The lectin pathway of complement in pneumococcal infection
Lead Research Organisation:
University of Leicester
Department Name: Infection Immunity and Inflammation
Abstract
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.
Technical Summary
Infections with Streptococcus pneumoniae (the pneumococcus) are the leading cause of bacterial pneumonia, otitis media, bacterial meningitis and septicaemia in children and adults worldwide. Invasive infection is associated with high mortality ranging from 5-35% depending on the site of infection, age and comorbidity. Nevertheless, a high percentage of the population carries commensal S. pneumoniae in the nasopharynx, implying that a healthy immune system is highly effective in keeping invasive infections at bay.
In light of the ever-increasing frequency of antibiotic resistance, it is paramount to understand how the breakdown of the orchestrated response of the innate and adaptive immune system leads to disease.
The complement system plays a key role in fighting S. pneumoniae infection, but the relative contributions of either of the three complement activation pathways and their crosstalk is far from being understood. The proposed work is based on a strong body of evidence showing that the most recently discovered activation pathway of complement, called the lectin activation pathway, is providing a critical degree of protection from pneumococcal infection with a dramatic increase of morbidity and mortality in gene-targeted mice with a total deficiency of lectin pathway functional activity. The severe predisposition of lectin pathway deficient animals for pneumococcal disease is explained by applicants discovery of a so far unknown function of the lectin pathway, which overcomes the ability of pathogenic strains of S. pneumoniae to protect themselves from complement attack by preventing the deposition of the activation fragment of the 4th component of complement (C4b) close to the bacterial surface. This protects bacteria from being opsonised via the classical pathway activation route as C4b is an essential component of the classical pathway C3 convertase C4b2a. The discovery of a novel lectin pathway specific C4-bypass activation route by the applicants, through which S. pneumoniae can be opsonised, is key in understanding the physiological importance of the lectin pathway in anti-pneumococcal immunity.
The proposed project aims:
(i) To determine the synergism and relative contributions of the lectin (LP) and classical (CP) pathways in pneumococcal infection;
(ii) To test the hypothesis that transient or permanent inhibition of the LP will disrupt the normal cellular and soluble inflammatory mediator response to pneumococcal infection;
(iii) To test the hypothesis that ficolin A is the recognition molecule initiating LP activation on pneumococci);
(iv) To elucidate the molecular composition and activation cascade of a novel MASP-2 dependent C4-bypass activation route of the LP.
In light of the ever-increasing frequency of antibiotic resistance, it is paramount to understand how the breakdown of the orchestrated response of the innate and adaptive immune system leads to disease.
The complement system plays a key role in fighting S. pneumoniae infection, but the relative contributions of either of the three complement activation pathways and their crosstalk is far from being understood. The proposed work is based on a strong body of evidence showing that the most recently discovered activation pathway of complement, called the lectin activation pathway, is providing a critical degree of protection from pneumococcal infection with a dramatic increase of morbidity and mortality in gene-targeted mice with a total deficiency of lectin pathway functional activity. The severe predisposition of lectin pathway deficient animals for pneumococcal disease is explained by applicants discovery of a so far unknown function of the lectin pathway, which overcomes the ability of pathogenic strains of S. pneumoniae to protect themselves from complement attack by preventing the deposition of the activation fragment of the 4th component of complement (C4b) close to the bacterial surface. This protects bacteria from being opsonised via the classical pathway activation route as C4b is an essential component of the classical pathway C3 convertase C4b2a. The discovery of a novel lectin pathway specific C4-bypass activation route by the applicants, through which S. pneumoniae can be opsonised, is key in understanding the physiological importance of the lectin pathway in anti-pneumococcal immunity.
The proposed project aims:
(i) To determine the synergism and relative contributions of the lectin (LP) and classical (CP) pathways in pneumococcal infection;
(ii) To test the hypothesis that transient or permanent inhibition of the LP will disrupt the normal cellular and soluble inflammatory mediator response to pneumococcal infection;
(iii) To test the hypothesis that ficolin A is the recognition molecule initiating LP activation on pneumococci);
(iv) To elucidate the molecular composition and activation cascade of a novel MASP-2 dependent C4-bypass activation route of the LP.