The lectin pathway of complement in pneumococcal infection

Lead Research Organisation: University of Leicester
Department Name: Infection Immunity and Inflammation


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.


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Ali YM (2014) Low-dose recombinant properdin provides substantial protection against Streptococcus pneumoniae and Neisseria meningitidis infection. in Proceedings of the National Academy of Sciences of the United States of America

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Almitairi JOM (2018) Structure of the C1r-C1s interaction of the C1 complex of complement activation. in Proceedings of the National Academy of Sciences of the United States of America

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Almitairi JOM (2018) Reply to Mortensen et al.: The zymogen form of complement component C1. in Proceedings of the National Academy of Sciences of the United States of America

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Asgari E (2014) Mannan-binding lectin-associated serine protease 2 is critical for the development of renal ischemia reperfusion injury and mediates tissue injury in the absence of complement C4. in FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Title Antibody based inhibitors for MASP-3 functional activity 
Description I developed a novel therapeutic tool to inhibit overshooting activation of the alternative pathway of complement activation under pathophysiological conditions and in inflammatory disease 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2015 
Provided To Others? Yes  
Impact This tool has been assessed for its ability to block haemolytic pathologies in in vivo models of haemolytic disease and proofed to effectively reduce 
Title Mouse specific rat anti MASP-2 antibodies 
Description We have established 3 different hybridoma lines producing mouse specific rat anti MASP-2 antibodies 
Type Of Material Antibody 
Year Produced 2009 
Provided To Others? Yes  
Impact We have developed the first ELISA measuring MASP-2 serum levels in the mouse. This can be used to monitor the state of lectin pathway activation during -for example- infection. 
Title Recombinant ficolin 
Description We have produced recombinant ficolin, a recognition subcomponent of the lectin activation pathway that specifically binds to pneumococci. 
Type Of Material Technology assay or reagent 
Year Produced 2012 
Provided To Others? Yes  
Impact We were able to demonstrate that i.p. application of recombinant ficolin significantly improved the clearance of pneumococci from the blood stream following intranasal infection and dramatically reduces pneumococci mediated mortality. 
Title recombinant properdin 
Description We have produced highly pure and functionally active mouse and human properdin and assessed this reagent as a therapeutic reagent to enhance resistance in pneumococcal infection. The work revealed for the first time that small amounts of this potent positive regulator of the innate immune response effectively enhances resistance against pneumococci with dramatically increased survival of infected mice and reduced bacteraemia. 
Type Of Material Technology assay or reagent 
Year Produced 2012 
Provided To Others? Yes  
Impact This opens a novel therapeutic approach to treat infection by boosting the innate immune response 
Title Therapeutic applications of recombinant properdin 
Description We have produced and purified recombinant polypeptides which have high biological activity that can be applied at low concentration in order to enhance the natural immune response to infection and thereby significantly increase resistance to infection related disease 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2012
Development Status Under active development/distribution
Impact This product provides an alternative and/or adjuvant approach in treating severe infectious disease 
Description Complement Therapeutics conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I presented a key note lecture at the international complement therapeutic meeting in Greece
Year(s) Of Engagement Activity 2015