Abstract
Depression of the peripheral blood platelet count during acute infection is a hallmark of dengue. This thrombocytopenia has been attributed, in part, to an insufficient level of platelet production by megakaryocytes that reside in the bone marrow (BM). Interestingly, it was observed that dengue patients experience BM suppression at the onset of fever. However, few studies focus on the interaction between dengue virus (DENV) and megakaryocytes and how this interaction can lead to a reduction in platelets. In the studies reported herein, BM cells from normal healthy rhesus monkeys (RM) and humans were utilized to identify the cell lineage(s) that were capable of supporting virus infection and replication. A number of techniques were employed in efforts to address this issue. These included the use of viral RNA quantification, nonstructural protein and infectivity assays, phenotypic studies utilizing immunohistochemical staining, anti-differentiation DEAB treatment, and electron microscopy. Cumulative results from these studies revealed that cells in the BM were indeed highly permissive for DENV infection, with human BM having higher levels of viral production compared to RM. DENV-like particles were predominantly observed in multi-nucleated cells that expressed CD61+. These data suggest that megakaryocytes are likely the predominant cell type infected by DENV in BM, which provides one explanation for the thrombocytopenia and the dysfunctional platelets characteristic of dengue virus infection.
Highlights
Bone marrow (BM) is the principal site for blood cell formation; the daily production of which in adults is 2.5 billion red cells and platelets each, and 1.0 billion granulocytes per kilogram of body weight
All subsequent experiments were performed utilizing unfractionated BM cells to demonstrate the infectability of cells by dengue virus
To demonstrate the infectiousness of the virus obtained in supernatants from infected BM cell cultures, aliquots of randomly selected samples of the cultures from day 2 and 5 containing similar amounts of viral RNA were incubated with fresh Vero cells
Summary
Bone marrow (BM) is the principal site for blood cell formation; the daily production of which in adults is 2.5 billion red cells and platelets each, and 1.0 billion granulocytes per kilogram of body weight. There is extensive evidence implicating the involvement of the BM in dengue virus infection. Pain localized to the BM suggests the involvement of this organ during dengue virus infection. In vitro studies have found that cells in the BM are highly permissive for dengue virus infection [2] and are more so than those from the spleen, lymph node, and thymus [3]. This view is supported by the documentation of a case which reported the transmission of dengue virus from a donor to a recipient as a result of a BM transfusion [4]. Fever was noticed 2 days after the donation, and it was later confirmed that the donor was infected with dengue type 4 by serological tests
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