Dengue virus (DENV) infection can cause severe, life-threatening events, and no specific treatments of DENV infection are currently approved. Although thrombocytopenia is frequently observed in dengue patients, its pathogenesis is still not fully understood. Previous studies have suggested that DENV-induced thrombocytopenia occurs through viral-replication-mediated megakaryopoiesis inhibition in the bone marrow; however, the exact mechanism for megakaryopoiesis suppression remains elusive. In this study, a reductionist approach was applied, in which C57B/6J mice were inoculated with recombinant DENV-envelope protein domain III (DENV-EIII) instead of the full viral particle. Our results demonstrated that DENV-EIII-suppressed megakaryopoiesis is similar to those observed with DENV infection. Furthermore, in agreement with our in vivo analyses, DENV-EIII sufficiently suppressed the megakaryopoiesis of progenitor cells from murine bone marrow and human cord blood in vitro. Additional analyses suggested that autophagy impairment and apoptosis are involved in DENV-EIII-mediated suppression of megakaryopoiesis. These data suggest that, even without viral replication, the binding of DENV-EIII to the cell surface is sufficient to suppress megakaryopoiesis.
Dengue virus (DENV) infections may cause life-threatening dengue hemorrhagic fever (DHF).Suppressed protective immunity was shown in these patients. Although several hypotheses have been formulated, the mechanism of DENV-induced immunosuppression remains unclear. Previously, we found that cross-reactive antibodies against tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 1 (death receptor 4 [DR4]) were elicited in DHF patients, and that anti-DR4 autoantibody fractions were elicited by nonstructural protein 1 (NS1) immunizations in experimental mice. In this study, we found that anti-DR4 antibodies could suppress B lymphocyte function in vitro and in vivo. Treatment with the anti-DR4 immunoglobulin (Ig) induced caspase-dependent cell death in immortalized B lymphocyte Raji cells in vitro. Anti-DR4 Igs elicited by NS1 and DR4 immunizations markedly suppressed mouse spleen transitional T2 B (IgM + IgD + ), bone marrow pre-pro-B (B220 + CD43 + ), pre-B (B220 + CD43 − ), and mature B cell (B220 + IgD + ) subsets in mice. Furthermore, functional analysis revealed that the pre-elicitation of anti-NS1 and anti-DR4 Ig titers suppressed subsequently neutralizing antibody production by immunization with DENV envelop protein. Our data suggest that the elicitation of anti-DR4 titers through DENV NS1 immunization plays a suppressive role in humoral immunity in mice.The dengue virus (DENV) is a mosquito-borne single positive-stranded RNA virus belonging to the Flaviviridae family (genus Flavivirus); the 4 major serotypes of DENV cause self-limiting dengue fever (DF) and life-threatening dengue hemorrhagic fever (DHF) 1 . It has been estimated that 50 million cases of DENV infections occur, and approximately 500,000 patients have been hospitalized with DHF, mainly in tropical and subtropical regions 2 . Evidence has suggested that because of the geographical extension of DENV infection and increases in the number of DENV cases and disease severity, DF and DHF have become major public health problems, with more than one-third of the global population residing in high-transmission-risk areas 3-5 . DHF is a complex disease, and its mechanism remains elusive. Currently, no specific treatment or effective vaccine is available for immunization cycle) in 1 wk intervals and then the bone marrow and spleen lymphocytes were analyzed 7 d later using aforementioned B cell markers. To analyze the potential suppressive effect of prior immunizations of NS1 on later induction of neutralizing antibody, C57BL/6J mice were first immunized with rGST, rNS1, rDR4 and rTACI by 2 immunization cycles (50 µg immunogen/mouse/immunization cycle) and then immunized with 2 additional immunization cycles of DENV rEIII in 1 wk intervals. The anti-EIII titer and the DENV-neutralizing property of these polyclonal antibody fractions were then analyzed.Statistical analyses. The means, standard deviations, and statistics for the quantifiable data were calculated using Microsoft Office Excel 2003, SigmaPlot 10 and SPSS 17. Significance of data...
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