The Interferon-Stimulated Gene Ifitm3 Restricts West Nile Virus Infection and Pathogenesis
The Interferon-Stimulated Gene Ifitm3 Restricts West Nile Virus Infection and Pathogenesis
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DOI：
10.1128/jvi.00581-16
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发表时间：
2016-09-01
影响因子：
5.4
通讯作者：
Diamond, Michael S.
中科院分区：
文献类型：
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作者：
Gorman, Matthew J.;Poddar, Subhajit;Diamond, Michael S.
干扰素诱导的跨膜蛋白（IFITM）家族的蛋白质抑制细胞培养物中的几种不同的包膜病毒的感染，凭借其限制进入和融合从晚期内涵体的能力。由于很少有研究评估Ifitm 3在体内限制病毒发病机制的重要性，我们研究了其作为抗西尼罗河病毒（WNV），脑炎黄病毒，在细胞和小鼠的抗病毒基因的意义。Ifitm 3（-/-）小鼠更容易受到致死性WNV感染，这与外周器官和中枢神经系统组织中更大的病毒积累有关。由于直接颅内接种后未观察到脑或脊髓中病毒负荷的差异，因此Ifitm 3可能在非神经元细胞中起抗病毒蛋白的作用。与此一致，在多步生长分析中，Ifitm 3（-/-）成纤维细胞而不是树突状细胞导致更高的WNV产量。此外，反式互补实验表明，Ifitm 3抑制WNV感染独立于Ifitm 1，Ifitm 2，Ifitm 5和Ifitm 6。除了对细胞中病毒感染的直接影响外，对WNV感染的Ifitm 3（-/-）小鼠的免疫应答分析显示，B细胞、CD 4（+）T细胞和抗原特异性CD 8（+）T细胞的总数减少。最后，骨髓嵌合体实验表明，Ifitm 3在辐射抗性和辐射敏感性细胞中起作用，因为只有当Ifitm 3在两个隔室中都不存在时，才在脑中观察到更高水平的WNV。我们的分析表明，Ifitm 3限制西尼罗河病毒的发病可能通过多种机制，包括直接控制感染的细胞亚群。重要作为哺乳动物宿主对病毒感染的反应的一部分，数百个干扰素刺激基因（ISGs）被诱导。单个ISG的抑制活性根据特定的细胞类型和病毒病原体而变化。在ISG中，已报道编码干扰素诱导的跨膜蛋白（IFITM）的基因在细胞培养物中抑制多个病毒家族。然而，很少有报道评估IFITM基因对病毒体内发病机制的影响。在这项研究中，我们的特点是Ifitm 3对西尼罗河病毒（WNV），脑炎黄病毒的抗病毒活性，使用Ifitm 3的靶向基因缺失的小鼠。基于广泛的病毒学和免疫学分析，我们确定Ifitm 3通过限制病毒在外周器官中的积累以及随后在中枢神经系统组织中的积累来保护小鼠免受WNV诱导的死亡。我们的数据表明，Ifitm 3通过多种机制和功能限制WNV的发病机制，部分通过控制不同细胞类型的感染。
The interferon-induced transmembrane protein (IFITM) family of proteins inhibit infection of several different enveloped viruses in cell culture by virtue of their ability to restrict entry and fusion from late endosomes. As few studies have evaluated the importance of Ifitm3 in vivo in restricting viral pathogenesis, we investigated its significance as an antiviral gene against West Nile virus (WNV), an encephalitic flavivirus, in cells and mice. Ifitm3(-/-) mice were more vulnerable to lethal WNV infection, and this was associated with greater virus accumulation in peripheral organs and central nervous system tissues. As no difference in viral burden in the brain or spinal cord was observed after direct intracranial inoculation, Ifitm3 likely functions as an antiviral protein in nonneuronal cells. Consistent with this, Ifitm3(-/-) fibroblasts but not dendritic cells resulted in higher yields of WNV in multistep growth analyses. Moreover, transcomplementation experiments showed that Ifitm3 inhibited WNV infection independently of Ifitm1, Ifitm2, Ifitm5, and Ifitm6. Beyond a direct effect on viral infection in cells, analysis of the immune response in WNV-infected Ifitm3(-/-) mice showed decreases in the total number of B cells, CD4(+) T cells, and antigen-specific CD8(+) T cells. Finally, bone marrow chimera experiments demonstrated that Ifitm3 functioned in both radioresistant and radiosensitive cells, as higher levels of WNV were observed in the brain only when Ifitm3 was absent from both compartments. Our analyses suggest that Ifitm3 restricts WNV pathogenesis likely through multiple mechanisms, including the direct control of infection in subsets of cells.IMPORTANCEAs part of the mammalian host response to viral infections, hundreds of interferon-stimulated genes (ISGs) are induced. The inhibitory activity of individual ISGs varies depending on the specific cell type and viral pathogen. Among ISGs, the genes encoding interferon-induced transmembrane protein (IFITM) have been reported to inhibit multiple families of viruses in cell culture. However, few reports have evaluated the impact of IFITM genes on viral pathogenesis in vivo. In this study, we characterized the antiviral activity of Ifitm3 against West Nile virus (WNV), an encephalitic flavivirus, using mice with a targeted gene deletion of Ifitm3. Based on extensive virological and immunological analyses, we determined that Ifitm3 protects mice from WNV-induced mortality by restricting virus accumulation in peripheral organs and, subsequently, in central nervous system tissues. Our data suggest that Ifitm3 restricts WNV pathogenesis by multiple mechanisms and functions in part by controlling infection in different cell types.