AXL-Mediated Productive Infection of Human Endothelial Cells by Zika Virus.
AXL-Mediated Productive Infection of Human Endothelial Cells by Zika Virus.
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DOI：
10.1161/circresaha.116.309866
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发表时间：
2016-11-11
影响因子：
20.1
通讯作者：
Wang TT
中科院分区：
文献类型：
--
作者：
Liu S;DeLalio LJ;Isakson BE;Wang TT
蚊媒寨卡病毒 (ZIKV) 现在被认为是一种血源性病原体，这引发了一个重要问题：该病毒如何进入人类血液。 ZIKV 流行对全球血液供应的迫在眉睫的威胁也需要新的疗法来阻止病毒通过输血传播。我们打算表征 ZIKV 对人内皮细胞 (EC) 的趋向性，并提供潜在的干预目标。我们对 ZIKV RNA 进行了免疫染色、噬菌斑测定和定量 RT-PCR，以评估 ZIKV 可能感染 ECs。非洲和南美 ZIKV 毒株都很容易感染人脐静脉内皮细胞 (HUVEC) 以及源自主动脉、冠状动脉以及隐静脉的人 EC。受感染的 EC 释放出具有感染性的子代病毒。与非洲毒株相比，南美 ZIKV 分离株在 EC 中复制速度更快，并且具有部分细胞病变，表明这些分离株的毒力增强。流式细胞术分析显示ECs的敏感性与细胞表面AXL受体酪氨酸激酶水平呈正相关。功能获得和功能丧失研究进一步表明，AXL 是 ZIKV 在结合后步骤进入所必需的。最后，AXL 激酶的小分子抑制剂显着减少了 EC 的 ZIKA 感染。我们确定 EC 是 ZIKV 感染的关键细胞类型。这些数据支持了 ZIKV 血行传播的观点，并表明 AXL 是抗病毒治疗的新靶点。
The mosquito-borne Zika virus (ZIKV) is now recognized as a blood-borne pathogen, raising an important question about how the virus gets into human bloodstream. The imminent threat of the ZIKV epidemic to the global blood supply also demands novel therapeutics to stop virus transmission though transfusion. We intend to characterize ZIKV tropism for human endothelial cells (ECs) and provide potential targets for intervention. We conducted immunostaining, plaque assay, and quantitative RT-PCR of ZIKV RNA to evaluate the possible infection of ECs by ZIKV. Both the African and the South American ZIKV strains readily infect human umbilical vein endothelial cells (HUVECs) and human ECs derived from aortic and coronary artery as well as the saphenous vein. Infected ECs released infectious progeny virus. Compared to the African strains, South American ZIKV isolates replicate faster in ECs and are partially cytopathic, suggesting enhanced virulence of these isolates. Flow cytometric analyses showed that the susceptibility of ECs positively correlated with the cell-surface levels of AXL receptor tyrosine kinase. Gain- and loss-of-function studies further revealed that AXL is required for ZIKV entry at a post-binding step. Lastly, small molecule inhibitors of the AXL kinase significantly reduced ZIKA infection of ECs. We identified EC as a key cell type for ZIKV infection. These data support the view of hematogenous dissemination of ZIKV and implicate AXL as a new target for antiviral therapy.