Suppressive effect of dengue virus envelope protein domain III on megakaryopoiesis

Abstract

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.

New insight on dengue virus-induced thrombocytopenia

“…In the current study, Lin et al (2017) suggest that DENV-envelope protein domain III (DENV-EIII) is sufficient to suppress differentiation of megakaryocytes to thrombocytes and that replication within haematopoietic precursors is not required. 12 The investigators hypothesized that engagement of DENV-EIII with the cell surface would be sufficient to perturb cell signaling and the differentiation of the thrombocyte progenitors. 12 Previous research has shown that DENV antigens are present on the surface of thrombocytes and that virions can enter into these cells through engagement with DC-SIGN.…”

“…12 The investigators hypothesized that engagement of DENV-EIII with the cell surface would be sufficient to perturb cell signaling and the differentiation of the thrombocyte progenitors. 12 Previous research has shown that DENV antigens are present on the surface of thrombocytes and that virions can enter into these cells through engagement with DC-SIGN. 4,9 To test their hypothesis, the investigators confirmed that DENV-EIII could bind to megakaryocytes, and then administered DENV-EIII to a mouse model and progenitor cells from both murine bone marrow and human cord blood.…”

“…Treatment with DENV-EIII reduced megakaryocyte numbers in each of these model systems. 12 In order to understand how DENV-EIII suppressed megakaryopoiesis, megakaryocytic differentiation was performed using human cord blood-derived CD34 C cells. Cells treated with DENV-EIII had altered autophagy profiles and increased markers associated with apoptosis.…”

“…Cells treated with DENV-EIII had altered autophagy profiles and increased markers associated with apoptosis. 12 Previous studies have demonstrated that altered autophagy profiles can lead to cell death of megakaryocytes. 13 These data suggest that DENV-EIII alone can modulate autophagy and induce apoptosis in progenitor and mature megakaryocytes.…”

Suppressed humoral immunity is associated with dengue nonstructural protein NS1-elicited anti-death receptor antibody fractions in mice

“…1B) of polyclonal anti-NS1 Igs induce cell death of lymphoid cell lines, we used affinity-enriched fractions of the anti-NS1 Ig (anti-NS1-TACI Ig and anti-NS1-DR4 Ig) plus additional proteins [e.g. recombinant glutathione S-transferase (rGST; a negative control protein 23,30,31 ), recombinant NS1 (rNS1), recombinant TACI (rTACI) and recombinant DR4 (rDR4)] to perform neutralization experiments. Data indicated that anti-NS1-DR4 and anti-NS1-TACI Ig treatments induced cell death of Raji and Jurkat cells in a dose dependent manner (Suppl.…”