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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. [ABSTRACT FROM AUTHOR]

Dengue Virus (DV) infects between 50 and 100 million people globally, with public health costs totaling in the billions. It is the causative agent of dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), vector-borne diseases that initially predominated in the tropics. Due to the expansion of its mosquito vector, Aedes spp., DV is increasingly becoming a global problem. Infected individuals may present with a wide spectrum of symptoms, spanning from a mild febrile to a life-threatening illness, which may include thrombocytopenia, leucopenia, hepatomegaly, hemorrhaging, plasma leakage and shock. Deciphering the underlining mechanisms responsible for these symptoms has been hindered by the limited availability of animal models that can induce classic human pathology. Currently, several permissive non-human primate (NHP) species and mouse breeds susceptible to adapted DV strains are available. Though virus replication occurs in these animals, none of them recapitulate the cardinal features of human symptomatology, with disease only occasionally observed in NHPs. Recently our group established a DV serotype 2 intravenous infection model with the Indian rhesus macaque, which reliably produced cutaneous hemorrhages after primary virus exposure. Further manipulation of experimental parameters (virus strain, immune cell expansion, depletion, etc.) can refine this model and expand its relevance to human DF. Future goals include applying this model to elucidate the role of pre-existing immunity upon secondary infection and immunopathogenesis. Of note, virus titers in primates in vivo and in vitro, even with our model, have been consistently 1000-fold lower than those found in humans. We submit that an improved model, capable of demonstrating severe pathogenesis may only be achieved with higher virus loads. Nonetheless, our DV coagulopathy disease model is valuable for the study of select pathomechanisms and testing DV drug and vaccine candidates.

Scientific investigations designed to better understand and assess the distinguishing clinical characteristics pave the way to a successful treatment for a disease. Since the peripheral blood is obtained easily, the most frequent type of investigation performed on infectious agents focuses on the hematological components of blood drawn from patients. Bone marrow aspirates, although somewhat more difficult to obtain, should be evaluated more frequently because they provide additional information, giving us a glimpse into the development of the disease. Understanding the distinct and unique changes in hematological components of the bone marrow induced by a particular pathogen or corresponding to a specific illness may be a valuable asset for the diagnosis and prognosis of disease. A good example of a pathogen that could be better evaluated with greater knowledge of the bone marrow is dengue, one of the most important public vector-borne human diseases. Owing to the multitude of clinical manifestations and the dynamic alterations of various blood components over time, this disease is one of the most difficult to prevent and treat in humans. Although large amounts of data have been generated in the literature, there remains a large gap between this information and its relevance for the purpose of patient care. While evaluating the cellular components in the circulated blood from ill patients provides us with valuable information about the pathogenesis of various pathogens, there are other players participating in the progression to disease. The goal of this review is to emphasize the importance of bone marrow hematopoietic progenitor cells in disease and to inspire other researchers to incorporate them into their investigations on dengue pathogenesis. It is anticipated that the knowledge derived from these investigations not only elicit original concepts on the pathogenesis of dengue but also foster a new way of thinking in terms of vaccine or therapeutic development to prevent and treat dengue.