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Title: Perivascular orchestration of neutrophil recruitment in S. pneumoniae meningitis
Author: Gil, Eliza
ISNI:       0000 0004 9352 5876
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2020
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Pneumococcal meningitis has a mortality rate of >20% despite antibiotic treatment and 50% of survivors have persistent neurodisability. The disease is associated with the marked infiltration of neutrophils into the brain, and the cytopathic inflammatory responses mediated by these cells results in severe tissue damage. The diminution of neutrophil recruitment, alongside antibiotic treatment, therefore represents a novel therapeutic opportunity. The interaction of perivascular macrophages (PVMs), pericytes and endothelial cells has been described to play an important role in neutrophil recruitment in mouse models of soft tissue infection. The cerebral vasculature has the highest density of pericytes in the body, as well as uniquely located perivascular macrophages. The role of pericytes in the response to cerebral infection has not been described. We hypothesized that cerebral pericytes play a central role in orchestrating the inflammatory response in pyogenic meningitis. I used an in vitro transwell model of the blood-brain barrier (BBB) involving the coculture of primary human brain pericytes (HBVP) and a cerebromicrovascular endothelial cell line (hCMEC/D3), along with conditioned media from human monocyte-derived macrophages (MDMs) to model PVM responses, to investigate the interaction of these cells in orchestrating the inflammatory response at the BBB in response to infection with S. pneumoniae. Neutrophil recruitment was enhanced by the presence of HBVP under all conditions tested, most potently in response to S. pneumoniae-stimulated macrophages. HBVP were shown to be sensitive to signalling by many of the pro-inflammatory mediators secreted by MDMs in response to S. pneumoniae. HBVP secreted a broad repertoire of chemokines in response to these mediators, most potently neutrophil chemokines. These chemokines were shown to be actively transported across the endothelial barrier, most likely by atypical chemokine receptor 1, enabling them to interact with circulating leukocyte populations. I propose a model whereby cerebrovascular tissue resident innate immune cells act as sentinels of neuroinfection, activating the endothelial and pericyte layer of the blood-brain barrier, with the pericytes markedly amplifying neutrophil recruitment to the site of infection via secretion of neutrophil chemokines.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available