Mathias Ziersch, Dominik Harms, Lena Neumair, Anke Kurreck, Reimar Johne, C-Thomas Bock, Jens Kurreck
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These target regions will reduce the risk of viral escape through mutations, as they belong to the most conserved regions in the HEV genome. The siRNAs targeting the ORF3 efficiently inhibited viral replication in A549 cells after HEV infection. Importantly, the siRNA was also highly effective at inhibiting HEV in the persistently infected A549 cell line, which provides a suitable model for chronic infection in patients. Furthermore, we showed that a 5' triphosphate modification on the siRNA sense strand activates the RIG-I receptor, a cytoplasmic pattern recognition receptor that recognizes viral RNA. Upon activation, RIG-I triggers a signaling cascade, effectively suppressing HEV replication. 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引用次数: 0
摘要
戊型肝炎病毒(HEV)对全球健康构成严重威胁,估计每年感染人数达 2000 万。尽管戊型肝炎病毒感染是一种自限性疾病,但在大多数情况下,戊型肝炎病毒感染会导致严重后果,尤其是孕妇和原有肝病患者。我们设计了针对 HEV 的小干扰 RNA(siRNA),它们靶向螺旋酶结构域和开放阅读框 3(ORF3)。这些靶区属于戊型肝炎病毒基因组中最保守的区域,可以降低病毒通过突变逃逸的风险。靶向 ORF3 的 siRNA 能有效抑制 HEV 感染 A549 细胞后的病毒复制。重要的是,siRNA 对持续感染的 A549 细胞系中的 HEV 也有很强的抑制作用,而 A549 细胞系是患者慢性感染的合适模型。此外,我们还发现 siRNA 有义链上的 5' 三磷酸修饰能激活 RIG-I 受体,RIG-I 是一种细胞质模式识别受体,能识别病毒 RNA。激活后,RIG-I 触发信号级联,有效抑制 HEV 复制。这种将激活适应性免疫反应和固有的 RNAi 途径相结合的双重作用策略成功地抑制了 HEV 的复制,并有可能开发出新的疗法。
Combining RNA Interference and RIG-I Activation to Inhibit Hepatitis E Virus Replication.
Hepatitis E virus (HEV) poses a significant global health threat, with an estimated 20 million infections occurring annually. Despite being a self-limiting illness, in most cases, HEV infection can lead to severe outcomes, particularly in pregnant women and individuals with pre-existing liver disease. In the absence of specific antiviral treatments, the exploration of RNAi interference (RNAi) as a targeted strategy provides valuable insights for urgently needed therapeutic interventions against Hepatitis E. We designed small interfering RNAs (siRNAs) against HEV, which target the helicase domain and the open reading frame 3 (ORF3). These target regions will reduce the risk of viral escape through mutations, as they belong to the most conserved regions in the HEV genome. The siRNAs targeting the ORF3 efficiently inhibited viral replication in A549 cells after HEV infection. Importantly, the siRNA was also highly effective at inhibiting HEV in the persistently infected A549 cell line, which provides a suitable model for chronic infection in patients. Furthermore, we showed that a 5' triphosphate modification on the siRNA sense strand activates the RIG-I receptor, a cytoplasmic pattern recognition receptor that recognizes viral RNA. Upon activation, RIG-I triggers a signaling cascade, effectively suppressing HEV replication. This dual-action strategy, combining the activation of the adaptive immune response and the inherent RNAi pathway, inhibits HEV replication successfully and may lead to the development of new therapies.
期刊介绍:
Viruses (ISSN 1999-4915) is an open access journal which provides an advanced forum for studies of viruses. It publishes reviews, regular research papers, communications, conference reports and short notes. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. We also encourage the publication of timely reviews and commentaries on topics of interest to the virology community and feature highlights from the virology literature in the ''News and Views'' section. Electronic files or software regarding the full details of the calculation and experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material.