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J. Virol.文章:受IFNα和IL28B调控的let-7s通过靶向IGF2BP1发挥抗丙肝病毒作用

丙型肝炎病毒(HCV)是引发严重肝脏疾病的主要原因,而干扰素联合利巴韦林是大多数国家中抗HCV感染的标准治疗方案。据信IFN应答基因参与了抗病毒反应,而新的证据表明miRNA也参与病毒感染的控制。中国医学科学院病原所的研究者采用ABI miRNA TLDA技术对IFNα和IL28B处理的肝细胞样品的约750个miRNA进行检测,并采用体外细胞培养来源的HCV产量作为指标对差异表达的miRNA的抗HCV活性进行评价。检测发现let-7b在肝癌细胞中具有显著的抗HCV效果,其抗病毒机制是通过抑制HCV复制和病毒蛋白翻译途径发挥的。抑制let-7b能够阻碍IFNα和IL28B的抗HCV效果。进而研究者发现胰岛素样生长因子2-mRNA结合蛋白,IGF2BP1,是let-7b的直接靶基因。IGF2BP1是HCV复制是必要成分,其表达在IFNα和IL28B处理细胞中处于低水平。破坏let-7b结合序列的seed区域后将丧失其抗病毒活性。其他let-7家族成员也能够一直IGF2BP1表达并具有抗HCV功能。总之,本研究发现了一个I型和III型干扰素通过miRNA靶向基因的机制抑制HCV复制的例子。这些研究确认了miRNA在宿主抗病毒免疫应答中的重要作用,并提供了抗HCV治疗的新的候选因子。该研究已经发表在2013年J. Virol.杂志上。本研究中miRNA定量PCR检测工作由博奥生物集团有限公司完成。


原文摘要:
High-Throughput Profiling of Alpha Interferon- and Interleukin-28B-Regulated MicroRNAs and Identification of let-7s with Anti-Hepatitis C Virus Activity by Targeting IGF2BP1
Hepatitis C virus (HCV) infection is a major cause of severe liver disease. Interferon (IFN)/ribavirin treatment remains the standard therapeutic regimen for HCV infection in most countries. IFN-stimulated genes are believed to contribute to antiviral effects. However, emerging evidence suggests that microRNAs (miRNAs), a class of noncoding small RNAs, are involved in the control of viral infection. Here, we systematically profiled the hepatocyte expression of a set of 750 miRNAs in response to alpha interferon (IFN-α) and interleukin-28B (IL-28B) treatments. The anti-HCV activity of differentially expressed miRNAs was evaluated using cell culture-derived HCV in vitro. The results demonstrate that let-7b had a significant anti-HCV effect by inhibiting HCV replication and viral protein translation in human hepatoma cells. In particular, we show that the inhibition of let-7b attenuated the anti-HCV effects of IFN-α and IL-28B. Furthermore, we show that the host factor insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is a target of let-7b. IGF2BP1 was required for HCV replication, and its expression was downregulated by IFN-α and IL-28B. Deletion of the wild-type seed region of let-7b abolished its antiviral activity. Finally, we demonstrate that other let-7 family miRNAs were able to inhibit HCV and to suppress IGF2BP1 expression. In conclusion, we provide an example of a host miRNA regulated by type I and type III IFNs that inhibits HCV replication and infectivity by targeting host targets. These results highlight the important role of miRNAs in the host antiviral immune response and provide a novel candidate for anti-HCV therapy.
原文出处:
http://jvi.asm.org/content/87/17/9707.abstract