Abstract
One of the most important clinical signs of dengue virus infection is the reduction of white blood cells and platelets in human peripheral blood (leukopenia and thrombocytopenia, respectively), which may significantly impair the clearance of dengue virus by the immune system. The cause of thrombocytopenia and leukopenia during dengue infection is still unknown, but may be related to severe suppression of bone marrow populations including hematopoietic stem cells and megakaryocytes, the progenitors of white blood cells and platelets respectively. Here, we explored the possibility that bone marrow suppression, including ablation of megakaryocyte populations, is caused by dengue virus infection of megakaryocytes. We used three different models to measure dengue virus infection and replication: in vitro, in a human megakaryocyte cell line with viral receptors, ex vivo, in primary human megakaryocytes, and in vivo, in humanized mice. All three systems support dengue virus infection and replication, including virus strains from serotypes 1, 2, and 3, and clinical signs, in vivo; all assays showed viral RNA and/or infectious viruses 7–14 days post-infection. Although we saw no significant decrease in cell viability in vitro, there was significant depletion of mature megakaryocytes in vivo. We conclude that megakaryocytes can produce dengue viruses in the bone marrow niche, and a reduction of cell numbers may affect bone marrow homeostasis.
Highlights
Dengue virus (DENV; Flavivirus) is the most common cause of hemorrhagic fever in humans, worldwide
Over half of the world’s population lives in an at risk area for dengue virus infection, and this number will continue to grow as climate change allows the mosquito vectors of dengue virus to expand their breeding ranges to more temperate climates
There are no specific treatments for dengue virus infection
Summary
Dengue virus (DENV; Flavivirus) is the most common cause of hemorrhagic fever in humans, worldwide. Approximately 390 million DENV infections occur [1], with an estimated 50 million becoming symptomatic, 500,000 progressing to hemorrhagic fever, and 50,000 resulting in death [2, 3]. The World Health Organization (WHO) estimates that over half of the world’s population (4.5 billion people) live in an area at-risk for DENV infection, including residents of the southern United States and US territories [5]. This number is expected to increase as climate change allows for the expansion of the host range of DENV’s primary vector, the Aedes aegypti mosquito [2]. Understanding the mechanisms leading to DENV disease will allow for the production of more effective DENV vaccines and treatments
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