The lectin pathway of complement in pneumococcal infection

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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.