Neisseria meningitidis is a pervasive bacterial coloniser of the human nasopharynx with up to 40% carriage in the population. Paradoxically, invasive disease occurs in only ~1 in 100,000 individuals. Sophisticated immune evasion mechanisms allow the bacterium to persist in the host, yet these adaptations may also enable its transition from a harmless commensal to an invasive pathogen. Dendritic cells (DC) are principal controllers of mucosal immunity, and bacteria can exploit their maturation process to evade the immune system. In this study, it is reported for the first time that live serogroup B meningococcus (NmB) impedes DC maturation by disrupting STAT1 through dephosphorylation of tyrosine 701 (Y701). DC were therefore refractory to interferon stimulation—which is essential for DC function—and had low levels of maturation markers and other STAT1 dependent genes. Interestingly, infected DC retained the activity of other major signalling pathways, including the MAP kinases, which induced PD L1hi DC that were CD4+ T-cell suppressive. Disruption of STAT1 also had the major effect of dampening SOCS1 and CISH expression, which are critical for homeostatic control of DC inflammatory cytokine production, and correlated with enhanced inflammatory cytokine production. Restoration of STAT1-Y701 phosphorylation reprogrammed DC towards a typical CD86hi maturation state, normalised cytokine profiles and T-cell responses. These data establish an unconventional inflammatory pathway for the meningococcus, but also link immune evasion and pathogenesis via a shared mechanism. These findings elucidate how NmB may undermine immunity within the normal mucosa but also inflict damage in the context of septicaemia due to uncontrolled inflammation.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:746040 |
| Date | January 2015 |
| Creators | Copland, A. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1472931/ |
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