We read with interest the article by Luxenburger and Thimme, summarising current knowledge about hepatic sequelae in the context of SARS-CoV-2 infection.1 As acute liver injury is observed in one-third of the patients with hospitalised COVID-192 3 and chronic liver disease is associated with higher mortality rates,4 a detailed understanding of hepatic susceptibility and dysfunction in the context of SARS-CoV-2 infection is of utmost importance. Previous studies have provided evidence of hepatic infection,5–7 however, the molecular mechanisms underlying acute liver injury associated with SARS-CoV-2 infection are not well understood. Here we show that primary human hepatocytes (PHH) can be productively infected with SARS-CoV-2. Donor-specific production kinetics were observed, with de novo viral secretion from PHH increasing in a time-dependent manner for four out of six donors (figure 1A). To explore virus replication and host gene dysregulation in parallel, Illumina sequencing of time point-matched infected and uninfected PHH was performed, followed by mapping to host and virus scaffolds. Increases in viral genome coverage over time corresponded to increasing rates of secreted virus (figure 1B). On the host side, detectable messenger RNA (mRNA) expression of known or suspected SARS-CoV-2 entry factors was observed for all PHH donors (figure 1C). Despite robust viral replication, host transcriptional responses were delayed until 72 hours post infection (hpi) and correlated with specific type III and interferon-β (IFN) induction in three donors (D1–3; termed reactive), while two donors remained unreactive, even though low levels of viral replication were observed (D4–5; figure 1C). These observations imply a viral replication threshold must be crossed to trigger robust host responses in PHH. Interestingly, one donor (D6; termed pre-activated) possessed abundant IFN-encoding transcripts independent of infection status or sampling time, resulting in high baseline interferon stimulated gene expression which prevented productive infection (figure 1A–C). Of note, similar …

中文翻译：

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SARS-CoV-2 人原代肝细胞的生产性感染可诱导抗病毒和促炎反应


我们饶有兴趣地阅读了 Luxenburger 和 Thimme 的文章，总结了当前有关 SARS-CoV-2 感染情况下肝脏后遗症的知识。1 三分之一的住院 COVID-192 3 和慢性肝损伤患者观察到急性肝损伤肝病与较高的死亡率相关，4 详细了解 SARS-CoV-2 感染背景下的肝易感性和功能障碍至关重要。先前的研究提供了肝脏感染的证据，5-7 然而，与 SARS-CoV-2 感染相关的急性肝损伤的分子机制尚不清楚。在这里，我们证明原代人肝细胞 (PHH) 可以有效地感染 SARS-CoV-2。观察到供体特异性生产动力学，六分之四的供体中，PHH 的从头病毒分泌量以时间依赖性方式增加（图 1A）。为了同时探索病毒复制和宿主基因失调，对时间点匹配的感染和未感染的 PHH 进行了 Illumina 测序，然后映射到宿主和病毒支架。随着时间的推移，病毒基因组覆盖率的增加对应于分泌病毒率的增加（图1B）。在宿主方面，所有 PHH 供体均观察到已知或疑似 SARS-CoV-2 进入因子的可检测信使 RNA (mRNA) 表达（图 1C）。尽管病毒复制强劲，但宿主转录反应延迟至感染后 72 小时 (hpi)，并与三名供体 (D1-3；称为反应性) 中的特定 III 型和干扰素-β (IFN) 诱导相关，而两名供体仍无反应，尽管观察到病毒复制水平较低（D4-5；图 1C）。 这些观察结果表明，必须跨越病毒复制阈值才能触发 PHH 中强烈的宿主反应。有趣的是，一名供体（D6；称为预激活）拥有丰富的 IFN 编码转录本，与感染状态或采样时间无关，导致高基线干扰素刺激基因表达，从而阻止了生产性感染（图 1A-C）。值得注意的是，类似...