Liu Tianxu, Li Jian, Yin Xin, Lu Fengmin, Zhao Hui, Wang Lin, Qin Cheng-Feng
Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China.
Gut. 2025 Feb 6;74(3):467-476. doi: 10.1136/gutjnl-2024-332784.
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.
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).
In vitro transcribed and capped full-length HAV RNA was encapsulated into LNP and was intravenously inoculated to -/- 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.
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.
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.
经肠道传播的肝炎病毒，如甲型肝炎病毒（HAV）和戊型肝炎病毒（HEV），仍然是对公共卫生的重大威胁。然而，缺乏稳定可靠的HAV和HEV感染动物模型。
本研究旨在通过静脉注射脂质纳米颗粒（LNP）包裹的全长病毒RNA（LNP-vRNA），在多种小动物中建立HAV和HEV感染。
将体外转录并加帽的全长HAV RNA封装到LNP中，静脉接种到 -/- 小鼠体内，将HEV RNA接种到兔子和沙鼠体内。通过逆转录定量聚合酶链反应（RT-qPCR）、酶联免疫吸附测定（ELISA）和免疫组织化学测定病毒学参数。通过苏木精-伊红（H&E）染色分析肝脏组织病理学变化。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疗效。
静脉注射LNP-vRNA后，在粪便中检测到稳定的病毒排出，并且从接种动物的肝脏中回收了有传染性的HAV或HEV。在注射LNP-vRNA（HAV）的小鼠和注射LNP-vRNA（HEV）的兔子中观察到肝脏损伤。蒙古沙鼠也易受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。
这种基于LNP-vRNA的稳定且标准化的动物模型为研究经肠道传播的肝炎病毒的发病机制和评估对策提供了一个强大的平台，并且可以进一步扩展到其他不易在体外或体内培养的病毒。
