The role of peptidoglycan in the biology of meningococcal infection

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

Neisseria meningitidis is an important cause of blood poisoning and a serious type of meningitis (infection of the layers around the brain). We will examine how an important part of the outside of the bacterium, a molecule called peptidoglycan (PG), affects the ability of this bug to cause blood stream infection. We will find out how PG is made by bacteria and how the human body recognises PG and responds to it. Humans have receptors called Nods that bind to PG and this leads to the inflammatory response to infection which can be harmful to us when we have infections. Remarkably PG is present in all bacteria and Nods are found in plants as well as animals. So the way they interact is of fundamental importance in understanding how infections are dealt with and removed by the body. Neisseria meningitidis is a dangerous bacterium and finding out how it causes disease will help us come up with ways of blocking infection, either by killing the bacterium or stopping the damage it causes.

Technical Summary

Peptidoglycan (PG) is necessary for maintaining the structural integrity of bacteria, and has a crucial role as a pathogen associated molecular pattern; PG degradation products are recognised ligands of the Nod (Nucleotide-binding oligomerisation domain) proteins, a recently described family of intracytoplasmic receptors which trigger the pro-inflammatory response to infection. The aim of this proposal is to define the contribution of PG metabolism and the mechansims underlying Nod signalling to the biology of infection caused by Neisseria meningitidis, a leading cause of septicaemia and meningitis. This bacterium elicits a dramatic pro-inflammatory response in the host which contributes to the high mortality from systematic infection. We have identified attenuating N. meningitidis mutants which are expected to have increased release of degradation products compared with the wild-type strain, thereby increasing recognition through Nod proteins. The objectives of the research are to:1) understand the contribution of PG to the bacteraemic stage of infection, 2) determine structure:function relationships between PG and signalling through the Nod family of receptors, and 3) to establish the mechanism underlying PG:Nod signalling and its impact on meningococcal bacteraemia and the inflammatory response to infection.

Publications

10 25 50
 
Description MRC Programme Grant
Amount £2,116,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2010 
End 02/2015
 
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
 
Description Article written by PhD student 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact A PhD student in my lab wrote an article on our outreach activities

Not certain
Year(s) Of Engagement Activity 2016
 
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