萄球菌成孔毒素α-溶血素（α-毒素）和潘通-瓦伦丁白细胞杀死素（PVL）作用的相互矛盾的结果。这两种毒素都与严重的坏死性感染有关。它们表现出细胞溶解作用，这种作用仅限于某些细胞类型；然而，它们的作用机制在很大程度上是未知的。本项目旨在研究确定的金黄色葡萄球菌毒力因子，特别是α-毒素和PVL，对人白细胞和内皮细胞的影响，这些细胞在血管内和血管周围感染期间与细菌密切接触。在葡萄球菌方面，将探索与α-毒素和PVL共同作用并参与感染过程的其他因素。在宿主细胞侧，将分析在感染过程中被激活并诱导细胞死亡的受体和信号转导途径。详细了解金黄色葡萄球菌的细胞溶解活性为严重金黄色葡萄球菌感染的治疗干预提供了新的理论依据。

Staphylococcus aureus is a frequent human pathogen, which can induce a multitude of serious diseases, such as endocarditis, pneumonia, soft-tissue infections and septic shock. The course of infection is determined by various staphylococcal virulence factors, including the release of toxins, bacterial adhesion and host cell invasion. Only recently, different research groups, which applied murine disease models, have published conflicting results concerning the role of the S. aureus pore-forming toxins α-hemolysin (α-toxin) and Panton-Valentine leukocidin (PVL). Both toxins have been associated with severe necrotizing infections. They exhibit cytolytic effects, which are restricted to certain cell types; however, their mechanisms of action are largely unknown. This project is designed to investigate the impact of defined S. aureus virulence factors, with special regard to α-toxin and PVL, on human leucocytes and endothelial cells, which come into close contact to bacteria during endo- and perivascular infections. On the staphylococcal side additional factors will be explored, which act together with α-toxin and PVL and contribute to the infection process. On the host cell side receptors and signal transduction pathways will be analyzed, which are activated during the infection process and induce cell death. Detailed knowledge about the cytolytic activity of S. aureus provides new rationale for therapeutic intervention in severe S. aureus infections.