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Title: The interaction of Staphylococcus aureus with macrophages
Author: Jubrail, Jamil
ISNI:       0000 0004 5349 1077
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2014
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Macrophages are essential during the innate immune response to bacterial pathogens. They have a variety of roles during bacterial infections that extend beyond phagocytosis and intracellular killing. The interaction of Staphylococcus aureus with macrophages has not been completely characterised. Moreover, how S. aureus is able to manipulate the macrophage host defence has produced conflicting results. This thesis has examined the kinetics of phagocytosis and intracellular killing of S. aureus by macrophages, as well as identifying key features of these processes, and developed a mathematical model to describe the interaction of S. aureus with macrophages. Exposure of macrophages to S. aureus at a range of doses demonstrated that macrophages accumulated intracellular bacteria but although they could kill fixed numbers of intracellular bacteria they showed a finite capacity to kill bacteria. There was an initial rapid phase of intracellular killing post phagocytosis and then a more gradual decline in intracellular, viable bacteria, with persistence of intracellular bacteria for extended periods of time. Macrophages maintained viability following S. aureus challenge over time and macrophage mediated apoptosis was not apparent. As well as this, at the point when macrophages had exhausted their ability to kill intracellular bacteria they still demonstrated an ability to phagocytose and accumulate further intracellular bacteria. This thesis also demonstrated that intracellular bacteria were able to persist intracellularly for up to 3 days post infection and then macrophages were lysed by intracellular bacteria. The released bacteria were ingested by other macrophages and as a result an intracellular pool of bacteria was maintained. Examination of the cell death process revealed it was not apoptosis but probably necrosis. I also explored the intracellular compartment where S. aureus were residing and was able to show that the majority of intracellular bacteria were in a phagolysosome that was not appropriately acidified but that the majority of the bacteria colocalised with the late endosomal markers lysosome associated membrane protein 1 or 2 (LAMP-1/2). In contrast the majority of Escherichia coli and Streptococcus pneumoniae were found to be in phagolysosomes that were appropriately acidified. This thesis describes a novel mathematical model for the interaction of S. aureus with macrophages. The mathematical model showed that macrophages had the ability to phagocytose S. aureus at a rate that depended on the extracellular bacterial concentration. However, the model revealed that macrophages showed a finite capacity to clear intracellular bacteria which over time gave rise to a population of macrophages that were unable to kill all of the bacteria they had phagocytosed. Overall this thesis has shown that macrophages can phagocytose S. aureus and they accumulate intracellular bacteria over time efficiently. However, they show only a limited capacity to kill intracellular bacteria and in response to S. aureus macrophage apoptosis is not engaged. This thesis demonstrates that prolonged intracellular persistence of S. aureus in macrophages is beneficial to the bacterium and over time they lyse the macrophage and are released and re-ingested by other macrophages. This thesis suggests that the ability to break this release and re-ingestion cycle could lead to better therapeutic management of S. aureus disease.
Supervisor: Dockrell, David ; Marriott, Helen ; Best, Alex Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available