Molecular analysis of meningococcal ligand - host receptor interactions as a prelude to the development of disease management strategies
Professor Mumtaz Virji
- Start Date:
01 January 2001
Bristol University, Bristol, UK
The proposal is to develop in vitro models that mimic human cell surfaces which may be encountered by meningococci in a healthy host or after infection / inflammation induced by other microbes. The impetus for the proposed investigation is derived from epidemiological evidence, which suggests that the incidence of meningococcal disease increases following viral infections. Viral infections, either directly or indirectly, may alter cell surface receptors and our preliminary observations suggest that host cell CEACAM receptors at high densities support attachment of capsulate, Opa-expressing phenotypes that are not adherent at low receptor densities. We wish to test the hypothesis that increased receptor density of CEACAMs allows greater penetration of meningococci into cells or through cell barriers that express the molecules. Further, we wish to test how simultaneous ligation of receptor variants with the capacity to deliver distinct cellular signals affect the outcome of bacterial interactions. The studies will use well-characterised phenotypic variants of meningococci to investigate cellular interactions and test the effects of antibodies and synthetic peptides related to Opa and CEACAMs in modulating the interactions. These investigations will highlight how host and bacterial features may promote invasion of cellular barriers in a post-inflammation model. The knowledge will help in evaluating potential candidates (e.g. peptides / peptidomimetics) for use as vaccines and in disease management.
Results from this study have been published in scientific journals as follows:
Hill DJ, Edwards AM, Rowe HA, Virji M.
Carcinoembryonic antigen-related cell adhesion molecule (CEACAM)-binding recombinant polypeptide confers protection against infection by respiratory and urogenital pathogens.
Mol Microbiol 2005 Mar;55(5):1515-27.
Bradley CJ, Griffiths NJ, Rowe HA, Heyderman RS, Virji M,
Critical determinants of the interactions of capsule-expressing Neisseria meningitidis with host cells: the role of receptor density in increased cellular targeting via the outer membrane Opa proteins.
Cell Microbiol 2005 Oct;7(10):1490-503.