Uronen-Handsson, Heli Anneli;
(2004)
Dendritic cell interactions with Neisseria meningitidis.
Doctoral thesis (Ph.D.), University College London.
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Abstract
Group B Neisseria meningitidis is a human pathogen, for which a vaccine is still not available. Immune responses to bacteria are initiated by dendritic cells (DCs), which phagocytose and process bacterial antigens for presentation to T cells. In this study, interactions between human monocyte derived DCs and N. meningitidis were investigated. Maximal cytokine production by DCs in response to N. meningitidis was shown to depend on physical contact and internalisation of the bacteria by DCs. The majority of DCs making cytokines had internalised N. meningitidis and inhibition of phagocytosis impaired cytokine production, especially IL-12. Phagocytosis of N. meningitidis was shown to depend on LPS expressed by the bacteria. Phagocytosis of the LPS deficient mutant bacteria was poor and occurred at a very low rate. By regulating the expression of LPS, it was shown that restoration of bacterial LPS biosynthesis restored both phagocytosis and cytokine production by DCs. In addition, optimal phagocytosis and cytokine production required the presence of LPS binding protein. DC responses to novel bacterial mutants expressing LPS with modified oligosaccharide core or lipid A were examined. Optimal phagocytosis and cytokine production were shown to depend on the precise oligosaccharide and lipid A structures. The expression and localisation of Toll-like receptors (TLR) 2 and 4 in human DCs was investigated. TLR2 and TLR4 were not present on the surface but were detected inside the DCs in association with tubulovesicular structures close to the Golgi complex. Co-localisation of TLR2 and TLR4 with DC microtubules was observed. Depolymerisation of the microtubule network disrupted intracellular TLR2 and TLR4 and inhibited IL12 production in response to N. meningitidis but did not prevent phagocytosis. These results suggested that TLR activation by N. meningitidis required for IL12 production occurred inside DCs and not on the cell surface. These findings have important implications for designing vaccines that will induce protective immune responses to group B N. meningitidis.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D. |
| Title: | Dendritic cell interactions with Neisseria meningitidis. |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10102487 |
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