Dynamics of bacterial killing by the membrane attack complex

为了避免细菌在血液中传播，我们的免疫系统包含所谓的补体系统，这是一个庞大的蛋白质武器库，共同促进炎症和靶标微生物。补体相当惊人的功能之一是穿透革兰氏阴性细菌(如大肠杆菌)的膜，从而杀死细菌。在某些情况下，我们可能希望增强这种免疫功能，例如对抗细菌感染；在其他情况下，如败血症，这可能有助于防止患者过度活跃的免疫系统造成潜在的致命影响。对于任何这样的治疗方法的发展，有一个良好的了解补体是如何工作的。在这个项目中，我们集中在膜攻击复合体，由补体用来在细菌的细胞膜上形成毛孔。到目前为止，人们已经对MAC攻击单膜模型系统如脂泡和红细胞等进行了许多结构和功能的研究。然而，革兰氏阴性细菌的包膜由双层膜组成，中间有一层网状的肽聚糖层。目前尚不清楚MAC如何克服这三重障碍。为了解决这个问题，我们将使用一种特殊类型的显微镜，原子力显微镜，在这种显微镜下，当细菌受到MAC攻击时，一根锋利的针可以追踪细菌的表面。简单地说，通过可视化MAC在细菌表面的形成和随后对细菌包膜的影响，我们将确定MAC杀死细菌的机制。

To avoid the spreading of bacteria in the blood stream, our immune system contains the so-called complement system, a large arsenal of proteins that collectively promote inflammation and target microbes. One of complement's rather spectacular functions is that of piercing the membranes of Gram-negative bacteria such as E. coli, thus killing the bacteria. In some cases, we may wish to enhance this immune function, for example to counter bacterial infections; in other cases, such as sepsis, it may be beneficial to prevent a patient's overactive immune system from causing potentially lethal effects. For the development of any such therapeutic approaches, it helps to have a sound understanding of how complement works.In this project, we focus on the membrane attack complex, used by complement to form pores in the membranes of bacteria. So far, many structural and functional studies have been carried out on the MAC attacking single-membrane model systems such as lipid vesicles and red blood cells. However, the envelope of Gram-negative bacteria consists of a double membrane with a mesh-like peptidoglycan layer in between. At present, it is not clear how the MAC overcomes this triple barrier. To address this question, we will use a special type of microscopy, atomic force microscopy, in which a sharp needle can trace the surface of a bacterium as it is being attacked by the MAC. Briefly, by thus visualising the formation of MAC on the bacterial surface and the subsequent effects on the bacterial envelope, we will determine the mechanisms by which the MAC kills bacteria.