Dengue viruses infect human megakaryocytes, with probable clinical consequences.

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. Author summary Dengue virus is the most common cause of viral hemorrhagic fever in humans. 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. Currently, there are no specific treatments for dengue virus infection. Understanding how dengue virus causes hemorrhagic fever could inform the development of these much needed treatments. Populations of important immune system mediators, such as white blood cells and platelets, are significantly dysregulated during dengue virus infection. These cells originate in the bone marrow, which experiences significant suppression, including a complete ablation of megakaryocytes (platelet progenitor cells), during DENV infection. Here, we add to the knowledge on how dengue virus induces bone marrow suppression by investigating whether dengue virus infects human megakaryocytes. We discovered that dengue virus infects human megakaryocytes in vitro, ex vivo, and in vivo models of dengue virus infection; however, dengue virus infection does not appear to directly affect viability of human megakaryocytes. Future studies will investigate whether infected megakaryocytes are still able to perform their functions of producing platelets and maintaining bone marrow homeostasis.