Jak Inhibitors Modulate Production of Replication-Competent Zika Virus in Human Hofbauer, Trophoblasts, and Neuroblastoma cells.
Jak Inhibitors Modulate Production of Replication-Competent Zika Virus in Human Hofbauer, Trophoblasts, and Neuroblastoma cells.
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DOI：
10.20411/pai.v2i2.190
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发表时间：
2017-01-01
影响因子：
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通讯作者：
Schinazi, Raymond F
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作者：
Gavegnano, Christina;Bassit, Leda C;Schinazi, Raymond F
寨卡病毒（ZIKV）是一种黄病毒，与胎儿脑畸形、出生缺陷和小头畸形有关，并与格林-巴利综合征有关。寨卡病毒通过胎盘传播给胎儿的机制尚不完全清楚。在此，我们定义了临床相关细胞中调节感染的关键事件，包括原代胎盘巨噬细胞（人霍夫鲍尔细胞；HC）、滋养层细胞和神经母细胞瘤细胞。与先前的发现一致，HC和滋养细胞对寨卡病毒感染是允许的。通过Jak抑制（使用ruxolitinib）减少干扰素信号，显著增加HC、滋养细胞和神经母细胞中ZIKV的复制。ruxolitinib处理的HC中ZIKV产生的增强与HLA-DR和DC-SIGN表达的增加有关。核苷类似物阻断鲁索利替尼介导的细胞外病毒的产生。虽然低水平的寨卡病毒感染发生在未处理的HC和滋养层细胞中，但复制病毒粒子不能感染幼稚的Vero细胞。这些来自未经治疗的HC的缺陷病毒粒子具有“薄外套”，表明其结构不成熟。阻断Jak信号（用ruxolitinib）可以恢复复制能力，因为在这些条件下产生的病毒粒子会对初始Vero细胞产生细胞病变作用。这些数据表明，Jak-STAT信号直接影响原代胎盘细胞产生复制能力病毒的能力，并且是临床相关细胞（包括HC和滋养细胞）成熟病毒粒子产生的关键决定因素。设计靶向药物以防止寨卡病毒在胎盘中复制，应考虑到Jak信号，其阻断对寨卡病毒感染的影响，以及随后对胎儿的传播。
Zika Virus (ZIKV) is a flavivirus that has been implicated in causing brain deformations, birth defects, and microcephaly in fetuses, and associated with Guillain-Barre syndrome. Mechanisms responsible for transmission of ZIKV across the placenta to the fetus are incompletely understood. Herein, we define key events modulating infection in clinically relevant cells, including primary placental macrophages (human Hofbauer cells; HC), trophoblasts, and neuroblastoma cells. Consistent with previous findings, HC and trophoblasts are permissive to ZIKV infection. Decrease of interferon signaling by Jak inhibition (using ruxolitinib) significantly increased ZIKV replication in HC, trophoblasts, and neuroblasts. Enhanced ZIKV production in ruxolitinib-treated HC was associated with increased expression of HLA-DR and DC-SIGN. Nucleoside analogs blocked ruxolitinib-mediated production of extracellular virus. Although low-level ZIKV infection occurred in untreated HC and trophoblasts, replicating virions were incapable of infecting naive Vero cells. These deficient virions from untreated HC have "thin-coats" suggesting an immature structure. Blocking Jak signaling (with ruxolitinib) restored replication competence as virions produced under these conditions confer cytopathic effects to naive Vero cells. These data demonstrate that Jak-STAT signaling directly impacts the ability of primary placental cells to produce replication-competent virus and is a key determinant in the production of mature virions in clinically relevant cells, including HC and trophoblasts. Design of targeted agents to prevent ZIKV replication in the placenta should consider Jak signaling, the impact of its block on ZIKV infection, and subsequent transmission to the fetus.