Neisseria meningitidis is a major cause of bacterial meningitis in children and young adults world-wide. The commercially available vaccine is not effective against all major serogroups. In order to cause meningitis, the bacteria must cross two host barriers. They must enter the bloodstream from the mucosal epithelium of the nasopharynx, and from there cross the blood/brain barrier to cause inflammation of the meninges. Meningococci can gain access to the cerebrospinal fluid by crossing the endothelial cells of either the meningeal capillaries or the choroid plexus. In either case, the bacteria must interact closely with endothelial cells. Therefore, elucidation of the molecular events that govern meningococcal interactions with endothelial cells is crucial to our understanding of the pathogenesis of this disease, and of the striking tropism of this bacterial pathogen for the meninges. Identification of endothelial cell-binding adhesins may also contribute to the development of better meningococcal vaccines. We will study these events by identifying and characterizing bacterial genes and gene products responsible for promoting their adherence to and invasion of primary human endothelial cells. This will be done by standard bacterial genetic and biochemical approaches. We will construct meningococcal adhesion mutants, and assess their ability to invade the CSF.
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