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Dynamics of bacterial killing by the membrane attack complex

膜攻击复合物杀灭细菌的动力学

基本信息

批准号：
MR/R000328/1
负责人：
Bart Hoogenboom
金额：
$ 57.27万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FR000328%2F1
关键词：
Dynamics bacterial killing membrane attack

项目摘要

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.

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，这是一个大型的蛋白质库，共同促进炎症和靶向微生物。补体的一个相当惊人的功能是穿透革兰氏阴性细菌如大肠杆菌的细胞膜。大肠杆菌，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，它可能有利于防止患者过度活跃的免疫系统造成潜在的致命影响。对于任何此类治疗方法的开发，它有助于对补体如何工作有一个良好的理解。在这个项目中，我们专注于膜攻击复合物，补体用于在细菌膜上形成孔。迄今为止，已经对MAC攻击单膜模型系统如脂囊泡和红细胞进行了大量的结构和功能研究。然而，革兰氏阴性菌的包膜由双层膜组成，其间具有网状肽聚糖层。目前尚不清楚陆委会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，其中一个锋利的针可以跟踪细菌的表面，因为它被MAC攻击。简而言之，通过观察MAC在细菌表面上的形成以及随后对细菌包膜的影响，我们将确定MAC杀死细菌的机制。