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.

中文翻译：

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重述戊型肝炎病毒与宿主的相互作用并促进人类肝源性类器官中抗病毒药物的发现

嗜肝病毒天然具有狭窄的宿主和组织嗜性，对稳健的实验模型的开发提出了挑战。类器官技术的出现为推动该领域向前发展提供了独特的机会。在这里，我们证明了具有胆管细胞或肝细胞表型的胎儿和成人肝脏的三维培养类器官支持戊型肝炎病毒 (HEV) 的复制。接种传染性 HEV 颗粒表明，人肝源性类器官支持 HEV 感染的整个生命周期。通过将类器官导向 transwell 系统中的极化单层，我们观察到 HEV 颗粒主要是顶端分泌。全基因组转录组学和 tRNAome 分析揭示了病毒复制引发的强烈宿主反应。类器官中的药物筛选发现 brequinar 和高三尖杉酯碱是有效的 HEV 抑制剂，它们也能有效对抗携带 G1634R 突变的利巴韦林耐药变异体。因此，在肝源性类器官中成功再现 HEV 感染将有助于病毒与宿主相互作用的研究和抗病毒疗法的开发。