通过双链依赖RNA的RLR受体介导的坏死病激活先天性抗病毒免疫应答。,Scientific Reports

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通过双链依赖RNA的RLR受体介导的坏死病激活先天性抗病毒免疫应答。
Scientific Reports ( IF 3.8 ) Pub Date : 2016-Mar-03 , DOI: 10.1038/srep22550
Wei Wang , Wei-Hua Wang , Kazem M. Azadzoi , Ning Su , Peng Dai , Jianbin Sun , Qin Wang , Ping Liang , Wentao Zhang , Xiaoying Lei , Zhen Yan , Jing-Hua Yang

病毒在宿主细胞中诱导双链RNA（dsRNA）。哺乳动物系统已经开发了dsRNA依赖的识别受体，例如RLRs，该受体将dsRNA的长链段识别为PAMPs，以激活干扰素介导的抗病毒途径和严重感染中的细胞凋亡。在这里，我们报告了通过dsRNA依赖的RLR受体介导的坏死病抵抗来自不同类别病毒的感染的有效抗病毒免疫反应。我们证明在嵌合RLR受体dsCARE的存在下，病毒感染的A549细胞被有效杀死。它可测量地抑制干扰素抗病毒途径，但促进IL-1β的产生。通过形态评估，磷脂酰丝氨酸暴露，半胱天冬酶的裂解和化学抑制排除了细胞凋亡的参与，并始终提示RLR受体介导的坏死病是感染细胞死亡的潜在机制。RIP1-RIP3坏死体的形成，MLKL蛋白的募集和组织蛋白酶D的激活增强了肾病通路。基因敲低证实了RIP1和RIP3的作用。此外，坏死病抑制剂necrostatin-1而不是泛半胱天冬酶抑制剂zVAD阻止了dsCARE依赖的感染细胞死亡。我们的数据提供了令人信服的证据，表明嵌合RLR受体改变了感染细胞对坏死病的常见干扰素抗病毒反应，并导致病毒感染的细胞迅速死亡。这种机制可以作为一种有效的抗病毒策略。

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Activation of innate antiviral immune response via double-stranded RNA-dependent RLR receptor-mediated necroptosis.

Viruses induce double-stranded RNA (dsRNA) in the host cells. The mammalian system has developed dsRNA-dependent recognition receptors such as RLRs that recognize the long stretches of dsRNA as PAMPs to activate interferon-mediated antiviral pathways and apoptosis in severe infection. Here we report an efficient antiviral immune response through dsRNA-dependent RLR receptor-mediated necroptosis against infections from different classes of viruses. We demonstrated that virus-infected A549 cells were efficiently killed in the presence of a chimeric RLR receptor, dsCARE. It measurably suppressed the interferon antiviral pathway but promoted IL-1β production. Canonical cell death analysis by morphologic assessment, phosphatidylserine exposure, caspase cleavage and chemical inhibition excluded the involvement of apoptosis and consistently suggested RLR receptor-mediated necroptosis as the underlying mechanism of infected cell death. The necroptotic pathway was augmented by the formation of RIP1-RIP3 necrosome, recruitment of MLKL protein and the activation of cathepsin D. Contributing roles of RIP1 and RIP3 were confirmed by gene knockdown. Furthermore, the necroptosis inhibitor necrostatin-1 but not the pan-caspase inhibitor zVAD impeded dsCARE-dependent infected cell death. Our data provides compelling evidence that the chimeric RLR receptor shifts the common interferon antiviral responses of infected cells to necroptosis and leads to rapid death of the virus-infected cells. This mechanism could be targeted as an efficient antiviral strategy.

更新日期：2016-03-05

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