Mechanisms of complement-mediated pulmonary immunity to Streptococcus pneumoniae

肺炎是世界上最常见的感染之一，最常由肺炎链球菌（也称为肺炎球菌）引起。因此，肺炎球菌是导致过早死亡的一个重要原因，每年导致100多万儿童死亡。我们迫切需要了解身体是如何阻止肺炎球菌引起肺部感染的，以便设计有效的方法来减少这种损失。人体免疫系统中防止肺炎球菌引起肺部感染的一个重要组成部分是补体系统，这是一系列可以与细菌结合并帮助预防疾病的蛋白质。然而，补体究竟如何阻止肺炎球菌引起肺炎尚不清楚，本建议的目的是确定补体帮助肺防御控制肺炎球菌感染的机制。一种可能性是，与细菌结合的补体有助于肺部的白细胞摄取并杀死肺炎球菌，另一种可能性是，补体蛋白的激活起到了警告信号的作用，导致身体将免疫防御指向肺部。该提案将评估这两种可能性在多大程度上有助于肺部防御肺炎球菌。将研究补体对肺炎球菌与两种不同类型的人类白细胞相互作用的影响，以确定这两种细胞类型中哪一种可能在感染期间使用补体杀死肺炎球菌。这一结果将通过实验得到进一步的证实，这些实验将感染经过基因改造的小鼠，使它们的补体缺乏肺炎球菌。利用这些实验，我们将能够评估补体缺失对白细胞功能和肺炎实际发展过程中机体反应的影响，由于感染免疫反应的复杂性，不使用动物实验就不可能获得这些数据。从该提案中获得的信息将大大提高我们对肺部如何抵御肺炎球菌的认识，并应导致未来的治疗旨在预防或治疗这一致命感染的重要原因。研究结果将发表在科学期刊上，重要的结果将通过伦敦大学学院网站和宣传办公室向公众传播。

Pneumonia is one of the most common infections worldwide, and is most often caused by the bacteria Streptococcus pneumoniae (otherwise known as the pneumococcus). As a consequence pneumococcus is an important cause of premature death, killing over a million children per year. We urgently need to understand how the body prevents the pneumococcus from causing lung infections in order to design effective methods of reducing this toll. One important component of the bodies immune system for preventing pneumococcus from causing lung infections is the complement system, a series of proteins that can bind to bacteria and help prevent disease. However, exactly how complement stops the pneumococcus from causing pneumonia is not known, and the aim of this proposal is to identify the mechanisms by which complement helps lung defences control infection by pneumococcus. One possibility is that complement bound to the bacteria help white cells in the lung ingest and kill the pneumococcus, and the other possibility is that activation of complement proteins act as a warning signal that results in the body directing its immune defences to the lung. The proposal will evaluate the degree to which these two possibilities contribute to lung defence against pneumococcus. The effect of complement on the interactions of pneumococcus with two different types of human white cells will be investigated to identify which of these two cell types are likely to use complement during infection to kill the pneumococcus. The results will be reinforced by experiments infecting mice that have been genetically engineered so that they are deficient in complement with pneumococcus. Using these experiments we will be able to assess the effects of loss of complement on white cell functions and the bodies response during the actual development of pneumonia, data which the complexity of the immune response to infection makes impossible to obtain without using animal experiments. The information obtained from the proposal will substantially improve our knowledge of how the lungs defend against the pneumococcus, and should lead to future therapies aimed at preventing or treating this important cause of lethal infection. The results will be published in science journals, and important results disseminated to the general public via the UCL website and publicity office.