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Publications (4)13.44 Total impact

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    ABSTRACT: Vascular permeability, thrombocytopenia, liver pathology, complement activation and altered hemostasis accompanying a febrile disease are the hallmarks of the dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), a major arthropod-borne viral disease that causes significant morbidity and mortality throughout tropical countries. We studied tissues from 13 children who died of acute DHF/DSS at the Childrens’ Hospital, Yangon, Myanmar. Dengue viral RNA from each of the four dengue viruses (DENV) was detected by RT-PCR in 11 cases and dengue viral proteins (envelope, NS1 or NS3) were detected in one or more tissues from all 13 cases. Formalin-fixed and frozen tissues were studied for evidence of virus infection using monoclonal antibodies against DENV structural and non-structural antigens (E, NS1 and non-secreting NS3). In the liver, DENV infection occurred in hepatocytes and Kupffer cells but not in endothelial cells. Liver damage was associated with deposition on hepatocytes of complement components of both classical and alternative pathways. Evidence of dengue viral replication was observed in macrophage-like cells in spleens and lymph nodes. No dengue antigens were detected in endothelial cells in any organ. Germinal centers (GC) of spleen and lymph nodes showed marked reduction in the number of lymphocytes that were replaced by eosinophilic deposits which contained dengue antigens as well as immunoglobulins, and complement components (C3, C1q and C9). The latter findings had previously been reported but overlooked as a diagnostic feature.
    Human pathology 01/2014; · 3.03 Impact Factor
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    ABSTRACT: Dengue virus infection is an important mosquito-borne disease and a public health problem worldwide. A better understanding of interactions between human cellular host and dengue virus proteins will provide insight into dengue virus replication and cellular pathogenesis. The glycosylated envelope protein of dengue virus, DENV E, is processed in the endoplasmic reticulum of host cells and therefore reliant on host processing functions. The complement of host ER functions involved and nature of the interactions with DENV E has not been thoroughly investigated. By employing a yeast two-hybrid assay, we found that domain III of DENV E interacts with human immunoglobulin heavy chain binding protein (BiP). The relevance of this interaction was demonstrated by co-immunoprecipitation and co-localization of BiP and DENV E in dengue virus-infected cells. Using the same approach, association of DENV E with two other chaperones, calnexin and calreticulin was also observed. Knocking-down expression of BiP, calnexin, or calreticulin by siRNA significantly decreased the production of infectious dengue virions. These results indicate that the interaction of these three chaperones with DENV E plays an important role in virion production, likely facilitating proper folding and assembly of dengue proteins.
    Biochemical and Biophysical Research Communications 01/2009; 379(2):196-200. · 2.28 Impact Factor
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    ABSTRACT: Dengue fever (DF) and dengue hemorrhagic fever (DHF) are important public health problems in tropical regions. Abnormal hemostasis and plasma leakage are the main patho-physiological changes in DHF. However, hepatomegaly, hepatocellular necrosis and fulminant hepatic failure are occasionally observed in patients with DHF. Dengue virus-infected liver cells undergo apoptosis but the underlying molecular mechanism remains unclear. Using a yeast two-hybrid screen, we found that dengue virus capsid protein (DENV C) physically interacts with the human death domain-associated protein Daxx, a Fas-associated protein. The interaction between DENV C and Daxx in dengue virus-infected liver cells was also demonstrated by co-immunoprecipitation and double immunofluorescence staining. The two proteins were predominantly co-localized in the cellular nuclei. Fas-mediated apoptotic activity in liver cells constitutively expressing DENV C was induced by anti-Fas antibody, indicating that the interaction of DENV C and Daxx involves in apoptosis of dengue virus-infected liver cells.
    Biochemical and Biophysical Research Communications 11/2007; 362(2):334-9. · 2.28 Impact Factor
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    ABSTRACT: Vascular leakage and shock are the major causes of death in patients with dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Thirty years ago, complement activation was proposed to be a key underlying event, but the cause of complement activation has remained unknown. The major nonstructural dengue virus (DV) protein NS1 was tested for its capacity to activate human complement in its membrane-associated and soluble forms. Plasma samples from 163 patients with DV infection and from 19 patients with other febrile illnesses were prospectively analyzed for viral load and for levels of NS1 and complement-activation products. Blood and pleural fluids from 9 patients with DSS were also analyzed. Soluble NS1 activated complement to completion, and activation was enhanced by polyclonal and monoclonal antibodies against NS1. Complement was also activated by cell-associated NS1 in the presence of specific antibodies. Plasma levels of NS1 and terminal SC5b-9 complexes correlated with disease severity. Large amounts of NS1, complement anaphylatoxin C5a, and the terminal complement complex SC5b-9 were present in pleural fluids from patients with DSS. Complement activation mediated by NS1 leads to local and systemic generation of anaphylatoxins and SC5b-9, which may contribute to the pathogenesis of the vascular leakage that occurs in patients with DHF/DSS.
    The Journal of Infectious Diseases 05/2006; 193(8):1078-88. · 5.85 Impact Factor