Inhibition of interferon-stimulated JAK-STAT signaling by a tick-borne flavivirus and identification of NS5 as an interferon antagonist
Inhibition of interferon-stimulated JAK-STAT signaling by a tick-borne flavivirus and identification of NS5 as an interferon antagonist
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DOI：
10.1128/jvi.79.20.12828-12839.2005
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发表时间：
2005-10-01
影响因子：
5.4
通讯作者：
Bloom, ME
中科院分区：
文献类型：
--
作者：
Best, SM;Morris, KL;Bloom, ME
蜱传脑炎（TBE）病毒复合体，黄病毒属，可引起严重的脑炎，脑膜炎和/或出血热。有效的干扰素（IFN）应答对于从黄病毒感染中恢复至关重要，而蚊媒黄病毒可以抑制这种应答。然而，很少有人知道IFN信号和TBE病毒之间的相互作用。Langat病毒（LGTV）是TBE病毒复合体的成员，对IFN的抗病毒作用高度敏感。然而，LGTV感染抑制IFN-α/β或IFN-γ应答启动子驱动的IFN诱导的报告基因表达。这表明LGTV可以抑制IFN介导的JAK-STAT（Janus kinase-signal transducer and activator of transcription）信号转导途径。抑制机制是由于在IFN-α信号传导期间Janus激酶Jak 1和Tyk 2磷酸化的阻断以及IFN-γ刺激后至少Jak 1磷酸化的失败。为了确定负责的病毒蛋白，我们单独表达了所有非结构（NS）蛋白，并检查了它们抑制信号转导的能力。单独表达NS 5抑制STAT 1磷酸化应答IFN，从而鉴定NS 5为潜在的IFN拮抗剂。NS 5和细胞蛋白之间的相互作用的检查显示，NS 5与IFN-α/β和IFN-γ受体复合物相关。重要的是，JAK-STAT信号传导和NS 5-IFN受体相互作用的抑制在LGTV感染的人单核细胞衍生的树突状细胞中得到证实，这是早期病毒复制的重要靶细胞。由于NS 5可能干扰对病毒感染的先天性和获得性免疫应答，因此该蛋白可能在病毒发病机制中具有重要作用。
The tick-borne encephalitis (TBE) complex of viruses, genus Flavivirus, can cause severe encephalitis, meningitis, and/or hemorrhagic fevers. Effective interferon (IFN) responses are critical to recovery from infection with flaviviruses, and the mosquito-borne flaviviruses can inhibit this response. However, little is known about interactions between IFN signaling and TBE viruses. Langat virus (LGTV), a member of the TBE complex of viruses, was found to be highly sensitive to the antiviral effects of IFN. However, LGTV infection inhibited IFN-induced expression of a reporter gene driven by either IFN-alpha/beta- or IFN-gamma-responsive promoters. This indicated that LGTV can inhibit the IFN-mediated JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathway of signal transduction. The mechanism of inhibition was due to blocks in the phosphorylation of both Janus kinases, Jak1 and Tyk2, during IFN-alpha signaling and at least a failure of Jak1 phosphorylation following IFN-gamma stimulation. To determine the viral protein(s) responsible, we individually expressed all nonstructural (NS) proteins and examined their ability to inhibit signal transduction. Expression of NS5 alone inhibited STAT1 phosphorylation in response to IFN, thus identifying NS5 as a potential IFN antagonist. Examination of interactions between NS5 and cellular proteins revealed that NS5 associated with IFN-alpha/beta and -gamma receptor complexes. Importantly, inhibition of JAK-STAT signaling and NS5-IFN receptor interactions were demonstrated in LGTV-infected human monocyte-derived dendritic cells, important target cells for early virus replication. Because NS5 may interfere with both innate and acquired immune responses to virus infection, this protein may have a significant role in viral pathogenesis.