Host epithelial responses to Neisserial colonisation

Neisseria meningitidis is a bacterium that colonises the human nasopharyngeal mucosal surface. Occasionally, it can migrate from the nasopharynx to cause potentially lifethreatening meningitis and septicaemia. In contrast, closely related bacteria such as Neisseria lactamica, colonise the nasopharynx but do not cause invasive disease. Interaction differences between N. meningitidis and N. lactamica with the human host at the colonisation stage are poorly defined. I hypothesise that early interactions of N. meningitidis and N. lactamica with respiratory epithelial cells are associated with differential host cell responses, and that these may be capable of altering the outcome of the interaction. Experiments were undertaken to describe the interactions of N. meningitidis and N. lactamica with a human bronchial epithelial cell line. Association and invasion studies indicated a similar extent of association and invasion of N. meningitidis and N. lactamica. Human epithelial gene expression profiles in response to N. meningitidis and N. lactamica were determined using a genome wide microarray platform. Comparison of live and dead bacteria enabled the identification of host responses specifically to live Neisseria while comparison of the N. meningitidis capand pilE- mutants allowed the identification of host responses to non-capsule and pili factors, such as secreted proteins. Selected genes were further verified at the transcript and protein level. Host metabolic and energy production processes were associated with both neisserial species, suggesting that both N. meningitidis and N. lactamica utilise host resources for energy. In contrast, the data indicated that while N. meningitidis down-regulates host defence genes, N. lactamica initiates a proinflammatory response, suggesting specific colonisation processes that may lead to different clinical outcomes. Treatment of the epithelial cells with neisserial secreted proteins showed that they may be directing some of these differential responses, suggesting novel mechanisms for modulation of the host response.EThOS - Electronic Theses Online ServiceAgency for Science, Technology and Research, Singapore (A*STAR)GBUnited Kingdo