Modified vaccinia virus Ankara triggers type I IFN production in murine conventional dendritic cells via a cGAS/STING-mediated cytosolic DNA-sensing pathway.
Modified vaccinia virus Ankara triggers type I IFN production in murine conventional dendritic cells via a cGAS/STING-mediated cytosolic DNA-sensing pathway.
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DOI：
10.1371/journal.ppat.1003989
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发表时间：
2014-04
期刊：
影响因子：
6.7
通讯作者：
Deng L
中科院分区：
文献类型：
--
作者：
Dai P;Wang W;Cao H;Avogadri F;Dai L;Drexler I;Joyce JA;Li XD;Chen Z;Merghoub T;Shuman S;Deng L
安卡拉改良痘苗病毒（MVA）是一种减毒痘病毒，已被设计为抗传染性病原体和癌症的疫苗。我们的目标是了解MVA如何调节树突状细胞（dc）的先天免疫，这可以为疫苗设计提供见解。在这项研究中，我们使用小鼠骨髓来源的树突状细胞，评估了I型干扰素（IFN）基因诱导和蛋白分泌对MVA感染的反应。我们报道MVA感染在小鼠常规树突状细胞（cdc）中引起I型IFN的产生，但在浆细胞样树突状细胞（pDCs）中没有。转录因子IRF3 （IFN调节因子3）和IRF7以及IFNAR1 （IFN α / β受体1）介导的正反馈回路是诱导的必要条件。I型IFN的MVA诱导完全依赖于STING （IFN基因刺激因子）和新发现的胞质DNA传感器cGAS（环鸟苷单磷酸-腺苷单磷酸合成酶）。MVA感染cdc会触发TBK1 （Tank-binding kinase 1）和IRF3的磷酸化，在没有cGAS和STING的情况下，IRF3会被消除。此外，静脉注射MVA在野生型小鼠中诱导I型IFN，而在缺乏STING或IRF3的小鼠中则没有。用内体和溶酶体酸化抑制剂或溶酶体酶组织蛋白酶B抑制剂治疗cdc可减弱MVA诱导的I型IFN产生，这表明溶酶体酶处理病毒粒子对MVA感知很重要。综上所述，我们的研究结果证明了cGAS/ sting介导的细胞质dna传感途径在MVA诱导I型IFN在cDCs中的关键作用。我们提出证据表明，在mva感染的cdc中，牛痘毒力因子E3和N1抑制IRF3的激活和IFNB基因的诱导。修饰安卡拉牛痘病毒（MVA）是一种减毒牛痘毒株，亲本基因组大量缺失，使其在哺乳动物细胞中无法复制。MVA是一种安全有效的天花和猴痘疫苗。已对MVA作为传染病和癌症的疫苗载体进行了研究。树突状细胞在先天免疫和适应性免疫中发挥重要作用。更好地了解dc中的先天免疫传感器如何检测MVA，将指导开发更有效的MVA疫苗。我们报告了我们的研究结果，MVA感染通过新发现的DNA传感器cGAS、其接头STING和转录因子IRF3和IRF7介导的细胞质DNA传感途径诱导传统树突状细胞产生I型干扰素（IFN）。相比之下，野生型痘苗病毒不能激活这一途径。此外，我们发现牛痘毒力因子E3和N1在细胞质dna传感途径中发挥抑制作用。
Modified vaccinia virus Ankara (MVA) is an attenuated poxvirus that has been engineered as a vaccine against infectious agents and cancers. Our goal is to understand how MVA modulates innate immunity in dendritic cells (DCs), which can provide insights to vaccine design. In this study, using murine bone marrow-derived dendritic cells, we assessed type I interferon (IFN) gene induction and protein secretion in response to MVA infection. We report that MVA infection elicits the production of type I IFN in murine conventional dendritic cells (cDCs), but not in plasmacytoid dendritic cells (pDCs). Transcription factors IRF3 (IFN regulatory factor 3) and IRF7, and the positive feedback loop mediated by IFNAR1 (IFN alpha/beta receptor 1), are required for the induction. MVA induction of type I IFN is fully dependent on STING (stimulator of IFN genes) and the newly discovered cytosolic DNA sensor cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase). MVA infection of cDCs triggers phosphorylation of TBK1 (Tank-binding kinase 1) and IRF3, which is abolished in the absence of cGAS and STING. Furthermore, intravenous delivery of MVA induces type I IFN in wild-type mice, but not in mice lacking STING or IRF3. Treatment of cDCs with inhibitors of endosomal and lysosomal acidification or the lysosomal enzyme Cathepsin B attenuated MVA-induced type I IFN production, indicating that lysosomal enzymatic processing of virions is important for MVA sensing. Taken together, our results demonstrate a critical role of the cGAS/STING-mediated cytosolic DNA-sensing pathway for type I IFN induction in cDCs by MVA. We present evidence that vaccinia virulence factors E3 and N1 inhibit the activation of IRF3 and the induction of IFNB gene in MVA-infected cDCs. Modified vaccinia virus Ankara (MVA) is an attenuated vaccinia strain with large deletions of the parental genome that render it non-replicative in mammalian cells. MVA is a safe and effective vaccine against both smallpox and monkeypox. MVA has been investigated as a vaccine vector for infectious diseases and cancers. Dendritic cells (DCs) play important roles in innate and adaptive immunity. A better understanding of how MVA is detected by innate immune sensors in DCs would guide the development of more effective MVA-based vaccines. We report our findings that MVA infection induces the production of type I interferon (IFN) in conventional dendritic cells via a cytosolic DNA-sensing pathway mediated by the newly discovered DNA sensor cGAS, its adaptor STING, and transcription factors IRF3 and IRF7. By contrast, wild-type vaccinia virus fails to activate this pathway. Furthermore, we show that vaccinia virulence factors E3 and N1 play inhibitory roles in the cytosolic DNA-sensing pathway.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.89.11.4825
发表时间：
1992-06-01
影响因子：
11.1
作者：
CHANG, HW;WATSON, JC;JACOBS, BL
通讯作者：
JACOBS, BL
影响因子：
7
作者：
Barber GN
通讯作者：
Barber GN
影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
DOI：
10.1073/pnas.95.8.4516
发表时间：
1998-04-14
影响因子：
11.1
作者：
Deussing, J;Roth, W;Villadangos, JA
通讯作者：
Villadangos, JA