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Recapitulating hepatitis E virus–host interactions and facilitating antiviral drug discovery in human liver–derived organoids

Hepatotropic viruses naturally have narrow host and tissue tropisms, challenging the development of robust experimental models. The advent of organoid technology provides a unique opportunity for moving the field forward. Here, we demonstrate that three-dimensional cultured organoids from fetal and...

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Autores principales: Li, Pengfei, Li, Yunlong, Wang, Yijin, Liu, Jiaye, Lavrijsen, Marla, Li, Yang, Zhang, Ruyi, Verstegen, Monique M. A., Wang, Yining, Li, Tian-Cheng, Ma, Zhongren, Kainov, Denis E., Bruno, Marco J., de Man, Robert A., van der Laan, Luc J. W., Peppelenbosch, Maikel P., Pan, Qiuwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8769558/
https://www.ncbi.nlm.nih.gov/pubmed/35044825
http://dx.doi.org/10.1126/sciadv.abj5908
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author Li, Pengfei
Li, Yunlong
Wang, Yijin
Liu, Jiaye
Lavrijsen, Marla
Li, Yang
Zhang, Ruyi
Verstegen, Monique M. A.
Wang, Yining
Li, Tian-Cheng
Ma, Zhongren
Kainov, Denis E.
Bruno, Marco J.
de Man, Robert A.
van der Laan, Luc J. W.
Peppelenbosch, Maikel P.
Pan, Qiuwei
author_facet Li, Pengfei
Li, Yunlong
Wang, Yijin
Liu, Jiaye
Lavrijsen, Marla
Li, Yang
Zhang, Ruyi
Verstegen, Monique M. A.
Wang, Yining
Li, Tian-Cheng
Ma, Zhongren
Kainov, Denis E.
Bruno, Marco J.
de Man, Robert A.
van der Laan, Luc J. W.
Peppelenbosch, Maikel P.
Pan, Qiuwei
author_sort Li, Pengfei
collection PubMed
description Hepatotropic viruses naturally have narrow host and tissue tropisms, challenging the development of robust experimental models. The advent of organoid technology provides a unique opportunity for moving the field forward. Here, we demonstrate that three-dimensional cultured organoids from fetal and adult human liver with cholangiocyte or hepatocyte phenotype support hepatitis E virus (HEV) replication. Inoculation with infectious HEV particles demonstrates that human liver–derived organoids support the full life cycle of HEV infection. By directing organoids toward polarized monolayers in a transwell system, we observed predominantly apical secretion of HEV particles. Genome-wide transcriptomic and tRNAome analyses revealed robust host responses triggered by viral replication. Drug screening in organoids identified brequinar and homoharringtonine as potent HEV inhibitors, which are also effective against the ribavirin resistance variant harboring G1634R mutation. Thus, successful recapitulation of HEV infection in liver-derived organoids shall facilitate the study of virus-host interactions and development of antiviral therapies.
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spelling pubmed-87695582022-02-01 Recapitulating hepatitis E virus–host interactions and facilitating antiviral drug discovery in human liver–derived organoids Li, Pengfei Li, Yunlong Wang, Yijin Liu, Jiaye Lavrijsen, Marla Li, Yang Zhang, Ruyi Verstegen, Monique M. A. Wang, Yining Li, Tian-Cheng Ma, Zhongren Kainov, Denis E. Bruno, Marco J. de Man, Robert A. van der Laan, Luc J. W. Peppelenbosch, Maikel P. Pan, Qiuwei Sci Adv Biomedicine and Life Sciences Hepatotropic viruses naturally have narrow host and tissue tropisms, challenging the development of robust experimental models. The advent of organoid technology provides a unique opportunity for moving the field forward. Here, we demonstrate that three-dimensional cultured organoids from fetal and adult human liver with cholangiocyte or hepatocyte phenotype support hepatitis E virus (HEV) replication. Inoculation with infectious HEV particles demonstrates that human liver–derived organoids support the full life cycle of HEV infection. By directing organoids toward polarized monolayers in a transwell system, we observed predominantly apical secretion of HEV particles. Genome-wide transcriptomic and tRNAome analyses revealed robust host responses triggered by viral replication. Drug screening in organoids identified brequinar and homoharringtonine as potent HEV inhibitors, which are also effective against the ribavirin resistance variant harboring G1634R mutation. Thus, successful recapitulation of HEV infection in liver-derived organoids shall facilitate the study of virus-host interactions and development of antiviral therapies. American Association for the Advancement of Science 2022-01-19 /pmc/articles/PMC8769558/ /pubmed/35044825 http://dx.doi.org/10.1126/sciadv.abj5908 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Li, Pengfei
Li, Yunlong
Wang, Yijin
Liu, Jiaye
Lavrijsen, Marla
Li, Yang
Zhang, Ruyi
Verstegen, Monique M. A.
Wang, Yining
Li, Tian-Cheng
Ma, Zhongren
Kainov, Denis E.
Bruno, Marco J.
de Man, Robert A.
van der Laan, Luc J. W.
Peppelenbosch, Maikel P.
Pan, Qiuwei
Recapitulating hepatitis E virus–host interactions and facilitating antiviral drug discovery in human liver–derived organoids
title Recapitulating hepatitis E virus–host interactions and facilitating antiviral drug discovery in human liver–derived organoids
title_full Recapitulating hepatitis E virus–host interactions and facilitating antiviral drug discovery in human liver–derived organoids
title_fullStr Recapitulating hepatitis E virus–host interactions and facilitating antiviral drug discovery in human liver–derived organoids
title_full_unstemmed Recapitulating hepatitis E virus–host interactions and facilitating antiviral drug discovery in human liver–derived organoids
title_short Recapitulating hepatitis E virus–host interactions and facilitating antiviral drug discovery in human liver–derived organoids
title_sort recapitulating hepatitis e virus–host interactions and facilitating antiviral drug discovery in human liver–derived organoids
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8769558/
https://www.ncbi.nlm.nih.gov/pubmed/35044825
http://dx.doi.org/10.1126/sciadv.abj5908
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