For human commensal Neisseria meningitidis (Nm) to initiate the pathology of which it is capable it must be able to cross cellular barriers, and once crossed, survive in the blood. It has been established by several studies that susceptibility to infection by Nm increases markedly following viral infection. A potential causative mechanism for this observed temporal effect may include the upregulation of bacterial receptors on host cells in response to virallyinduced cytokines. The initial part of the study presented aims to clarify the effect of inflammatory cytokines in upregulating epithelial receptors targeted by Nm. Results demonstrated that treatment of epithelial monolayers with IFN-V led to de novo synthesis of major Opa receptor, CEACAM1, which in turn, led to increased invasion of host cells by capsulate Opa-expressing bacteria. This is dependent on the activation of Nuclear factor-kappa B (NFKB) as demonstrated by the abrogation of infiltration in the presence of NFKB inhibitors. Once the bacterium has invaded the epithelial layer, the next step in pathogenesis is traversing the endothelial barrier of the host vasculature. Vitronectin (Vn) has been implicated previously in mediating adhesion to and invasion of human brain microvascular endothelial cells (HBMEC) by Opc-expressing Nm. The aim of the second part of the study was to investigate the nature of the Opc-Vn interaction. The data demonstrated that Opc-expressing Nm preferentially bind directly to the activated form of human Vn (aVn) in which sulphotyrosines YS6 and YS9 are exposed. Accordingly, cell association and invasion was abrogated in the presence of both sulphated Vn peptide spanning residues 43-68 and conformation-dependent antibody 8E6 binding at this site. Monomeric preparations of native Vn were also unable to support endothelial interactions with Nm. A second, lower affinity interaction was also observed in the presence of heparin with data indicating that the same region of Opc is responsible for both interactions.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:690035 |
| Date | January 2015 |
| Creators | Griffiths, Natalie |
| Publisher | University of Bristol |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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