IFN-κ suppresses the replication of influenza A viruses through the IFNAR-MAPK-Fos-CHD6 axis
IFN-κ suppresses the replication of influenza A viruses through the IFNAR-MAPK-Fos-CHD6 axis
复制标题
IFN-γ通过IFNAR-MAPK-Fos-CHD6轴抑制甲型流感病毒的复制。
DOI：
10.1126/scisignal.aaz3381
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发表时间：
2020-04-07
影响因子：
7.3
通讯作者：
Xu, Jianqing
中科院分区：
文献类型：
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作者：
He, Yongquan;Fu, Weihui;Xu, Jianqing
I型干扰素（IFN）是抵抗病毒感染的第一道防线。使用甲型流感病毒感染的小鼠模型，我们发现IFN-κ是感染H9 N2（一种低致病性甲型禽流感病毒）后最早响应的I型IFN之一，而这种早期诱导在感染引起禽流感的H7N9病毒后不会发生。IFN-κ在培养的人肺细胞中有效地抑制各种流感病毒的复制，并且染色体结构域解旋酶DNA结合蛋白6（chromodomain helicase DNA binding protein 6，CHD 6）是IFN-κ的抗病毒活性的主要效应物，但不是IFN-α或IFN-β的抗病毒活性的主要效应物。CHD 6的诱导需要I型IFN受体亚基IFNAR 1和IFNAR 2、促分裂原活化蛋白激酶（MAPK）p38和转录因子c-Fos，但不依赖于信号转导和转录激活因子1（STAT 1）活性。此外，我们发现，用IFN-κ预处理保护小鼠免受致命的流感病毒攻击。总之，我们的研究结果确定了一个IFN-kappa特异性途径，限制甲型流感病毒，并提供证据表明，IFN-kappa可能有潜力作为预防和治疗剂对甲型流感病毒。
Type I interferons (IFNs) are the first line of defense against viral infection. Using a mouse model of influenza A virus infection, we found that IFN-kappa was one of the earliest responding type I IFNs after infection with H9N2, a low-pathogenic avian influenza A virus, whereas this early induction did not occur upon infection with the epidemic-causing H7N9 virus. IFN-kappa efficiently suppressed the replication of various influenza viruses in cultured human lung cells, and chromodomain helicase DNA binding protein 6 (CHD6) was the major effector for the antiviral activity of IFN-kappa, but not for that of IFN-alpha or IFN-beta. The induction of CHD6 required both of the type I IFN receptor subunits IFNAR1 and IFNAR2, the mitogen-activated protein kinase (MAPK) p38, and the transcription factor c-Fos but was independent of signal transducer and activator of transcription 1 (STAT1) activity. In addition, we showed that pretreatment with IFN-kappa protected mice from lethal influenza viral challenge. Together, our findings identify an IFN-kappa-specific pathway that constrains influenza A virus and provide evidence that IFN-kappa may have potential as a preventative and therapeutic agent against influenza A virus.