State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University , Wuhan, China.
Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University , Wuhan, China.
mBio. 2023 Aug 31;14(4):e0086723. doi: 10.1128/mbio.00867-23. Epub 2023 May 24.
The host innate immune system's defense against viral infections depends heavily on type I interferon (IFN-I) production. Research into the mechanisms of virus-host interactions is essential for developing novel antiviral therapies. In this study, we compared the effect of the five members of the microRNA-200 (miR-200) family on IFN-I production during viral infection and found that miR-200b-3p displayed the most pronounced regulatory effect. During viral infection, we discovered that the transcriptional level of microRNA-200b-3p (miR-200b-3p) increased with the infection of influenza virus (IAV) and vesicular stomatitis virus (VSV), and miR-200b-3p production was modulated by the activation of the ERK and p38 pathways. We identified cAMP response element binding protein (CREB) as a novel transcription factor that binds to the miR-200b-3p promoter. MiR-200b-3p reduces NF-κB and IRF3-mediated IFN-I production by targeting the 3' untranslated region (3' UTR) of TBK1 mRNA. Applying miR-200b-3p inhibitor enhances IFN-I production in IAV and VSV-infected mouse models, thus inhibiting viral replication and improving mouse survival ratio. Importantly, in addition to IAV and VSV, miR-200b-3p inhibitors exhibited potent antiviral effects against multiple pathogenic viruses threatening human health worldwide. Overall, our study suggests that miR-200b-3p might be a potential therapeutic target for broad-spectrum antiviral therapy. IMPORTANCE The innate immune response mediated by type I interferon (IFN-I) is essential for controlling viral replication. MicroRNAs (miRNAs) have been found to regulate the IFN signaling pathway. In this study, we describe a novel function of miRNA-200b-3p in negatively regulating IFN-I production during viral infection. miRNA-200b-3p was upregulated by the MAPK pathway activated by IAV and VSV infection. The binding of miRNA-200b-3p to the 3' UTR of TBK1 mRNA reduced IFN-I activation mediated by IRF3 and NF-κB. Application of miR-200b-3p inhibitors exhibited potent antiviral effects against multiple RNA and DNA viruses. These results provide fresh insight into understanding the impact of miRNAs on host-virus interactions and reveal a potential therapeutic target for common antiviral intervention.
宿主固有免疫系统抵御病毒感染在很大程度上依赖于 I 型干扰素（IFN-I）的产生。研究病毒-宿主相互作用的机制对于开发新型抗病毒疗法至关重要。在这项研究中，我们比较了 microRNA-200（miR-200）家族的五个成员在病毒感染期间对 IFN-I 产生的影响，发现 miR-200b-3p 表现出最显著的调节作用。在病毒感染过程中，我们发现 microRNA-200b-3p（miR-200b-3p）的转录水平随着流感病毒（IAV）和水疱性口炎病毒（VSV）的感染而增加，miR-200b-3p 的产生受到 ERK 和 p38 途径激活的调节。我们确定 cAMP 反应元件结合蛋白（CREB）作为一种新型转录因子，可与 miR-200b-3p 启动子结合。miR-200b-3p 通过靶向 TBK1 mRNA 的 3'非翻译区（3'UTR）来减少 NF-κB 和 IRF3 介导的 IFN-I 产生。应用 miR-200b-3p 抑制剂可增强 IAV 和 VSV 感染小鼠模型中的 IFN-I 产生，从而抑制病毒复制并提高小鼠存活率。重要的是，除了 IAV 和 VSV，miR-200b-3p 抑制剂对威胁全球人类健康的多种致病病毒表现出强大的抗病毒作用。总之，我们的研究表明，miR-200b-3p 可能是广谱抗病毒治疗的潜在治疗靶点。
由 I 型干扰素（IFN-I）介导的固有免疫反应对于控制病毒复制至关重要。已发现 microRNAs（miRNAs）可调节 IFN 信号通路。在这项研究中，我们描述了 miR-200b-3p 在病毒感染期间负调控 IFN-I 产生的新功能。miR-200b-3p 被 IAV 和 VSV 感染激活的 MAPK 途径上调。miR-200b-3p 与 TBK1 mRNA 的 3'UTR 结合，降低了 IRF3 和 NF-κB 介导的 IFN-I 激活。应用 miR-200b-3p 抑制剂对多种 RNA 和 DNA 病毒表现出强大的抗病毒作用。这些结果为理解 miRNA 对宿主-病毒相互作用的影响提供了新的见解，并揭示了常见抗病毒干预的潜在治疗靶点。
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