AXL promotes Zika virus infection in astrocytes by antagonizing type I interferon signalling
AXL promotes Zika virus infection in astrocytes by antagonizing type I interferon signalling
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AXL 通过拮抗 I 型干扰素信号传导促进星形胶质细胞中的寨卡病毒感染
DOI：
10.1038/s41564-017-0092-4
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发表时间：
2018-03-01
影响因子：
28.3
通讯作者：
Xu, Jianqing
中科院分区：
文献类型：
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作者：
Chen, Jian;Yang, Yi-feng;Xu, Jianqing
寨卡病毒（ZIKV）与新生儿小头畸形和格林-巴利综合征有关（1,2）。虽然在了解寨卡病毒感染与小头畸形之间的因果关系方面取得了进展（3-9），但人们对寨卡病毒的生命周期和发病机制知之甚少。特别是，关于AXL的作用有相互矛盾的报道，AXL是TAM家族激酶受体，最初被描述为ZIKV的进入受体（10-22）。在这里，我们发现，虽然基因切除AXL可以保护原代人星形胶质细胞和星形细胞瘤细胞系免受ZIKV感染，但敲除AXL并不能阻止ZIKV的进入。我们发现，相反，AXL的存在减弱了zikv诱导的I型干扰素（IFN）信号基因的激活，包括几种I型干扰素和IFN刺激基因。敲除I型IFN受体α链（IFNAR1）恢复了AXL敲除的星形细胞对ZIKV感染的易感性。进一步的实验表明，AXL以STAT1/ stat2依赖的方式调节SOCS1（一种已知的I型IFN信号抑制因子）的表达。总之，我们的研究结果表明，AXL不太可能作为ZIKV的进入受体，而可能通过拮抗I型IFN信号传导促进人类星形胶质细胞中的ZIKV感染。
Zika virus (ZIKV) is associated with neonatal microcephaly and Guillain-Barre syndrome(1,2). While progress has been made in understanding the causal link between ZIKV infection and microcephaly(3-9), the life cycle and pathogenesis of ZIKV are less well understood. In particular, there are conflicting reports on the role of AXL, a TAM family kinase receptor that was initially described as the entry receptor for ZIKV(10-22). Here, we show that while genetic ablation of AXL protected primary human astrocytes and astrocytoma cell lines from ZIKV infection, AXL knockout did not block the entry of ZIKV. We found, instead, that the presence of AXL attenuated the ZIKV-induced activation of type I interferon (IFN) signalling genes, including several type I IFNs and IFN-stimulating genes. Knocking out type I IFN receptor alpha chain (IFNAR1) restored the vulnerability of AXL knockout astrocytes to ZIKV infection. Further experiments suggested that AXL regulates the expression of SOCS1, a known type I IFN signalling suppressor, in a STAT1/STAT2-dependent manner. Collectively, our results demonstrate that AXL is unlikely to function as an entry receptor for ZIKV and may instead promote ZIKV infection in human astrocytes by antagonizing type I IFN signalling.