Background Enterically transmitted hepatitis viruses, such as hepatitis A virus (HAV) and hepatitis E virus (HEV), remain notable threats to public health. However, stable and reliable animal models of HAV and HEV infection are lacking. Objective This study aimed to establish HAV and HEV infections in multiple small animals by intravenously injecting lipid nanoparticle (LNP)-encapsulated full-length viral RNAs (LNP-vRNA). Design In vitro transcribed and capped full-length HAV RNA was encapsulated into LNP and was intravenously inoculated to Ifnar −/− mice, and HEV RNA to rabbits and gerbils. Virological parameters were determined by RT-qPCR, ELISA and immunohistochemistry. Liver histopathological changes were analysed by H&E staining. Antiviral drug and vaccine efficacy were further evaluated by using the LNP-vRNA-based animal model. Results On intravenous injection of LNP-vRNA, stable viral shedding was detected in the faeces and infectious HAV or HEV was recovered from the livers of the inoculated animals. Liver damage was observed in LNP-vRNA (HAV)-injected mice and LNP-vRNA (HEV)-injected rabbits. Mongolian gerbils were also susceptible to LNP-vRNA (HEV) injections. Finally, the antiviral countermeasures and in vivo function of HEV genome deletions were validated in the LNP-vRNA-based animal model. Conclusion This stable and standardised LNP-vRNA-based animal model provides a powerful platform to investigate the pathogenesis and evaluate countermeasures for enterically transmitted hepatitis viruses and can be further expanded to other viruses that are not easily cultured in vitro or in vivo. All data relevant to the study are included in the article or uploaded as online supplemental information.

中文翻译：

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利用基于脂质纳米颗粒的全长病毒基因组 RNA 递送系统建立肠道传播的肝炎病毒动物模型


背景 甲型肝炎病毒 （HAV） 和戊型肝炎病毒 （HEV） 等肠道传播的肝炎病毒仍然是对公共卫生的显著威胁。然而，缺乏稳定可靠的 HAV 和 HEV 感染动物模型。目的 通过静脉注射脂质纳米颗粒 （LNP） 封装的全长病毒 RNA （LNP-vRNA） 来确定多种小动物的 HAV 和 HEV 感染情况。设计 将体外转录和加帽的全长 HAV RNA 封装到 LNP 中，并静脉接种给 Ifnar −/- 小鼠，静脉接种给兔子和沙鼠。通过 RT-qPCR 、 ELISA 和免疫组化测定病毒学参数。通过 H&E 染色分析肝脏组织病理学变化。通过使用基于 LNP-vRNA 的动物模型进一步评估抗病毒药物和疫苗的有效性。结果 静脉注射 LNP-vRNA 后，在粪便中检测到稳定的病毒脱落，并从接种动物的肝脏中回收感染性 HAV 或 HEV。在 LNP-vRNA （HAV） 注射小鼠和 LNP-vRNA （HEV） 注射兔子中观察到肝损伤。蒙古沙鼠也容易受到 LNP-vRNA （HEV） 注射的影响。最后，在基于 LNP-vRNA 的动物模型中验证了 HEV 基因组缺失的抗病毒对策和体内功能。结论 这种稳定且标准化的基于 LNP-vRNA 的动物模型为研究肠道传播肝炎病毒的发病机制和评估对策提供了强大的平台，并且可以进一步扩展到其他不易体外或体内培养的病毒。与研究相关的所有数据都包含在文章中或作为在线补充信息上传。