Dengue viruses infect human megakaryocytes, with probable clinical consequences
Dengue viruses infect human megakaryocytes, with probable clinical consequences
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DOI：
10.1371/journal.pntd.0007837
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发表时间：
2019-11-01
影响因子：
3.8
通讯作者：
Rico-Hesse, Rebecca
中科院分区：
文献类型：
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作者：
Vogt, Megan B.;Lahon, Anismrita;Rico-Hesse, Rebecca
登革热病毒感染最重要的临床症状之一是人外周血中的白细胞和血小板减少(分别为白细胞减少和血小板减少)，这可能会显著损害免疫系统对登革病毒的清除。登革热感染期间血小板减少和白细胞减少的原因尚不清楚，但可能与骨髓细胞群严重抑制有关，包括造血干细胞和巨核细胞，它们分别是白细胞和血小板的祖细胞。在这里，我们探索了骨髓抑制，包括去除巨核细胞群，是由登革热病毒感染巨核细胞引起的可能性。我们使用了三种不同的模型来测量登革病毒的感染和复制：在体外，在带有病毒受体的人巨核细胞系中，在体外，在原代人类巨核细胞中，以及在体内，在人源化的小鼠中。所有三个系统都支持登革热病毒的体内感染和复制，包括来自血清1、2和3型的病毒株和临床症状；所有检测结果都显示感染后7-14天有病毒RNA和/或传染性病毒。虽然我们在体外没有看到细胞存活率显著下降，但体内成熟的巨核细胞有显著的耗尽。我们的结论是，巨核细胞可以在骨髓内产生登革病毒，细胞数量的减少可能会影响骨髓的自我稳定。作者摘要登革病毒是人类病毒性出血热的最常见原因。世界上一半以上的人口生活在登革热病毒感染的高危地区，随着气候变化允许登革热病毒的蚊子媒介将繁殖范围扩大到更温和的气候，这一数字将继续增长。目前，还没有针对登革热病毒感染的特效药。了解登革热病毒是如何导致出血热的，可以为这些亟需的治疗方法的发展提供信息。在登革热病毒感染过程中，重要的免疫系统介质，如白细胞和血小板的数量明显失调。这些细胞起源于骨髓，在DENV感染期间，骨髓经历了显著的抑制，包括完全消融巨核细胞(血小板前体细胞)。在这里，我们通过研究登革病毒是否感染人类巨核细胞来增加关于登革病毒如何诱导骨髓抑制的知识。我们在体外、体外和体内模型中都发现登革病毒感染人巨核细胞；然而，登革病毒感染似乎并不直接影响人巨核细胞的活性。未来的研究将调查受感染的巨核细胞是否仍然能够发挥其产生血小板和维持骨髓内环境稳定的功能。
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.