The role of mononuclear phagocytes in dengue immunopathogenesis

Bhatia, Kanika Devi. (2003). The role of mononuclear phagocytes in dengue immunopathogenesis PhD Thesis, School of Molecular and Microbial Sciences, The University of Queensland.

       
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Author Bhatia, Kanika Devi.
Thesis Title The role of mononuclear phagocytes in dengue immunopathogenesis
School, Centre or Institute School of Molecular and Microbial Sciences
Institution The University of Queensland
Publication date 2003
Thesis type PhD Thesis
Supervisor Young, Paul
Total pages 204
Collection year 2003
Language eng
Subjects L
270303 Virology
780105 Biological sciences
Formatted abstract Dengue virus causes two forms of disease, dengue fever (DF) and dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS). The acute nature and lack of pathology observed in conjunction with disease has suggested a role for proinflammatory cytokines. One possible source of these cytokines are macrophages and monocytes, the main target of infection in vivo. A risk factor for the development of severe disease is the presence of cross-reactive, non-neutralising antibodies, thought to enhance infectivity of dengue for mononuclear phagocytes. This process, termed antibody dependent enhancement (ADE), is mediated by Fc receptors (FcR). The FcR also mediate a number of other cellular processes including cytokine secretion and apoptosis, processes that have previously been implicated to play a role in pathogenesis. This study has examined the influence of ADE on cytokine production and apoptosis in infected mononuclear phagocytes.

Infection of RAW264.7, a murine macrophage cell line with dengue resulted in the induction of TNF-α, IL-1β and inducible nitric oxide synthase (iNOS) mRNA. This response was also observed following exposure to inactivated virus, suggesting that virus binding/entry plays a role in activation. Cells infected with immune complexes demonstrated a pattern of mRNA expression, distinct from that observed in cells infected with virus alone. TNF-α and IL-1β mRNA demonstrated differences in temporal expression, suggesting that immune complexes alter the kinetics of cytokine induction. ADE also acted to increase the level of TNF-α secreted.

Studies on TNF-α processing and secretion have shown that IFNγ acts to alter the processing of TNF-α elicited by LPS, favouring the production of the membrane form of TNF-α (TmTNF-α). TmTNF-α mediates different functions from its secreted counterpart; its expression may be capable of altering the nature of pathogenesis. IFNγ is found at elevated levels in the sera of DF and DHF/DSS patients implicating a potential role in the development of disease. However, experiments in this study were unable to demonstrate a role for IFNγ in the modulation of TNF-α production in dengue infected RAW264.7 cells. Although cells infected with immune complexes did demonstrate such an alteration suggesting that, like IFNγ and LPS treatment, infection with immune complexes favours the production of TmTNF-α.

Several studies have implicated a role for apoptosis in the pathogenesis of dengue infection. Experiments described in this thesis have demonstrated that infection of RAW264.7 results in their apoptosis. However, apoptosis was not observed in the human monocyte cell lines, K562 and U937. The induction of apoptosis in macrophages but not monocytes suggests that apoptosis might be modulated by the state of differentiation of the cell.

This study has demonstrated that ADE acts to modulate cytokine induction, processing and secretion elicited by infection. This study has also shown that dengue is able to induce apoptosis in murine macrophages but not in human monocytes. The potential roles of these factors in pathogenesis are discussed.
Keyword Dengue
Dengue viruses

 
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Created: Fri, 24 Aug 2007, 18:18:42 EST