Suppression of the IFN-α and -β Induction through Sequestering IRF7 into Viral Inclusion Bodies by Nonstructural Protein NSs in Severe Fever with Thrombocytopenia Syndrome Bunyavirus Infection
Suppression of the IFN-α and -β Induction through Sequestering IRF7 into Viral Inclusion Bodies by Nonstructural Protein NSs in Severe Fever with Thrombocytopenia Syndrome Bunyavirus Infection
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DOI：
10.4049/jimmunol.1800576
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发表时间：
2019-02-01
影响因子：
4.4
通讯作者：
Xing, Zheng
中科院分区：
文献类型：
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作者：
Hong, Ye;Bai, Maosheng;Xing, Zheng
在病毒感染期间诱导I型IFN对于宿主防御至关重要。IRF 3和IRF 7作为关键转录因子在IFN诱导的激活中起关键作用。病毒已经进化出多种策略来逃避先天免疫。我们的前期研究表明，重症发热伴血小板减少综合征病毒（SFTSV）的非结构蛋白（NS）通过与Tank结合激酶1相互作用，将核因子κ B激酶抑制剂（IKK）复合物螯合到NS形成的包涵体中，从而抑制IFN-β的诱导。在这项研究中，我们表征了IRF 7在先天免疫中的独特功能及其在诱导IFN-α中的作用，特别是在SFTSV感染几种人类来源的细胞类型期间由NS调节。尽管IRF 3是组成型表达的，但IRF 7在响应SFTSV感染的各种细胞类型中被显著差异地诱导，促进IFN-α 2和IFN-α 4的诱导，并进一步诱导IFN-β，从而有助于抑制病毒复制。我们的数据表明，NS直接与IRF 7相互作用并将其隔离到包涵体中，这不同于IRF 3间接与NS相互作用。尽管NS与IRF 7的相互作用不抑制IRF 7磷酸化，但p-IRF 7被捕获在包涵体中，导致IFN-α 2和IFN-α 4诱导的显著降低，因此增强了病毒复制。病毒NS与IRF 7和IRF 3的相互作用以及随后将这些转录因子隔离到病毒包涵体中，这是该白蛉病毒使用的独特策略，可以确保有效逃避和抑制宿主先天免疫。
Induction of type I IFNs during viral infection is crucial for host defense. IRF 3 and IRF7 play a critical role as key transcription factors in the activation of the IFN induction. Viruses have evolved a variety of strategies to evade innate immunity. Our previous studies have shown that the nonstructural protein (NSs) of the severe fever with thrombocytopenia syndrome virus (SFTSV) can suppress the IFN-beta induction through its interaction with tank-binding kinase-1 and sequestering the inhibitor of nuclear factor kappa B kinase (IKK) complex into the inclusion bodies formed by NSs. In this study, we characterized the unique function of IRF7 in innate immunity and its role in inducing IFN-alpha in particular, regulated by NSs during the SFTSV infection in several cell types of human origin. Whereas IRF3 is constitutively expressed, IRF7 was significantly induced differentially in various cell types in response to SFTSV infection, promoted the induction of IFN-alpha 2 and -alpha 4, and further induced IFN-beta, thus contributing to suppressing the viral replication. Our data indicate that NSs directly interacted with and sequestered IRF7 into the inclusion bodies, which is different from IRF3 indirectly interacting with NSs. Although interaction of NSs with IRF7 did not inhibit IRF7 phosphorylation, p-IRF7 was trapped in the inclusion bodies, resulting in a significant reduction of the IFN-alpha 2 and -alpha 4 induction and therefore enhanced viral replication. Interaction of the viral NSs with both IRF7 and IRF3 and subsequent sequestration of these transcription factors into viral inclusion bodies, a unique strategy used by this phlebovirus, may ensure effective evasion and suppression of host innate immunity.