|dc.contributor.author||Bakmiwewa, Supun Madushani||-|
|dc.description.abstract||Cerebral malaria (CM) is a severe complication of malaria, and involves the central nervous system (CNS). Despite the significant negative impact of CM, its pathogenesis is not fully understood. Two theories, namely cerebral hypoxia and cytokine expression, are considered to be involved in the process. The present study investigated the potential interaction of these two theories in driving the development of CM. Astrocytes can be a major determinant of the outcome of CNS diseases, and we hypothesised that astrocytes, by responding to the pathways involved in the two theories, would drive the development of CM. The cytokines interferon-gamma (IFN-γ) and lymphotoxin-alpha (LT-α) are essential for the development of experimental CM in a murine model. The chemokine C-X-C motif ligand 10 (CXCL10) also is implicated in this process.
Both Malawian paediatric and mouse CM brain samples showed increased cytokine expression and astrocyte activation. Furthermore, by the use of Ifnγ-/- mice, it was shown that IFN-γ was involved in this CM-associated astrocyte activation. Cultured human primary astrocytes were directly activated by IFN-γ and LT-α to produce synergistic levels of CXCL10. This finding provides a potential mechanism by which astrocytes could be involved in the pathogenesis of CM, and sheds light on the possible role of LT-α in CM. Hypoxia had an effect on astrocytes, but their response to cytokines was not altered by hypoxia. However, oxygen-glucose deprivation resulted in a decline in cytokine-induced CXCL10 release by cultured astrocytes. Decreased production of CXCL10 has the potential to translate into less blood brain barrier damage.
Thus, the mechanisms underlying these two theories do interact at the astrocyte level, but astrocytes show both protective and pathological features as a result of this interaction. The present thesis shows that it is unlikely that the two mechanisms act together to reinforce the astrocytes’ pathological effects to cause CM.||en_AU|
|dc.publisher||University of Sydney||en_AU|
|dc.publisher||Sydney Medical School||en_AU|
|dc.publisher||Discipline of Pathology||en_AU|
|dc.rights||The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.||en_AU|
|dc.title||The Astrocyte: a Crossroads in Cerebral Malaria Pathogenesis||en_AU|
|dc.type.pubtype||Doctor of Philosophy Ph.D.||en_AU|
|dc.description.disclaimer||Access is restricted to staff and students of the University of Sydney . UniKey credentials are required. Non university access may be obtained by visiting the University of Sydney Library.||en_AU|
|Appears in Collections:||Sydney Digital Theses (University of Sydney Access only)|