Gamma Interferon-Induced Interferon Regulatory Factor 1-Dependent Antiviral Response Inhibits Vaccinia Virus Replication in Mouse but Not Human Fibroblasts
Gamma Interferon-Induced Interferon Regulatory Factor 1-Dependent Antiviral Response Inhibits Vaccinia Virus Replication in Mouse but Not Human Fibroblasts
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DOI：
10.1128/jvi.02042-08
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发表时间：
2009-02
影响因子：
5.4
通讯作者：
M. Trilling;Vu Thuy Khanh Le;A. Zimmermann;H. Ludwig;K. Pfeffer;G. Sutter;Geoffrey L. Smith;H. Hengel
中科院分区：
文献类型：
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作者：
M. Trilling;Vu Thuy Khanh Le;A. Zimmermann;H. Ludwig;K. Pfeffer;G. Sutter;Geoffrey L. Smith;H. Hengel
摘要 痘苗病毒 (VACV) 在小鼠和人类成纤维细胞中以相似的动力学和效率复制，产生相似滴度的感染性后代。在这里，我们证明在 VACV 感染之前对小鼠成纤维细胞进行γ干扰素（IFN-γ）而不是 IFN-α 或 IFN-β 预处理可诱导持久的抗病毒状态，从而阻止 VACV 复制。相比之下，高剂量的 IFN-γ 未能在人成纤维细胞中建立抗病毒状态。在小鼠成纤维细胞中，IFN-γ 在晚期基因转录水平上阻碍了病毒复制周期，并阻止了 VACV 基因组的增殖。 IFN-γ诱导的抗病毒状态总是能阻止不同VACV毒株的生长，但不能有效阻止节肢动物病毒的复制。 IFN-γ 效应需要在 VACV 感染之前通过 Janus 激酶 2 (Jak2) 和信号转导器和转录激活剂 1 (STAT1) 提供完整的 IFN-γ 受体信号传导。 IFN-γ处理的人类细胞的许可状态与VACV编码的IFN诱饵受体B8和B18无关，并且与STAT1同二聚体形成和DNA结合的完全破坏相关。与人类成纤维细胞不同，小鼠细胞以持久的 STAT1 激活做出反应，这种激活在 VACV 感染后得以保留。从小鼠细胞中删除干扰素调节因子 1 (IRF-1) 基因可以挽救 VACV 的有效复制，这表明 IRF-1 靶基因在 VACV 控制中具有关键作用。这些数据对于理解 VACV 发病机制以及识别人类宿主和小鼠模型之间不一致的 IFN-γ 反应具有重要意义。
ABSTRACT Vaccinia virus (VACV) replicates in mouse and human fibroblasts with comparable kinetics and efficiency, yielding similar titers of infectious progeny. Here we demonstrate that gamma interferon (IFN-γ) but not IFN-α or IFN-β pretreatment of mouse fibroblasts prior to VACV infection induces a long-lasting antiviral state blocking VACV replication. In contrast, high doses of IFN-γ failed to establish an antiviral state in human fibroblasts. In mouse fibroblasts, IFN-γ impeded the viral replication cycle at the level of late gene transcription and blocked the multiplication of VACV genomes. The IFN-γ-induced antiviral state invariably prevented the growth of different VACV strains but was not effective against the replication of ectromelia virus. The IFN-γ effect required intact IFN-γ receptor signaling prior to VACV infection through Janus kinase 2 (Jak2) and signal transducer and activator of transcription 1 (STAT1). The permissive state of IFN-γ-treated human cells was unrelated to the VACV-encoded IFN decoy receptors B8 and B18 and associated with a complete disruption of STAT1 homodimer formation and DNA binding. Unlike human fibroblasts, mouse cells responded with long-lasting STAT1 activation which was preserved after VACV infection. The deletion of the IFN regulatory factor 1 (IRF-1) gene from mouse cells rescued efficient VACV replication, demonstrating that IRF-1 target genes have a critical role in VACV control. These data have implications for the understanding of VACV pathogenesis and identify an incongruent IFN-γ response between the human host and the mouse model.