Ortega-Prieto A M, Skelton J K, Wai S N, Large E, Lussignol M, Vizcay-Barrena G, Hughes D, Fleck R A, Thursz M, Catanese M T, Dorner M
Section of Virology, Department of Medicine, Imperial College London, London, W2 1PG, UK.
Section of Hepatology, Department of Medicine, Imperial College London, London, W2 1NY, UK.
Nat Commun. 2018 Feb 14;9(1):682. doi: 10.1038/s41467-018-02969-8.
With more than 240 million people infected, hepatitis B virus (HBV) is a major health concern. The inability to mimic the complexity of the liver using cell lines and regular primary human hepatocyte (PHH) cultures pose significant limitations for studying host/pathogen interactions. Here, we describe a 3D microfluidic PHH system permissive to HBV infection, which can be maintained for at least 40 days. This system enables the recapitulation of all steps of the HBV life cycle, including the replication of patient-derived HBV and the maintenance of HBV cccDNA. We show that innate immune and cytokine responses following infection with HBV mimic those observed in HBV-infected patients, thus allowing the dissection of pathways important for immune evasion and validation of biomarkers. Additionally, we demonstrate that the co-culture of PHH with other non-parenchymal cells enables the identification of the cellular origin of immune effectors, thus providing a valuable preclinical platform for HBV research.
乙肝病毒（HBV）感染人数超过2.4亿，是一个重大的健康问题。使用细胞系和常规原代人肝细胞（PHH）培养物无法模拟肝脏的复杂性，这对研究宿主/病原体相互作用造成了重大限制。在此，我们描述了一种允许HBV感染的3D微流控PHH系统，该系统可维持至少40天。该系统能够重现HBV生命周期的所有步骤，包括患者来源的HBV复制和HBV共价闭合环状DNA（cccDNA）的维持。我们表明，HBV感染后的固有免疫和细胞因子反应与HBV感染患者中观察到的反应相似，从而能够剖析对免疫逃避重要的途径并验证生物标志物。此外，我们证明PHH与其他非实质细胞的共培养能够确定免疫效应器的细胞来源，从而为HBV研究提供了一个有价值的临床前平台。
