The Addition of Tumor Necrosis Factor plus Beta Interferon Induces a Novel Synergistic Antiviral State against Poxviruses in Primary Human Fibroblasts
The Addition of Tumor Necrosis Factor plus Beta Interferon Induces a Novel Synergistic Antiviral State against Poxviruses in Primary Human Fibroblasts
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DOI：
10.1128/jvi.01376-08
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发表时间：
2009-01-15
影响因子：
5.4
通讯作者：
McFadden, Grant
中科院分区：
文献类型：
--
作者：
Bartee, Eric;Mohamed, Mohamed R.;McFadden, Grant
肿瘤坏死因子和干扰素家族的成员已被证明独立地抑制多种病毒的复制。此外，以前的报告表明，用这些抗病毒细胞因子的不同组合治疗可以诱导一种协同抗病毒状态，这种协同抗病毒状态可能比单独添加这些细胞因子显著更有效。然而，这种细胞因子协同作用的机制及其对全球基因表达的影响还没有得到很好的描述。在这里，我们使用DNA微阵列分析来证明，用肿瘤坏死因子和干扰素-β处理未感染的原代人成纤维细胞可以诱导出一种独特的协同状态，其特征是数百个基因的显著扰动，这些基因是单独的细胞因子共同诱导的，以及超过850个新的宿主细胞基因的诱导。这种协同作用是由两种配体直接介导的，而不是由中间分泌因子介导的，这是完全阻止粘液瘤病毒在人成纤维细胞中高效复制和传播的必要条件和充分条件。相反，另外两种痘病毒，痘苗病毒和Tanapox病毒，在这些细胞中的复制只被协同抗病毒状态部分抑制，而这两种病毒向邻近细胞的传播被有效地阻止。综上所述，我们的数据表明，肿瘤坏死因子和干扰素-β的结合诱导了一种新的协同抗病毒状态，这种状态与任一种细胞因子单独诱导的状态非常不同。
Tumor necrosis factor (TNF) and members of the interferon (IFN) family have been shown to independently inhibit the replication of a variety of viruses. In addition, previous reports have shown that treatment with various combinations of these antiviral cytokines induces a synergistic antiviral state that can be significantly more potent than addition of any of these cytokines alone. The mechanism of this cytokine synergy and its effects on global gene expression, however, are not well characterized. Here, we use DNA microarray analysis to demonstrate that treatment of uninfected primary human fibroblasts with TNF plus IFN-beta induces a distinct synergistic state characterized by significant perturbations of several hundred genes which are coinduced by the individual cytokines alone, as well as the induction of more than 850 novel host cell genes. This synergy is mediated directly by the two ligands, not by intermediate secreted factors, and is necessary and sufficient to completely block the productive replication and spread of myxoma virus in human fibroblasts. In contrast, the replication of two other poxviruses, vaccinia virus and tanapox virus, are only partially inhibited in these cells by the synergistic antiviral state, whereas the spread of both of these viruses to neighboring cells was efficiently blocked. Taken together, our data indicate that the combination of TNF and IFN-beta induces a novel synergistic antiviral state that is highly distinct from that induced by either cytokine alone.