The lectin pathway of complement in pneumococcal infection

这项研究计划是基于强有力的证据，证明了最近才发现的免疫系统效应臂（称为补体凝集素途径）在对抗肺炎球菌感染中的突出作用。使用已建立的实验性肺炎链球菌气道感染模型，申请人观察到，与具有完整凝集素激活途径的小鼠相比，完全缺乏凝集素激活途径的基因靶向小鼠株在对抗肺炎链球菌感染方面严重受损，导致肺炎球菌疾病的严重程度和死亡率急剧增加。本研究旨在明确凝集素途径介导的免疫防御侵袭性肺炎球菌感染的关键成分和生化机制。利用体内感染模型来确定抗肺炎球菌免疫的关键角色，必须利用缺乏凝集素途径单一或几种组分的小鼠菌株的独特组合。在体内的工作得到了一系列复杂的生化分析的支持，这些分析使用细胞系中产生的重组蛋白在试管中重建和测量凝集素途径的功能活性。该工作计划还将包括分析致病性肺炎链球菌菌株逃避宿主补体系统攻击的分子机制，并可能解释凝集素途径激活途径在抵抗这些菌株感染中的重要作用。这项工作计划的结果将对了解人类肺炎球菌疾病的易感性具有广泛的影响。

This research proposal is based on a strong body of evidence demonstrating the prominent role of an only recently discovered effector arm of the immune system, termed the lectin pathway of complement, in fighting pneumococcal infections. Using an established model of experimental Streptococcus pneumoniae airway infection, the applicants observed that their gene-targeted mouse strain with a total deficiency of the lectin activation pathway is severely compromised in fighting S. pneumoniae infection resulting in a dramatic increase in the severity of pneumococcal disease and mortality, compared to mice with an intact lectin activation pathway. The proposed research aims to define the key components and biochemical mechanisms involved in lectin pathway mediated protection from invasive pneumococcal infection within the immune defense. The availability of a unique combination of mouse strains deficient of either single or several components of the lectin pathway is essential to define the key players in anti-pneumococcal immunity using in vivo models of infection. The in vivo work is supported by an array of sophisticated biochemical analyses using recombinant proteins generated in cell lines to reconstitute and measure lectin pathway functional activity in a test tube. The work programme will also include the analysis of a molecular mechanism used by pathogenic S. pneumoniae strains to evade from the attack of its host s complement system and may explain the essential role of the lectin pathway activation route in fighting infection with these strains. The results of this work programme will have wide implications for the understanding of predispositions to human pneumococcal disease.