Infection of bone marrow cells by dengue virus in vivo

Abstract

Abnormal bone marrow (BM) suppression is one of the hallmarks of dengue virus (DENV) infection in patients. Although the etiology remains unclear, direct viral targeting of the BM has been reasoned to be a contributing factor. The present studies were carried out in an effort to determine the potential effect of DENV infection on the cellularity of BM using a previously established nonhuman primate model of DENV-induced coagulopathy. BM aspirates were collected at various times from the infected nonhuman primate and cells were phenotypically defined and isolated using standard flow cytometry (fluorescence-activated cell sorting). These isolated cells were subjected to detection of DENV utilizing quantitative real-time reverse transcription polymerase chain reaction, electron microscopy, and immunostaining techniques. DENV RNA was detectable by quantitative real-time reverse transcription polymerase chain reaction in BM specimens and the presence of DENV-like particles within platelet was confirmed by electron microscopy. Enumeration of BM cells revealed a transient surge in cellularity at day 1, followed by a gradual decline from days 2 to 10 post infection. Detailed phenotypic studies showed similar kinetics in the frequencies of CD41+CD61+ cells, regardless of CD34 and CD45 expression. The CD61+ cells were not only the predominant cells that stained for DENV antigen but fluorescence-activated cell sorting–assisted isolation of CD61+ cells from the BM were shown to contain infectious DENV by coculture with Vero cells. These data support the view that intravenous infection of nonhuman primate with DENV leads to direct infection of the BM, which is likely to be a contributing factor for transient cell suppression in the peripheral blood characteristic of acute DENVinfection.

Inhibition of Megakaryocyte Development in the Bone Marrow Underlies Dengue Virus-Induced Thrombocytopenia in Humanized Mice

“…There is also evidence that DENV infection in an in vitro artificial BM reduced its ability to support hematopoiesis (12). Recently, evidence of direct infection in the BM was reported in a nonhuman primate model of DENV infection (13). Despite these significant efforts, the underlying mechanism of thrombocytopenia during dengue remains to be elucidated.…”

Transient Monocytosis Subjugates Low Platelet Count in Adult Dengue Patients

“…In general, immune cells with phagocytic capacity have been suggested to be infectable by DENV, especially cells with mannose-related receptors [15], DC-specific ICAM3-grabbing nonintegrin molecules [16], and CLEC5A [14] on the surface. However, recent evidence suggests that other immune cells, such as platelets and its precursor cells, megakaryocytes, are a favored target of DENV as well [17,18,19,20,21,22]. The latter may partially explain the dysfunction of platelets resulting in prolonged activated partial thromboplastin time (aPTT) during the early phase of dengue disease, and subsequent low platelet counts when the disease progresses to a critical stage [1].…”

The Role of Platelets in Viral Hemorrhagic Fevers

“…In conclusion, a detailed description of the hemorrhagic fever Hantavirus [166] SFTS [69] Hantavirus [139] Hantavirus [166] DENV [112,167,168] DENV [169] LASV [71] JUNV [74,170] JUNV [72] Ebola [62] a Destruction of platelets by direct interaction: SomeHFV can bind platelets directly causing activation and granules release.…”