Myxoma Virus Induces Type I Interferon Production in Murine Plasmacytoid Dendritic Cells via a TLR9/MyD88-, IRF5/IRF7-, and IFNAR-Dependent Pathway
Myxoma Virus Induces Type I Interferon Production in Murine Plasmacytoid Dendritic Cells via a TLR9/MyD88-, IRF5/IRF7-, and IFNAR-Dependent Pathway
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DOI：
10.1128/jvi.00104-11
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发表时间：
2011-10-01
影响因子：
5.4
通讯作者：
Deng, Liang
中科院分区：
文献类型：
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作者：
Dai, Peihong;Cao, Hua;Deng, Liang
痘病毒是在感染细胞的细胞质中复制的大型DNA病毒。粘液瘤病毒是属于兔痘病毒属的兔痘病毒。它在欧洲兔子中引起一种叫做多发性粘液瘤的致命疾病，但在非兔形目动物中不能持续任何可检测的感染。牛痘病毒是一种原型正痘病毒，曾被用作根除天花的疫苗。粘液瘤病毒在小鼠中是非致病性的，而牛痘病毒的全身感染即使在免疫活性小鼠中也可以是致命的。浆细胞样树突状细胞（Plasmacytoid dendritic cells，pDC）是一种分泌干扰素（interferon，IFN）的细胞，在抗病毒天然免疫中发挥重要作用。pDC如何感应痘病毒以诱导I型IFN产生还不清楚。在这里，我们报告了粘液瘤病毒而不是牛痘病毒感染的原代鼠pDC诱导IFN-α、IFN-β、肿瘤坏死因子（TNF）和白细胞介素-12p70（IL-12 p70）的产生。使用来自基因敲除小鼠的pDC，我们表明粘液瘤病毒诱导的先天性免疫应答需要内体DNA传感器TLR 9及其适配器MyD 88，转录因子IRF 5和IRF 7，以及IFNAR 1介导的I型IFN正反馈环。它独立于由线粒体衔接分子MAVS、TLR 3衔接TRIF或转录因子IRF 3介导的细胞质RNA传感途径。使用药理学抑制剂，我们证明，粘液瘤病毒诱导的I型IFN和IL-12 p70在小鼠pDC的生产也依赖于磷脂酰肌醇3-激酶（PI 3 K）和Akt。此外，我们的研究结果表明，N-末端Z-DNA/RNA结合结构域的牛痘病毒毒力因子E3，这是失踪的orthopathic M029蛋白表达的粘液瘤病毒，起着抑制作用，在痘病毒传感和先天性细胞因子的生产由小鼠pDC。
Poxviruses are large DNA viruses that replicate in the cytoplasm of infected cells. Myxoma virus is a rabbit poxvirus that belongs to the Leporipoxvirus genus. It causes a lethal disease called myxomatosis in European rabbits but cannot sustain any detectable infection in nonlagomorphs. Vaccinia virus is a prototypal orthopoxvirus that was used as a vaccine to eradicate smallpox. Myxoma virus is nonpathogenic in mice, whereas systemic infection with vaccinia virus can be lethal even in immunocompetent mice. Plasmacytoid dendritic cells (pDCs) are potent type I interferon (IFN)-producing cells that play important roles in antiviral innate immunity. How poxviruses are sensed by pDCs to induce type I IFN production is not well understood. Here we report that infection of primary murine pDCs with myxoma virus, but not with vaccinia virus, induces IFN-alpha, IFN-beta, tumor necrosis factor (TNF), and interleukin-12p70 (IL-12p70) production. Using pDCs derived from genetic knockout mice, we show that the myxoma virus-induced innate immune response requires the endosomal DNA sensor TLR9 and its adaptor MyD88, transcription factors IRF5 and IRF7, and the type I IFN positive-feedback loop mediated by IFNAR1. It is independent of the cytoplasmic RNA sensing pathway mediated by the mitochondrial adaptor molecule MAVS, the TLR3 adaptor TRIF, or the transcription factor IRF3. Using pharmacological inhibitors, we demonstrate that myxoma virus-induced type I IFN and IL-12p70 production in murine pDCs is also dependent on phosphatidylinositol 3-kinase (PI3K) and Akt. Furthermore, our results reveal that the N-terminal Z-DNA/RNA binding domain of vaccinia virulence factor E3, which is missing in the orthologous M029 protein expressed by myxoma virus, plays an inhibitory role in poxvirus sensing and innate cytokine production by murine pDCs.