The human nasopharynx is a reservoir of both commensal and pathogenic bacteria that can be easily transmitted from one individual to another. It has long been hypothesised that host commensal flora give protection from carriage of pathogens and invasive disease. The commensal Neisseria lactamica has previously been associated with protection against the closely related human pathogen Neisseria meningitidis, which is thought to be due to the acquisition of cross-reactive immunity to N. meningitidis. The objective of this study was to identify the extent of protection by N. lactamica in the absence of host immune cells, using an in vitro model of the human nasopharyngeal epithelium with the Detroit 562 (D562) cell line. N. lactamica has been demonstrated to attenuate the induction of innate inflammatory cytokines and chemokines from D562 cells challenged with N. meningitidis. For the first time in this study, N. lactamica was found to attenuate the induction of IL6, IL8 and TNFα from D562 cells challenged with the unrelated Gram-positive human pathogen Streptococcus pneumoniae. Attenuation by N. lactamica did not extend to suppression of MAPK pathways when stimulated with chemical agonists, but was able to suppress inflammation induced through the intracellular PAMP receptor TLR3, which is not involved in meningococcal or pneumococcal inflammation. This suggests a global mechanism of attenuation in host cells by N. lactamica. N. lactamica was further demonstrated to reduce association with and invasion of D562 epithelial cells by N. meningitidis serogroup B (MenB) by up to 60% and 90%, respectively. This suppression was dependent on live N. lactamica and did not require invasion of host cells by the commensal, suggesting an active mechanism employed by N. lactamica. The occasional human commensal coloniser Neisseria polysaccharea was found to reduce adhesion and invasion of MenB to a similar degree, however the related commensal Neisseria cinerea was not. The reduction in MenB association with host cells protected host cells from MenB-induced apoptosis, which was mediated by activation of caspase 3. This study demonstrates that commensal Neisseria spp. N. lactamica and N. polysaccharea protect the host at the nasopharyngeal epithelium from experimental colonisation and invasive disease by MenB. Additionally, commensal neisseriae protect against inflammation and cell death induced by the unrelated pathogen S. pneumoniae. Therefore, commensal neisseriae warrant further study to evaluate their effectiveness for use as probiotics to protect against bacterial pathogens responsible for meningitis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:606233 |
| Date | January 2014 |
| Creators | Page, K. |
| Publisher | University of the West of England, Bristol |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://eprints.uwe.ac.uk/22932/ |
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