Article Text

PDF

Original article
Characterisation of liver pathogenesis, human immune responses and drug testing in a humanised mouse model of HCV infection
  1. Choong Tat Keng1,
  2. Ching Wooen Sze2,
  3. Dahai Zheng1,
  4. Zhiqiang Zheng1,
  5. Kylie Su Mei Yong1,
  6. Shu Qi Tan3,
  7. Jessica Jie Ying Ong1,
  8. Sue Yee Tan1,
  9. Eva Loh4,
  10. Megha Haridas Upadya2,
  11. Chik Hong Kuick4,
  12. Hak Hotta5,
  13. Seng Gee Lim6,7,
  14. Thiam Chye Tan3,8,
  15. Kenneth T E Chang4,8,
  16. Wanjin Hong1,
  17. Jianzhu Chen9,10,
  18. Yee-Joo Tan1,2,
  19. Qingfeng Chen1,2,9
  1. 1Institute of Molecular and Cell Biology, Singapore, Singapore
  2. 2Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
  3. 3Department of Obstetrics & Gynaecology, KK Women's and Children's Hospital, Singapore, Singapore
  4. 4Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore, Singapore
  5. 5Division of Microbiology, Kobe University Graduate School of Medicine, Hyogo, Japan
  6. 6Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
  7. 7Department of Gastroenterology and Hepatology, National University Health System, Singapore, Singapore
  8. 8Duke-NUS Graduate Medical School, Singapore, Singapore
  9. 9Interdisciplinary Research Group in Infectious Diseases, Singapore-Massachusetts Institute of Technology Alliance for Research and Technology, Singapore, Singapore
  10. 10The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
  1. Correspondence to Dr Qingfeng Chen, Institute of Molecular and Cell Biology, Proteos, 61 Biopolis Drive, Singapore 138673, Singapore; qchen{at}imcb.a-star.edu.sg Dr Yee-Joo Tan, Department of Microbiology, MD4, Level 3, 5 Science Drive 2, National University of Singapore, Singapore 117597, Singapore; yee_joo_tan@nuhs.edu.sg

Abstract

Objective HCV infection affects millions of people worldwide, and many patients develop chronic infection leading to liver cancers. For decades, the lack of a small animal model that can recapitulate HCV infection, its immunopathogenesis and disease progression has impeded the development of an effective vaccine and therapeutics. We aim to provide a humanised mouse model for the understanding of HCV-specific human immune responses and HCV-associated disease pathologies.

Design Recently, we have established human liver cells with a matched human immune system in NOD-scid Il2rg−/− (NSG) mice (HIL mice). These mice are infected with HCV by intravenous injection, and the pathologies are investigated.

Results In this study, we demonstrate that HIL mouse is capable of supporting HCV infection and can present some of the clinical symptoms found in HCV-infected patients including hepatitis, robust virus-specific human immune cell and cytokine responses as well as liver fibrosis and cirrhosis. Similar to results obtained from the analysis of patient samples, the human immune cells, particularly T cells and macrophages, play critical roles during the HCV-associated liver disease development in the HIL mice. Furthermore, our model is demonstrated to be able to reproduce the therapeutic effects of human interferon alpha 2a antiviral treatment.

Conclusions The HIL mouse provides a model for the understanding of HCV-specific human immune responses and HCV-associated disease pathologies. It could also serve as a platform for antifibrosis and immune-modulatory drug testing.

  • HEPATITIS C
  • FIBROSIS
  • CYTOKINES
  • IMMUNOLOGY
  • IMMUNE-MEDIATED LIVER DAMAGE

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Statistics from Altmetric.com

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.