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.
Bibliographical noteFunding Information:
This research is supported by funding of the educational committee of Guangdong for specific program of key scientific research (2021ZDZX2016), National Natural Science Foundation of China (81802020 and 31770186), and Shenzhen government and SUSTech for talent research start-up funding (Y01416122 and Y01416222) to Yijin Wang; a VIDI grant (no. 91719300) from the Netherlands Organization for Scientific Research and the Dutch Cancer Society Young Investigator Grant (10140) to Q.P.; the European Regional Development Fund to the Mobilitas Pluss Project (MOBTT39) from Estonian Research Council to D.E.K.; and the China Scholarship Council for funding PhD fellowship to P.L. (no. 201808370170).
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