军事兽医研究所在干扰素诱导跨膜蛋白抗病毒取得新进展 - 中国病毒学论坛|我们一直在坚持！

2018年2月16日，军事医学研究院军事兽医研究所金宁一研究员课题组在Frontiers in Immunology在线发表题为 The Host Restriction Factor Interferon-Inducible Transmembrane Protein 3 Inhibits Vaccinia Virus Infection（《宿主限制因子干扰素诱导跨膜蛋白3抗痘苗病毒感染》）的研究论文。该工作通过系列实验，国内外首次证实了IFITM3对痘苗病毒具有抑制作用，是IFITM3抗DNA病毒的首个报道，将其抗病毒谱拓展到了一个新的领域，为进一步解析该蛋白的抗病毒机制及临床应用提供了科学依据。

众所周知，干扰素通过诱导大量的干扰素刺激基因表达建立宿主防御系统，其中干扰素诱导跨膜蛋白家族尤其是IFITM3通过抑制病毒膜融合阻断多种RNA病毒进入细胞。然而，IFITM3蛋白在宿主抵御DNA病毒中的作用仍然未知。以痘苗病毒为模式病毒，下调IFITM3的表达；尽管siRNA沉默其表达时并不影响病毒感染，但却影响I型IFN介导的抗痘苗病毒效果及病毒感染引起的细胞死亡效应。通过构建稳定表达该蛋白的细胞模型进行深入研究发现，外源表达IFITM3显著抑制痘苗病毒感染、增殖和复制，且这种抑制作用发生在病毒早期进入阶段。有意思的是，抑制效应主要针对于低pH环境下进入的病毒颗粒。该研究亦为探索病毒感染与宿主防御之间复杂关系提供了新的视角。

Interferons (IFNs) establish dynamic host defense mechanisms by inducing various IFN-stimulated genes (ISGs) that encodes many antiviral innate immune effectors. IFN-inducible transmembrane (IFITM) proteins have been identified as intrinsic antiviral effectors, which block the entry of a broad spectrum of enveloped RNA viruses by interrupting virus-endosomal fusion. However, antiviral activity of IFITM proteins against mammalian DNA virus has not been demonstrated till date. Here, we sought to investigate the antiviral activities and mechanisms of IFITM3 protein against poxvirus infection. Analysis of expression kinetics of cell endogenous IFITM3 protein indicated that vaccinia virus (VACV) infection suppressed its translation, which was independent of IRF3 phosphorylation triggered by VACV. Although silencing of endogenous IFITM proteins did not affect their baseline antiviral effects in the cell, it has reduced the IFN-α-mediated inhibition of VACV infection, and also modulated VACV-induced cell death. Moreover, we discovered that over-expression of IFITM3 significantly restricted VACV infection, replication and proliferation mainly by interfering with virus entry processes prior to the virus nucleocapsid entry into the cytoplasm. Interestingly, IFITM3 over-expression showed an impact on virus binding. Furthermore, IFITM3 interfered with the cytosolic entry of virus through low pH-dependent fashion. Taken together, our findings provide the first evidence of exogenously expressed IFITM3 protein restricting infection of an enveloped DNA virus, thus expanding their antiviral spectrum. This study further explores the complex mechanism and provides novel insights into the interaction between virus infection and host defense.