Jacobsen, MC; (2007) Regulation of endothelial E-selectin molecule expression by Neisseria meningitidis. Doctoral thesis , UCL (University College London).

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Abstract

Group B Neisseria meningitidis can induce severe sepsis in children. Whilst intensive care treatment has improved extensively over the last 20 years, morbidity and mortality remains high in patients with meningococcal sepsis. Neutrophil adherence to the endothelium mediated by adhesion molecule expression on both cell types is a prerequisite to the induction of vascular damage and capillary leakage which is characteristic of meningococcal sepsis. N. meningitidis and LPS are potent inducer of E-selectin surface expression, an adhesion molecule critical for neutrophil rolling. It has been shown that N. meningitidis is more potent than LPS alone at inducing E- selectin expression. This implies a role for LPS-independent mechanisms. This thesis investigates the molecular mechanisms regulating differential E-selectin expression in response to N. meningitidis and LPS. E-selectin surface expression was detected by FACS analysis and correlated with mRNA transcription detected by Real-Time RT- PCR. The E-selectin promoter was studied with an optimised transfection method using primary endothelial cells. Live and killed bacteria were able to induce higher levels and prolonged expression of E-selectin when compared to LPS. Bacteria induced E-selectin surface protein expression, which correlated with increased mRNA transcription. This suggested that differential E-selectin expression was largely regulated at the transcriptional level. Studies on the E-selectin promoter suggested that whilst LPS induced E-selectin expression was largely mediated by NFkB activity, WT bacteria were able to also activate the MAPK pathway. Studies elucidating the molecular mechanisms of disease progression may provide new targets for drug therapy and thereby improve patient outcome in meningococcal sepsis.

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