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

Exley RM
(2007)
Lactate acquisition promotes successful colonization of the murine genital tract by Neisseria gonorrhoeae.
in Infection and immunity

Exley RM
(2009)
Identification of meningococcal genes necessary for colonization of human upper airway tissue.
in Infection and immunity

Kugelberg E
(2008)
Mechanisms in Neisseria meningitidis for resistance against complement-mediated killing.
in Vaccine

Kugelberg E
(2010)
The influence of IS1301 in the capsule biosynthesis locus on meningococcal carriage and disease.
in PloS one

Li Y
(2009)
Secreted proteins of Neisseria meningitidis protect mice against infection.
in Vaccine

Lo H
(2009)
Mechanisms of avoidance of host immunity by Neisseria meningitidis and its effect on vaccine development.
in The Lancet. Infectious diseases

Ray K
(2009)
Life on the inside: the intracellular lifestyle of cytosolic bacteria.
in Nature reviews. Microbiology

Schneider MC
(2009)
Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates.
in Nature

Smith H
(2007)
Effect of host lactate on gonococci and meningococci: new concepts on the role of metabolites in pathogenicity.
in Infection and immunity

Uria MJ
(2008)
A generic mechanism in Neisseria meningitidis for enhanced resistance against bactericidal antibodies.
in The Journal of experimental medicine
Description | MRC Programme Grant |
Amount | £2,116,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
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 |