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Title: The effect of Streptococcus pneumoniae pneumonia on atherosclerosis
Author: Bazaz, Rohit
ISNI:       0000 0004 6350 1988
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2016
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A growing body of evidence from clinical studies suggests that community acquired pneumonia (CAP) can trigger acute coronary syndromes (ACS). However, the mechanisms underlying this association have yet to be identified. In particular, the effect of pneumonia on atherosclerotic plaque development and stability has yet to be ascertained. Streptococcus pneumoniae is the most common cause of CAP worldwide. This thesis investigates the effect of S.pneumoniae pneumoniae on markers of plaque vulnerability to rupture, with a focus on the role of the macrophage in the post-pneumonic plaque. I hypothesised that pneumonia results in acute, localised inflammatory changes within established atherosclerotic plaques, favouring an unstable phenotype that triggers ACS. In order to investigate this, I developed a unique mouse model of pneumococcal pneumonia in the context of established atherosclerotic plaque formation. The model used high fat diet fed Apolipoprotein E deficient mice, and involved intranasal instillation of type 4 S. pneumoniae followed by antibiotic recovery to achieve both high bacteraemia and survival rates. Using this model I have shown that pneumonia results in increased macrophage content in atherosclerotic lesions 2 weeks post infection, a marker for increased plaque vulnerability. However, by 8 weeks no significant difference in macrophage content was seen, and no significant difference in plaque smooth muscle or collagen content was seen at either time point. I also found evidence for pneumococcal invasion into thrombi, which may promote thrombotic complications following plaque rupture. Using microarray analysis of laser capture micro-dissected plaque macrophages, I identified downregulation of the expression of three genes coding for specific E3 ubiquitin ligases following pneumonia, and used pathway analysis to identify a significant perturbation in the ubiquitin proteasome system pathway as a result. Determining the effect of perturbations in this pathway on macrophage biology within the plaque, and on plaque stability, will require further experimental work.
Supervisor: Dockrell, David ; Francis, Sheila Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available