Zika virus antagonizes interferon response in patients and disrupts RIG-I-MAVS interaction through its CARD-TM domains
Zika virus antagonizes interferon response in patients and disrupts RIG-I-MAVS interaction through its CARD-TM domains
复制标题
寨卡病毒通过其 CARD-TM 结构域拮抗患者的干扰素反应并破坏 RIG-I-MAVS 相互作用
DOI：
10.1186/s13578-019-0308-9
复制
发表时间：
2019-06-07
影响因子：
7.5
通讯作者：
Zhu, Xun
中科院分区：
文献类型：
--
作者：
Hu, Yiwen;Dong, Xinhuai;Zhu, Xun
寨卡病毒（ZIKV）流行及其与严重并发症的联系对全球健康的新威胁凸显了更好地了解ZIKV致病机制的日益增长的需求。I型干扰素（IFN-I）在保护宿主免受ZIKV感染中的关键作用的累积证据在于以下发现：ZIKV已经进化出各种策略以通过抵消早期IFN诱导或随后的IFN信号传导来破坏宿主防御线。然而，ZIKV及其蛋白质的抗IFN能力的潜在机制，这可能有助于ZIKV的公认的广泛细胞向性和持久性，仍然不完全理解。我们发现ZIKV中抗病毒干扰素刺激基因和先天免疫传感器的转录特征程序，与健康供体的那些相比，感染的患者保持无活性，表明ZIKV能够在人类的自然感染过程中抑制IFN-1的诱导。此外，通过分析ZIKV NS 4A-过表达系统中或在实际ZIKV感染的情况下的分子相互作用，我们鉴定了ZIKV NS 4A直接结合MAVS，从而通过CARD-TM结构域中断RIG-I/MAVS相互作用，我们的发现共同揭示了ZIKV NS 4A靶向MAVS并通过废除MAVS而促成ZIKV免疫逃避。介导的IFN产生。从患者研究中获得的这些发现为我们关于ZIKV如何介导IFN-1系统抑制的理解增加了新的知识和分子细节，并且可以为未来开发抗ZIKV策略提供新的基础。
BackgroundThe emerging threat to global health associated with the Zika virus (ZIKV) epidemics and its link to severe complications highlights a growing need to better understand the pathogenic mechanisms of ZIKV. Accumulating evidence for a critical role of type I interferon (IFN-I) in protecting hosts from ZIKV infection lies in the findings that ZIKV has evolved various strategies to subvert the host defense line by counteracting the early IFN induction or subsequent IFN signaling. Yet, mechanisms underlying the counter-IFN capability of ZIKV and its proteins, which might contribute to the well-recognized broad cellular tropisms and persistence of ZIKV, remain incompletely understood.ResultsUsing RNA sequencing-based transcriptional profiling of whole blood cells isolated from patients acutely infected by ZIKV, we found that transcriptional signature programs of antiviral interferon-stimulated genes and innate immune sensors in ZIKV-infected patients remained inactive as compared to those of healthy donors, suggesting that ZIKV was able to suppress the induction of IFN-I during the natural infection process in humans. Furthermore, by analyzing the molecular interaction in a ZIKV NS4A-overexpression system, or in the context of actual ZIKV infection, we identified that ZIKV NS4A directly bound MAVS and thereby interrupted the RIG-I/MAVS interaction through the CARD-TM domains, leading to attenuated production of IFN-I.ConclusionsOur findings collectively revealed that ZIKV NS4A targeted MAVS and contributed to ZIKV immune evasion through abrogating MAVS-mediated IFN production. These findings obtained from patient studies have added new knowledge and molecular details to our understanding regarding how ZIKV mediates suppression of the IFN-I system and may provide anew basis for the future development of anti-ZIKV strategies.