Comparative pathogenesis of Ebola virus and Reston virus infection in humanized mice
Comparative pathogenesis of Ebola virus and Reston virus infection in humanized mice
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DOI：
10.1172/jci.insight.126070
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发表时间：
2019-11-01
期刊：
影响因子：
8
通讯作者：
Munoz-Fontela，Cesar
中科院分区：
文献类型：
--
作者：
Escudero-Perez，Beatriz;Ruibal，Paula;Munoz-Fontela，Cesar
埃博拉病毒属的丝状病毒包括 6 个物种，它们引起人类疾病的能力存在显着差异。从高毒力的埃博拉病毒到看似无致病性的雷斯顿病毒，病死率可能在 0% 到 90% 之间。为了了解这些差异的分子基础，必须建立尽可能忠实地再现人类疾病的疾病模型。非人灵长类动物 (NHP) 是丝状病毒发病机制的黄金标准模型，但由于雷斯顿病毒感染对 NHP 可能致命这一事实，比较研究存在偏差。在这里，我们使用具有人类造血功能的 HLA-A2 转基因、NOD-scid-IL-2γ 受体敲除 (NSG-A2) 小鼠来在类人环境中比较埃博拉病毒和雷斯顿病毒的发病机制。虽然雷斯顿病毒的致病性明显低于埃博拉病毒，但它杀死了 20% 的受感染小鼠，这一发现与肝脏炎症加剧和病毒复制有关。此外，在人源化小鼠中重现了不同埃博拉病毒种类在人类中的病死率。我们的研究结果表明，人源化小鼠可以作为测试新发现的丝状病毒致病性的假定模型，并表明有必要对雷斯顿病毒在人类中的发病机制进行进一步研究。
Filoviruses of the genus Ebolavirus include 6 species with marked differences in their ability to cause disease in humans. From the highly virulent Ebola virus to the seemingly nonpathogenic Reston virus, case fatality rates can range between 0% and 90%. In order to understand the molecular basis of these differences, it is imperative to establish disease models that recapitulate human disease as faithfully as possible. Nonhuman primates (NHPs) are the gold-standard models for filovirus pathogenesis, but comparative studies are skewed by the fact that Reston virus infection can be lethal for NHPs. Here we used HLA-A2–transgenic, NOD–scid–IL-2γ receptor–knockout (NSG-A2) mice reconstituted with human hematopoiesis to compare Ebola virus and Reston virus pathogenesis in a human-like environment. While markedly less pathogenic than Ebola virus, Reston virus killed 20% of infected mice, a finding that was linked to exacerbated inflammation and viral replication in the liver. In addition, the case fatality ratios of different Ebolavirus species in humans were recapitulated in the humanized mice. Our findings point to humanized mice as a putative model to test the pathogenicity of newly discovered filoviruses, and suggest that further investigations on Reston virus pathogenesis in humans are warranted.