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Hepatology
Original research
Establishment of enterically transmitted hepatitis virus animal models using lipid nanoparticle-based full-length viral genome RNA delivery system
  1. Tianxu Liu1,
  2. Jian Li2,3,
  3. Xin Yin4,
  4. Fengmin Lu1,5,
  5. Hui Zhao2,
  6. Lin Wang1,5,
  7. Cheng-Feng Qin2,3,6
  1. 1Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
  2. 2State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing 100071, China
  3. 3School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China
  4. 4State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang, China
  5. 5Shenzhen Blood Center, Shen Zhen, Guangdong, China
  6. 6Research Unit of Discovery and Tracing of Natural Focus Diseases, Chinese Academy of Medical Sciences, Beijing 100071, China
  1. Correspondence to Dr Lin Wang; lin_wang{at}pku.edu.cn; Professor Cheng-Feng Qin; qincf{at}bmi.ac.cn

Abstract

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.

  • ACUTE HEPATITIS
  • HEPATITIS A
  • HEPATITIS E

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

https://doi.org/10.1136/gutjnl-2024-332784

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as online supplemental information.

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    Footnotes

    • TL and JL are joint first authors.

    • LW and C-FQ are joint senior authors.

    • X @LFM

    • Contributors C-FQ and LW supervised and designed the study. C-FQ and LW are the guarantors. TL and JL performed the experiments and collected data and samples. TL and JL analysed the data. LW, C-FQ, TL, JL, FL, and HZ drafted the manuscript. All authors have read and edited the manuscript. The authors have full editorial control of the paper and have provided their final approval for all the content.

    • Funding This study was funded by the National Key Research and Development Program of China, Grant/Award Number: 2023YFC2306900, 2021YFC2302400; National Natural Science Foundation of China, Grant/Award Number: 82002143; C-FQ was supported by the National Science Fund for Distinguished Young Scholars (No. 81925025) of the NSFC and the Innovation Fund for Medical Sciences (No.2019RU040) of the Chinese Academy of Medical Sciences (CAMS); Clinical Medicine Plus X—Young Scholars Project of Peking University, the Fundamental Research Funds for the Central Universities; Sanming Project of Medicine in Shenzhen (No. SZSM202311032).

    • Competing interests C-FQ, JL and HZ have filed a patent related to the technology reported in this manuscript.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.