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Title: Evaluating the effects of dengue virus and iminosugar treatment on cellular unfolded protein response and redox homeostasis
Author: Perera, Nilanka
ISNI:       0000 0004 7971 6852
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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Dengue virus (DENV) infections cause significant morbidity worldwide. The complex host-viral interactions affecting viral replication and the host immune response result in variable disease severity in affected individuals. This thesis focuses on two such host responses implicated in DENV pathogenesis; unfolded protein response (UPR) and oxidative stress. DENV preferentially activated the proviral and pro-inflammatory IRE1-XBP1 arm of the UPR in monocyte-derived macrophages in vitro. Investigation of redox homeostasis revealed induction of reactive oxygen species and increase in total antioxidant capacity in DENV- infected macrophages. Further evaluation of peripheral blood mononuclear cells during early DENV-infection revealed increased XBP1s and reduced DDIT3 and HSPA5 transcripts in affected individuals who later developed severe dengue disease. Proteomics performed on the cell lysates revealed upregulation of the IRE1-mediated UPR pathway and differential expression of several protein markers in individuals who developed severe disease compared to non-severe disease potentially providing a foundation to develop markers of DENV disease severity. Iminosugars are broad spectrum antivirals targeting host ER glucosidases causing antiviral effects against DENV. The effects of iminosugars have not previously been studied in DENV-infected dendritic cells. The percentage of infected cells and secretion of DENV were reduced in dendritic cells treated with three DNJ-derived iminosugars in a dose-dependent manner. The specific infectivity was reduced at iminosugar doses exceeding 3.16 M which inhibited -glucosidase I. Furthermore, DENV-induced TNF levels were reduced with iminosugar treatment. Evaluation of the UPR in DENV-infected and 2THO-DNJ treated macrophages revealed a reduction in XBP1s levels compared to untreated cells and an increase in EDEM1 and ERDJ4 transcripts. However, the UPR was not required for the antiviral or anti-inflammatory effects of the iminosugar 2THO-DNJ. ROS levels and antioxidant capacity were also reduced in DENV-infected macrophages following treatment with 2THO-DNJ and MON-DNJ. Overall, this thesis describes the role of the UPR and oxidative stress in DENV infection and the effect of iminosugars on these host responses.
Supervisor: Zitzmann, Nicole Sponsor: Commonwealth Scholarship Commission
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available