Interactions between complement and Neisseria meningitidis

Lead Research Organisation: University of Oxford
Department Name: Sir William Dunn Sch of Pathology

Abstract

N. meningitis is an important human pathogen feared by parents and medical practitioneers alike. Each year around half a million people across the globe are affected by this bacterium which is a leading cause of meningitis and septicaemia in children.

Our challenge is to understand how the meningococcus escapes surveillance by our immune system to enter into the bloodstream where it causes disease and damage to infected individuals.

The bacterium lives in constant contact with humans (usually in the nasal passage), so it is exquisitely adapted to cope with our immune system. One example of this is that the bacterium binds a human molecule called factor H (fH) very tightly to its surface which acts to switch off immune responses. Additionally the bacterium covers itself with direct copies of human structures to camoflague itself when in the body.

Knowing the answer to how the bacterium avoids our immune responses would be enormously valuable for designing effective vaccines.

This project will examine how the bacterium avoids the complement system, a key aspect of human immunity in the nasal passages and the bloodstream. We know that complement is critical in protection against N. meningitidis as people who lack complement factors are at great risk from meningoccal infection, and all our measures of immunity are based on complement.

We will examine how complement factors are recruited to the surface of the bacterium and how this impacts on the development of the typical skin rash and the rapid progression of meningococcal disease.

This will also help identify novel vaccines and allow us to evaluate their ability to induce protection. It is already known that complement factors bind to vaccine candidates on several bacteria, including N. meningitidis and the leading cause of pneumonia, Streptococcus pneumoniae. Therefore determining complement binding sites on the meningococcus should lead to the discovery of further vaccine candidates.

Technical Summary

Neisseria meningitidis remains a leading cause of bacterial sepsis and meningitis throughout the world. It is estimated that there are approximately 500,000 cases of meningococcal disease p.a., with around 50,000 deaths. The progression of meningococcal disease can be extremely rapid, with death occurring within hours of the onset of the illness in some instances, and a significant number of survivors are left with permanent disabilities including neurological deficits and/or loss of limbs.

There remains an urgent need to understand the molecular basis of virulence of this important human pathogen, and to develop vaccines that are effective against a broad range of meningococcal strains.

The goal of this application is to define the interaction between N. meningitidis and the complement system. The complement system is the most ancient component of the mammalian immune system and is vital for immunity against the meningococcus. Our initial studies will focus on the interaction between factor H, the main negative regulator of complement activation, and its receptor on the surface of N. meningitidis, factor H binding protein (fHbp), and will provide fundamental insights into the pathogenesis of meningococcal colonisation and disease. As fHbp is a component of meningococcal vaccines in current clinical trials, the knowledge and models generated during the course of this work will be translated into the development and assessment of novel vaccines against meningococcal disease. Furthermore, we will define the interaction between this important human pathogen and other complement factors, as this will provide further insights into mechanisms of immune evasion and might identify further vaccine candidates.

Publications

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Faleri A (2014) Two cross-reactive monoclonal antibodies recognize overlapping epitopes on Neisseria meningitidis factor H binding protein but have different functional properties. in FASEB journal : official publication of the Federation of American Societies for Experimental Biology

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Lea SM (2012) Putting the structure into complement. in Immunobiology

 
Description Collaboration with Serum Institute of India
Amount £650,000 (GBP)
Funding ID BVR00970 
Organisation Serum Institute of India 
Sector Private
Country India
Start 01/2017 
End 12/2020
 
Description Evaluation of vaccine candidates 
Organisation Novartis
Department Vaccines and Diagnostics
Country United States 
Sector Private 
PI Contribution Understanding the basis of fHbp interactions with fH by mutagenesis of different variants of the bacterial protein.
Collaborator Contribution Providing monoclonal antibodies and NMR for analysis of proteins
Impact One manuscript submitted, one in preparation
Start Year 2011
 
Description Evaluation of vaccine candidates 
Organisation Public Health England
Country United Kingdom 
Sector Public 
PI Contribution Understanding the basis of fHbp interactions with fH by mutagenesis of different variants of the bacterial protein.
Collaborator Contribution Providing monoclonal antibodies and NMR for analysis of proteins
Impact One manuscript submitted, one in preparation
Start Year 2011
 
Description Evaluation of vaccine candidates 
Organisation University of Oxford
Department Department of Psychiatry
Country United Kingdom 
Sector Academic/University 
PI Contribution Understanding the basis of fHbp interactions with fH by mutagenesis of different variants of the bacterial protein.
Collaborator Contribution Providing monoclonal antibodies and NMR for analysis of proteins
Impact One manuscript submitted, one in preparation
Start Year 2011
 
Description Investigation into the role of fHbp in avoidance of complement mediated lysis 
Organisation University of Oxford
Department Sir William Dunn School of Pathology
Country United Kingdom 
Sector Academic/University 
PI Contribution We analysed binding of fH and its effect on the bacterium. Professor Lea's group analysed the structure of this interaction.
Collaborator Contribution Provided structural details to current research
Impact Paper in Nature. Further MRC funding
Start Year 2007
 
Title Non functional fHbps as vaccines 
Description Our structural analysis allowed us to generate non functional fHbps as vaccines against meningococcal disease. 
IP Reference Insufficient Information 
Protection Patent granted
Year Protection Granted
Licensed Yes
Impact Understanding the basis of the host pathogen interactions
 
Description Newspaper article on work 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Research was featured in the Daily Telegraph and Dail Mail

Not certain
Year(s) Of Engagement Activity 2009
 
Description Visit by school children 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact We had around 30 children of between 9-10 yrs old in the Department to discuss the development of antibiotics

Not certain
Year(s) Of Engagement Activity 2016