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Title: The molecular basis of persistent staphylococcal bacteraemia
Author: Painter, Kimberley Louise
ISNI:       0000 0004 5994 2561
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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In Staphylococcus aureus, the accessory gene regulator (Agr) system controls the expression of toxins that damage the host. Agr is required for bacterial survival in a range of animal infection models, although its role during bacteraemia is poorly understood. Agr is also important for survival of S. aureus in the presence of neutrophils in vitro, but there is paradoxical clinical evidence that loss of Agr (either via agr mutations or mutations that result in the small colony variant [SCV] phenotype) promotes bacterial survival during bacteraemia. Therefore, the aim of this thesis was to decipher the role of Agr in the survival of S. aureus in blood. Mutants with deletions in the agr operon or in genes that confer the SCV phenotype were tested alongside their isogenic wildtype strain in an ex vivo whole human blood model. Functional Agr was shown to be important for maximal survival of wildtype S. aureus in blood. However, S. aureus could survive in an Agr-independent manner as an SCV, the survival of which was much higher in blood than wildtype bacteria. This elevated SCV survival in blood was due to increased resistance to the neutrophil oxidative burst. For one SCV type, this was partly due to increased catalase activity, although this was not the case for the other type of SCV examined, suggesting additional mechanisms of oxidative stress resistance. Inductively coupled plasma mass-spectrometry revealed that SCVs had reduced levels of iron and increased levels of manganese relative to the wildtype, which could protect against exposure to reactive oxygen species. In conclusion, the data within this thesis support the importance of Agr for S. aureus survival in the blood, as well as revealing a novel Agr-independent mechanism by which S. aureus can persist in the host.
Supervisor: Edwards, Andrew ; Wigneshweraraj, Sivaramesh Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral