HTNV Sensitizes Host Toward TRAIL-Mediated Apoptosis-A Pivotal Anti-hantaviral Role of TRAIL
HTNV Sensitizes Host Toward TRAIL-Mediated Apoptosis-A Pivotal Anti-hantaviral Role of TRAIL
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DOI：
10.3389/fimmu.2020.01072
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发表时间：
2020-06-19
影响因子：
7.3
通讯作者：
Hou, Wei
中科院分区：
文献类型：
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作者：
Chen, Qing-Zhou;Wang, Xin;Hou, Wei
汉坦病毒可在欧亚大陆引起肾综合征出血热（HFRS），并已对中国的公共卫生造成威胁。 HFRS的发病机制复杂，涉及血管内皮细胞感染导致的毛细血管渗漏。越来越多的证据表明汉坦病毒可以诱导许多细胞凋亡，但其机制仍不清楚。我们的研究表明，汉坦病毒（HTNV）感染可以诱导原代人脐静脉内皮细胞（HUVEC）中TNF相关凋亡诱导配体（TRAIL）的表达，并使宿主细胞对TRAIL介导的细胞凋亡敏感。此外，TRAIL干扰可以抑制细胞凋亡、增强HTNV的产生以及减少IFN-β的产生，而外源TRAIL处理显示出相反的结果：增加细胞凋亡和IFN-β的产生以及降低病毒复制水平。我们还观察到HTNV的核衣壳蛋白（NP）和糖蛋白（GP）可以促进TRAIL及其受体的转录。由此可见，TRAIL在HTNV感染后上调，进而在体外表现出显着的抗病毒活性，并在HTNV感染的乳鼠模型中进一步证实TRAIL治疗显着降低病毒载量，减轻病毒引起的组织病变，增加凋亡细胞，降低死亡率。总之，这些结果表明 TRAIL 依赖性细胞凋亡和 IFN-0 产生可以抑制 HTNV 复制，TRAIL 治疗可能是 HTNV 感染的新治疗靶点。
Hantaviruses can cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and have led to public health threat in China. The pathogenesis of HFRS is complex and involves capillary leakage due to the infection of vascular endothelial cells. Accumulating evidence has demonstrated that hantavirus can induce apoptosis in many cells, but the mechanism remains unclear. Our studies showed that Hantaan virus (HTNV) infection could induce TNF-related apoptosis-inducing ligand (TRAIL) expression in primary human umbilical vein endothelial cells (HUVECs) and sensitize host cells toward TRAIL-mediated apoptosis. Furthermore, TRAIL interference could inhibit apoptosis and enhance the production of HTNV as well as reduce IFN-beta production, while exogenous TRAIL treatment showed reverse outcome: enhanced apoptosis and IFN-beta production as well as a lower level of viral replication. We also observed that nucleocapsid protein (NP) and glycoprotein (GP) of HTNV could promote the transcriptions of TRAIL and its receptors. Thus, TRAIL was upregulated by HTNV infection and then exhibited significant antiviral activities in vitro, and it was further confirmed in the HTNV-infected suckling mice model that TRAIL treatment significantly reduced viral load, alleviated virus-induced tissue lesions, increased apoptotic cells, and decreased the mortality. In conclusion, these results demonstrate that TRAIL-dependent apoptosis and IFN-0 production could suppress HTNV replication and TRAIL treatment might be a novel therapeutic target for HTNV infection.