Disruption of MDA5-Mediated Innate Immune Responses by the 3C Proteins of Coxsackievirus A16, Coxsackievirus A6, and Enterovirus D68
Disruption of MDA5-Mediated Innate Immune Responses by the 3C Proteins of Coxsackievirus A16, Coxsackievirus A6, and Enterovirus D68
复制标题
DOI：
10.1128/jvi.00546-17
复制
发表时间：
2017-07-01
影响因子：
5.4
通讯作者：
Yu, Xiao-Fang
中科院分区：
文献类型：
--
作者：
Rui, Yajuan;Su, Jiaming;Yu, Xiao-Fang
柯萨奇病毒A16(CV-A16)、柯萨奇病毒A6(CV-A6)和肠道病毒D68(EV-D68)属于短小病毒科(Picomaviridae)，是全球手足口病和儿童呼吸道疾病的主要病原。这些病毒的生物学特性，特别是它们与宿主天然免疫系统的相互作用，还没有得到很好的研究。在本研究中，我们发现来自CV-A16、CV-A6和EV-D68的3C(Pro)蛋白与黑色素瘤分化相关基因5(MDA5)结合，并抑制其与MAV的相互作用。因此，在维甲酸诱导的类基因受体(RLR)通路中，MDA5触发的I型干扰素(IFN)信号被CV-A16、CV-A6和EV-D68 3C(PRO)蛋白阻断。此外，CV-A16、CV-A6和EV-D68 3C(PRO)蛋白都能裂解转化生长因子β激活蛋白1(TAK1)，从而抑制核因子-kappaB的激活，这种宿主反应对Toll样受体(TLR)介导的信号转导也是至关重要的。因此，我们的数据表明，循环中的手足口病相关CV-A16和CV-A6以及严重呼吸道疾病相关的EV-D68已经开发出新的机制，通过靶向RLR和TLR途径中的关键因素来破坏宿主的先天性免疫反应。阻断不同肠道病毒和COX-SackieVirus的3C(Pro)蛋白干扰I型干扰素诱导的能力将恢复干扰素的抗病毒功能，提供一种新的抗病毒策略。这些病毒的致病机制在很大程度上是未知的。在这里，我们证明了CV-A16、CV-A6和EV-D68 3C(PRO)蛋白可以阻断MDA5触发的I型干扰素的诱导。这些病毒的3C(Pro)蛋白与MDA5结合，并抑制其与MAV的相互作用。此外，CV-A16、CV-A6和EV-D68 3C(PRO)蛋白切割TAK1以抑制NF-kappa B反应。因此，我们的数据表明，循环中的手足口病相关CV-A16和CV-A6以及严重呼吸道疾病相关的EV-D68已经发展出一种机制，通过同时靶向RLR和TLR途径中的关键因素来破坏宿主的先天性免疫反应。这些发现表明以CV-A16、CV-A6和EV-D68 3C(PRO)蛋白为靶点作为抗病毒策略的潜在优点。
Coxsackievirus A16 (CV-A16), CV-A6, and enterovirus D68 (EV-D68) belong to the Picomaviridae family and are major causes of hand, foot, and mouth disease (HFMD) and pediatric respiratory disease worldwide. The biological characteristics of these viruses, especially their interplay with the host innate immune system, have not been well investigated. In this study, we discovered that the 3C(pro) proteins from CV-A16, CV-A6, and EV-D68 bind melanoma differentiation-associated gene 5 (MDA5) and inhibit its interaction with MAVS. Consequently, MDA5-triggered type I interferon (IFN) signaling in the retinoic acid-inducible gene I-like receptor (RLR) pathway was blocked by the CV-A16, CV-A6, and EV-D68 3C(pro) proteins. Furthermore, the CV-A16, CV-A6, and EV-D68 3C(pro) proteins all cleave transforming growth factor beta-activated kinase 1 (TAK1), resulting in the inhibition of NF-kappa B activation, a host response also critical for Toll-like receptor (TLR)-mediated signaling. Thus, our data demonstrate that circulating HFMD-associated CV-A16 and CV-A6, as well as severe respiratory disease-associated EV-D68, have developed novel mechanisms to subvert host innate immune responses by targeting key factors in the RLR and TLR pathways. Blocking the ability of 3C(pro) proteins from diverse enteroviruses and cox-sackieviruses to interfere with type I IFN induction should restore IFN antiviral function, offering a potential novel antiviral strategy.IMPORTANCE CV-A16, CV-A6, and EV-D68 are emerging pathogens associated with hand, foot, and mouth disease and pediatric respiratory disease worldwide. The pathogenic mechanisms of these viruses are largely unknown. Here we demonstrate that the CV-A16, CV-A6, and EV-D68 3C(pro) proteins block MDA5-triggered type I IFN induction. The 3C(pro) proteins of these viruses bind MDA5 and inhibit its interaction with MAVS. In addition, the CV-A16, CV-A6, and EV-D68 3C(pro) proteins cleave TAK1 to inhibit the NF-kappa B response. Thus, our data demonstrate that circulating HFMD-associated CV-A16 and CV-A6, as well as severe respiratory disease-associated EV-D68, have developed a mechanism to subvert host innate immune responses by simultaneously targeting key factors in the RLR and TLR pathways. These findings indicate the potential merit of targeting the CV-A16, CV-A6, and EV-D68 3C(pro) proteins as an antiviral strategy.