The lectin pathway of complement in pneumococcal infection

肺炎球菌感染中补体的凝集素途径

• 批准号: G0801952/1
• 负责人: Wilhelm Schwaeble
• 金额: $ 70.52万
• 依托单位: University of Leicester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0801952%2F1
• 关键词: lectin; pathway; complement; pneumococcal; infection

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.

这项研究建议基于大量证据，证明最近才发现的一种免疫系统效应臂，称为补体凝集素途径，在抗击肺炎球菌感染方面具有突出作用。使用已建立的实验性肺炎链球菌呼吸道感染模型，申请人观察到，与凝集素激活途径完全缺失的小鼠相比，他们的基因靶向小鼠品系在对抗肺炎链球菌感染方面受到严重损害，导致肺炎球菌疾病的严重性和死亡率显著增加。本研究旨在明确凝集素途径在免疫防御中参与保护侵袭性肺炎球菌感染的关键成分和生化机制。对于利用体内感染模型确定抗肺炎球菌免疫中的关键角色，获得缺乏凝集素途径的单个或多个组分的独特的小鼠菌株组合是必不可少的。体内的工作得到了一系列复杂的生化分析的支持，这些分析使用在细胞系中产生的重组蛋白来重建和测量试管中凝集素途径的功能活性。该工作计划还将包括分析致病肺炎链球菌逃避其宿主S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对抗这些菌株感染方面的重要作用。这一工作方案的结果将对理解人类肺炎球菌病的易感性产生广泛的影响。