The influenza virus PB1-F2 protein has interferon antagonistic activity
The influenza virus PB1-F2 protein has interferon antagonistic activity
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DOI：
10.1515/bc.2011.174
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发表时间：
2011-12-01
影响因子：
3.7
通讯作者：
Ludwig, Stephan
中科院分区：
文献类型：
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作者：
Dudek, Sabine E.;Wixler, Ludmilla;Ludwig, Stephan
PB1-F2是流感病毒的一种非结构蛋白，由+1开放阅读框中的PB1基因片段编码。已有研究表明，PB1-F2参与了病毒的致病作用，但其潜在的致病机制尚不清楚。诱导I型干扰素和先天免疫反应是抵御病毒感染的第一道防线。在这里，我们展示了缺乏PB1-F2蛋白的甲型流感病毒(IAV)在感染的上皮细胞中诱导干扰素-β和干扰素刺激的基因表达增强。对PB1-F2介导的干扰素拮抗活性的分子机制研究表明，PB1-F2干扰RIG-I/MAVS蛋白复合体，从而抑制下游转录因子干扰素调节因子3的激活。体内研究也反映了这些发现，表明感染PR8野生型(Wt)病毒比感染PB1-F2缺陷的病毒导致更高的肺滴度和更严重的疾病发病。因此，在感染PB1-F2wt病毒的小鼠中，检测到更明显的免疫细胞在肺部的渗透。综上所述，我们证明了IAV的PB1-F2蛋白通过干扰RIG-I/MAVS复合体而显示出I型干扰素拮抗功能，这有助于增强体内的致病性。
PB1-F2 is a nonstructural protein of influenza viruses encoded by the PB1 gene segment from a +1 open reading frame. It has been shown that PB1-F2 contributes to viral pathogenicity, although the underlying mechanisms are still unclear. Induction of type I interferon (IFN) and the innate immune response are the first line of defense against viral infection. Here we show that influenza A viruses (IAVs) lacking the PB1-F2 protein induce an enhanced expression of IFN-beta and IFN-stimulated genes in infected epithelial cells. Studying molecular mechanisms underlying the PB1-F2-mediated IFN antagonistic activity showed that PB1-F2 interferes with the RIG-I/MAVS protein complex thereby inhibiting the activation of the downstream transcription factor IFN regulatory factor 3. These findings were also reflected in in vivo studies demonstrating that infection with PR8 wild-type (wt) virus resulted in higher lung titers and a more severe onset of disease compared with infection with its PB1-F2-deficient counterpart. Accordingly, a much more pronounced infiltration of lungs with immune cells was detected in mice infected with the PB1-F2 wt virus. In summary, we demonstrate that the PB1-F2 protein of IAVs exhibits a type I IFN-antagonistic function by interfering with the RIG-I/MAVS complex, which contributes to an enhanced pathogenicity in vivo.