RIG-I-Like Receptor-Mediated Recognition of Viral Genomic RNA of Severe Acute Respiratory Syndrome Coronavirus-2 and Viral Escape From the Host Innate Immune Responses.
RIG-I-Like Receptor-Mediated Recognition of Viral Genomic RNA of Severe Acute Respiratory Syndrome Coronavirus-2 and Viral Escape From the Host Innate Immune Responses.
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DOI：
10.3389/fimmu.2021.700926
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发表时间：
2021
影响因子：
7.3
通讯作者：
Oshiumi H
中科院分区：
文献类型：
--
作者：
Kouwaki T;Nishimura T;Wang G;Oshiumi H
RIG-I 样受体 (RLR)、RIG-I 和 MDA5 是细胞质病毒 RNA 传感器，可识别病毒双链 RNA 并触发信号以诱导抗病毒反应，包括 I 型干扰素的产生。严重急性呼吸综合征冠状病毒-2 (SARS-CoV-2) 引起了 2019 年冠状病毒病大流行。然而，RLR 在 SARS-CoV-2 先天免疫反应中的作用尚未完全阐明。在这里，我们研究了 RLR 在响应 SARS-CoV-2 的细胞因子表达中的作用，发现不仅 MDA5，RIG-I 也参与某些类型的人类细胞的先天免疫反应。将从 SARS-CoV-2 感染细胞中提取的总 RNA 转染到上皮细胞中，诱导 IFN-β、IP-10 和 Ccl5 mRNA 表达。通过敲除 RIG-I 或 MDA5，细胞因子表达减少，表明这两种蛋白是针对 SARS-CoV-2 的适当先天免疫反应所必需的。两个病毒基因组RNA区域强烈诱导I型IFN表达，并且病毒RNA的200个碱基片段以RIG-I依赖性方式优先诱导I型IFN。相比之下，SARS-CoV-2感染性颗粒几乎不诱导细胞因子表达，这表明病毒逃离了宿主反应。病毒9b蛋白抑制RIG-I和MAVS相互作用，病毒7a蛋白使TBK1蛋白不稳定，导致I型IFN表达所需的IRF-3磷酸化减弱。我们的数据阐明了 RLR 介导的 SARS-CoV-2 感染反应和病毒逃离宿主先天免疫反应的机制。
RIG-I-like receptors (RLR), RIG-I and MDA5, are cytoplasmic viral RNA sensors that recognize viral double-stranded RNAs and trigger signals to induce antiviral responses, including type I interferon production. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) caused the coronavirus disease 2019 pandemic. However, the RLR role in innate immune response to SARS-CoV-2 has not been fully elucidated. Here, we studied the roles of RLR in cytokine expression responding to SARS-CoV-2 and found that not only MDA5 but also RIG-I are involved in innate immune responses in some types of human cells. Transfection of total RNAs extracted from SARS-CoV-2-infected cells into epithelial cells induced IFN-β, IP-10, and Ccl5 mRNA expression. The cytokine expression was reduced by knockout of either RIG-I or MDA5, suggesting that both proteins are required for appropriate innate immune response to SARS-CoV-2. Two viral genomic RNA regions strongly induced type I IFN expression, and a 200-base fragment of viral RNA preferentially induced type I IFN in a RIG-I-dependent manner. In contrast, SARS-CoV-2 infectious particles hardly induced cytokine expression, suggesting viral escape from the host response. Viral 9b protein inhibited RIG-I and MAVS interaction, and viral 7a protein destabilized the TBK1 protein, leading to attenuated IRF-3 phosphorylation required for type I IFN expression. Our data elucidated the mechanism underlying RLR-mediated response to SARS-CoV-2 infection and viral escape from the host innate immune response.
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