Pathogenesis of dengue: subversion of innate immunity.
Doctoral thesis, UCL (University College London).
Dengue viruses (DENV) are mosquito-borne flaviviruses that cause a severe febrile illness, and sometimes a potentially lethal syndrome called dengue haemorrhagic fever (DHF). Despite decades of effort, the global resurgence of dengue is testament to the inadequacy of current control measures. Dengue has become an immense international public health concern: WHO estimates that there are 50-100 million dengue infections and 500,000 cases of DHF hospitalised each year. Thus dengue has a major economic impact in the developing world through loss of healthy life and utilisation of constrained health resources. Global dengue control is likely to require a combined approach based on the development of successful strategies for immunization and antiviral drugs, as well as vector control. Better understanding of DENV pathogenesis presents new opportunities for design of rationally attenuated vaccine candidates and antiviral therapies. This thesis focuses on understanding a critical step in DENV pathogenesis: evasion of human innate immune responses mediated by interferon. A lentiviral vector system was developed to express dengue non-structural (NS) proteins in human cells, and we used this to show that expression of dengue NS5 alone inhibited IFN-α, but not IFN-γ, signalling. The IFN-α signalling cascade is blocked downstream of Tyk2 phosphorylation: NS5 binds to the transcription factor STAT2 and inhibits its phosphorylation. The polymerase domain of NS5 is sufficient to block IFN-α induced signal transduction, and inhibition does not require NS5 nuclear translocation. We finally tested several hypotheses to explain why STAT2 degradation occurs in both DENV-infected and replicon-containing cells, but not when NS5 is expressed alone. The most important conclusion from this work is that DENV NS5 is a potent and specific type I IFN antagonist. The results of this study are an important step in defining the molecular pathogenesis of dengue, and provide clues to potential new approaches to combat this disease.
|Title:||Pathogenesis of dengue: subversion of innate immunity|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Infection and Immunity (Division of) > Research Department of Infection|
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