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Title: CD8+ T-cells responses in Dengue virus infection
Author: Wangteeraprasert, Apirath
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Dengue virus, which has four serotypes, has several clinical manifestations including asymptomatic infection, a self-limiting febrile illness termed dengue fever (DF) and a severe form characterized by plasma leakage termed dengue hemorrhagic fever (DHF). The pathogenesis of DHF is not fully understood and many studies have shown that it is more prevalent during secondary infection. In addition to a mechanism termed antibody dependent enhancement (ADE), the role of T-cells in the pathogenesis of dengue also has been investigated. It has been hypothesized that upon secondary infection dengue-specific memory T-cells generated during a previous infection, which are cross-reactive and have low avidity for the current serotype dominate the T-cell response. This phenomenon is called 'Original antigenic sin' and the consequence of this low avidity T-cell response may be ineffective viral elimination leading to increased production of inflammatory cytokines which could cause plasma leakage. To study CD8+ T-cell responses to dengue-peptide variants, HLA-A11-restricted NS3 133-142-specific T-cell clones were generated and their cytotoxicity, proliferation and cytokine production in response to variant epitopes was tested. The results support that the magnitude of T-cell responses is related to the strength of the TCR-peptide-MHC interaction. AG129 mice, which lack both IFN (symbol missing) and IFN (symbol missing) receptors, show susceptibility to dengue virus infection and develop symptoms seen during human infection such as vascular leakage. This allows for investigation of the role of T-cell responses generated towards sequential infections with well defined serotypes. Experiments that would be very difficult to carry out in human dengue patients. Splenocytes from sequentially infected AG129 mice were assayed for their response to whole dengue proteins from serotype 1 and 2 virus. New epitopes were identified and CD8+ T-cell lines and clones were generated and their functions studied using peptide variants. The results showed that dengue-specific cross-reactive memory CTLs displayed better recognition of epitopes encountered during primary immunisa tion as compare to those recognised during secondary immunisation, which supports the idea of original antigenic sin in dengue-specific CD8+ T -cells. In conclusion, this study focuses on cross-reactive dengue-specific CD8+ T-cells and their functions when recognizing heterologous dengue peptides to clarify their role in pathogenesis.
Supervisor: Mongkolsapaya, Juthathip ; Screaton, Gavin Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available