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.
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.
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.
