The role of endotoxin blebbing in the pathogenesis of meningococcal meningitis
Dr Thomas Evans, Professor Jonathon Cohen
- Start Date:
01 January 1997
Hammersmith Hospital, London, UK
Much evidence implicates endotoxin in the pathogenesis of invasive meningococcal disease. Endotoxin is known to be responsible for the production of tumour necrosis factor and the endothelial damage which underlies many of the pathophysiological features of Gram- negative sepsis, and clinical studies of patients with meningococcal septicaemia have shown that outcome is directly related to the level of endotoxin present within the blood stream An unusual feature of the Neisseria is their shedding of 'blebs' of outer bacterial membrane into the growth medium, and these blebs contains large amounts of endotoxin. However, not all strains of N. meningitidis show this blebbing phenomenon, which is a stable phenotypic characteristic and which is independent of serotype and antibiotic susceptibility. Analysis of strains isolated from patients with meningococcal sepsis and from healthy carriers shows that there is a much higher degree of endotoxin shedding from isolates derived from patients than from carriers, thus suggesting that the ability to shed large amounts of endotoxin is a virulence determinant for Neisseria Meninigitidis. However, the genetic and molecular basis of endotoxin shedding is completely unknown. The aims of this project are to isolate the genes responsible for endotoxin shedding in Group B meningococci, to determine the biological significance of endotoxin shedding, and to determine the relationship between antibody and complement on endotoxin shedding. Since endotoxin blebbing is independent of serotype, novel vaccine targets derived from work might offer a valuable advantage over existing serotype-dependent vaccines.