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The influence of bacterial structure on the host inflammatory response to Neisseria meningitidis

Dixon, Garth Leonard James; (2000) The influence of bacterial structure on the host inflammatory response to Neisseria meningitidis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The gram-negative bacterium Neisseria meningitidis is a significant cause of human disease worldwide. Systemic meningococcal disease is characterised by severe vascular endothelial injury and profound septic shock. Meningococci can be found associated with both endothelial cells and invading leukocytes in vasculitic lesions from patients with severe disease. Binding and migration of activated host inflammatory cells to endothelium is a central process in mediating vascular damage. The expression and function of cell adhesion molecules regulates the interaction between leukocytes and endothelial cells. This thesis is primarily concerned with how meningococci directly influence expression of these receptors on vascular endothelium. To address this, the expression of the vascular cell adhesion molecules CD62E, ICAM-1 and VCAM-1 on cultured human endothelial cells in response to meningococci was explored. Exposure of endothelial cells to Neisseria meningitidis and a range of isogenic mutants revealed that both capsule expression and lipopolysacchide (LPS) structure significantly influenced capacity of meningococci to induce expression of cell adhesion molecules. The pattern observed in response to meningococci was different to that of purified LPS, which is considered to be the primary inflammatory mediator in Neisseria meningitidis. Organisms induced greater expression of CD62E but were equally effective at inducing ICAM-1 and VCAM-1 expression than LPS alone. Cell adhesion molecule expression, activation of nuclear transcription factors required for CD62E expression and the response to the presence of a potent inhibitor of LPS activity, was determined on endothelial cells stimulated with purified LPS, parent meningococci and an isogenic meningococcal mutant completely deficient in LPS. The results suggest that potent induction of cell adhesion molecule expression is due to multiple signals from both LPS and non-LPS components within meningococci. This thesis also explored the contribution of both LPS and non-LPS components of Neisseria meningitidis on dendritic cell maturation and cytokine production. Dendritic cells are critical in the generation of both innate and adaptive immunity to invading bacteria. The results showed that LPS is required to be present within intact bacteria to elicit high-level cytokine production. Taken together, the results presented in this thesis provide further insight into how the structure of N. meningitidis effects the host response to this organism, and hence the pathogenesis of meningococcal disease.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The influence of bacterial structure on the host inflammatory response to Neisseria meningitidis
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10113606
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