The role of peptidoglycan in the biology of meningococcal infection

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.

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.