Early enterovirus translation deficits extend viral RNA replication and elicit sustained MDA5-directed innate signaling.
Early enterovirus translation deficits extend viral RNA replication and elicit sustained MDA5-directed innate signaling.
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肠道病毒(EVS)是一种单链正链RNA病毒，是最常见的人类病毒病原体。与RIG-I检测到的其他细胞质病毒RNA(VRNAs)不同，EV RNAs的感知主要由MDA5介导。EVS的进化具有快速的细胞毒性生命周期，作为宿主细胞干扰的一种手段，表面上抑制MDA5协调的抗病毒I型干扰素(干扰素)反应。这一策略的核心是病毒2A蛋白酶(2Apro)指导的真核细胞起始因子(EIF)4G-中央翻译起始支架和核糖体接头-的切割和核孔的降解。EV MDA5激动剂有一个耐人寻味的先天足迹，其特征是极性的TBK1-干扰素调节因子3(IRF3)信号，它刺激I型干扰素的持续释放，为原位癌症疫苗后抗肿瘤CD8+T细胞的启动提供背景。在这里，我们比较了野生型EV和高度减毒的重组脊髓灰质炎：鼻病毒嵌合体和癌症免疫治疗剂(PVSRIPO)之间的EV-宿主相互作用，以测试有针对性地抑制病毒生命周期中的离散步骤如何影响固有的抗病毒反应。我们的研究表明，PVSRIPO诱导的持续MDA5-TBK1-IRF3信号是2APro直接低效降解eIF4G的结果，而野生型EVS通过快速切割eIF4G来对抗宿主固有的I型干扰素防御。MDA5导向的深度减毒电动汽车的先天签名可能提供有效的先天免疫刺激资产，例如，在原位癌症疫苗接种策略中。多个模式识别受体感知vRNA并启动下游固有信号：内体Toll样受体(TLRs)3、7和8以及细胞质Rig-I样受体(RIG-I)RIG-I和MDA5。它们参与了不同的信号支架：线粒体抗病毒信号蛋白(RLR)、MyD88、与溶酶体上的SLC15A4相互作用的TLR适配器(TLR7和TLR8)以及Toll/IL-1R结构域诱导干扰素(TLR3)。凭借其不同寻常的vRNA结构和直接的宿主细胞进入路径，对EVS的先天反应独特地由MDA5协调。我们报道，PVSRIPO的细胞致病性的显著减弱和丧失触发了MDA5导向的极性TBK1-IRF3信号，从而产生多功能抗肿瘤CD8+T细胞反应的启动和体内持久的抗肿瘤监视。在这里，我们揭开了控制宿主I型干扰素反应抑制的EV-宿主关系，并表明PVSRIPO缺乏的直接宿主eIF4G裂解产生非对立的MDA5导向的下游信号级联反应，从而导致持续的I型干扰素释放。
Enteroviruses (EVs)—positive-sense single-strand RNA viruses of Picornaviridae—are among the most common human viral pathogens. Unlike other cytoplasmic viral RNAs (vRNAs), which are detected by RIG-I, sensing of EV RNAs is mediated primarily by MDA5. EVs evolved with rapid, cytotoxic life cycles as a means of host cell interference, ostensibly to suppress MDA5-orchestrated antiviral type-I interferon (IFN) responses. At the core of this strategy are viral 2A protease (2Apro)-directed cleavage of the eukaryotic initiation factor (eIF)4G—the central translation initiation scaffold and ribosome adaptor—and degradation of nuclear pores. EV MDA5 agonism has an intriguing innate footprint, characterized by polar TBK1-IFN regulatory factor 3 (IRF3) signaling, which fuels sustained type-I IFN release to provide context for antitumor CD8+ T-cell priming after in situ cancer vaccination. Here we compared EV-host interactions between wild-type EVs and the highly attenuated recombinant polio:rhinovirus chimera and cancer immunotherapy agent (PVSRIPO) to test how targeted inhibition of discrete steps in the viral life cycle affects the innate antiviral response. Our investigations demonstrate that sustained MDA5-TBK1-IRF3 signaling elicited by PVSRIPO is the result of inefficient immediate 2Apro-directed eIF4G degradation, while wild-type EVs counter host innate type-I IFN defenses via rapid eIF4G cleavage. The MDA5-directed innate signature of profoundly attenuated EVs may provide efficient innate immune-stimulatory assets, for example, in in situ cancer vaccination strategies. Multiple pattern recognition receptors sense vRNAs and initiate downstream innate signaling: endosomal Toll-like receptors (TLRs) 3, 7, and 8 and cytoplasmic RIG-I-like receptors (RLRs) RIG-I, and MDA5. They engage distinct signaling scaffolds: mitochondrial antiviral signaling protein (RLR), MyD88, and TLR-adaptor interacting with SLC15A4 on the lysosome (TLR7 and TLR8) and toll/IL-1R domain-containing adaptor inducing IFN (TLR3). By virtue of their unusual vRNA structure and direct host cell entry path, the innate response to EVs uniquely is orchestrated by MDA5. We reported that PVSRIPO’s profound attenuation and loss of cytopathogenicity triggers MDA5-directed polar TBK1-IRF3 signaling that generates priming of polyfunctional antitumor CD8+ T-cell responses and durable antitumor surveillance in vivo. Here we unraveled EV-host relations that control suppression of host type-I IFN responses and show that PVSRIPO’s deficient immediate host eIF4G cleavage generates unopposed MDA5-directed downstream signaling cascades resulting in sustained type-I IFN release.
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影响因子：
8.8
作者：
Feng Q;Hato SV;Langereis MA;Zoll J;Virgen-Slane R;Peisley A;Hur S;Semler BL;van Rij RP;van Kuppeveld FJ
通讯作者：
van Kuppeveld FJ
影响因子：
17.1
作者：
Brown MC;Holl EK;Boczkowski D;Dobrikova E;Mosaheb M;Chandramohan V;Bigner DD;Gromeier M;Nair SK
通讯作者：
Nair SK
影响因子：
7.3
作者：
Dragovich, PS;Prins, TJ;Worland, ST
通讯作者：
Worland, ST
DOI：
10.1073/pnas.0403998101
发表时间：
2004-09-14
影响因子：
11.1
作者：
Dufresne, AT;Gromeier, M
通讯作者：
Gromeier, M
影响因子：
12.4
作者：
Goetz, Christian;Everson, Richard G.;Gromeier, Matthias
通讯作者：
Gromeier, Matthias