Nuffield Department of Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK.
Nuffield Department of Medicine, University of Oxford, Oxford, UK; Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
Cell Rep. 2021 Apr 20;35(3):109020. doi: 10.1016/j.celrep.2021.109020. Epub 2021 Apr 5.
COVID-19, caused by the novel coronavirus SARS-CoV-2, is a global health issue with more than 2 million fatalities to date. Viral replication is shaped by the cellular microenvironment, and one important factor to consider is oxygen tension, in which hypoxia inducible factor (HIF) regulates transcriptional responses to hypoxia. SARS-CoV-2 primarily infects cells of the respiratory tract, entering via its spike glycoprotein binding to angiotensin-converting enzyme 2 (ACE2). We demonstrate that hypoxia and the HIF prolyl hydroxylase inhibitor Roxadustat reduce ACE2 expression and inhibit SARS-CoV-2 entry and replication in lung epithelial cells via an HIF-1α-dependent pathway. Hypoxia and Roxadustat inhibit SARS-CoV-2 RNA replication, showing that post-entry steps in the viral life cycle are oxygen sensitive. This study highlights the importance of HIF signaling in regulating multiple aspects of SARS-CoV-2 infection and raises the potential use of HIF prolyl hydroxylase inhibitors in the prevention or treatment of COVID-19.
由新型冠状病毒 SARS-CoV-2 引起的 COVID-19 是一个全球性的健康问题，迄今为止已造成超过 200 万人死亡。病毒复制受细胞微环境影响，其中需要考虑的一个重要因素是氧张力，缺氧诱导因子（HIF）调节对缺氧的转录反应。SARS-CoV-2 主要感染呼吸道细胞，通过其刺突糖蛋白与血管紧张素转换酶 2（ACE2）结合进入细胞。我们证明，缺氧和 HIF 脯氨酰羟化酶抑制剂罗沙司他通过 HIF-1α 依赖性途径降低 ACE2 的表达并抑制肺上皮细胞中的 SARS-CoV-2 进入和复制。缺氧和罗沙司他抑制 SARS-CoV-2 RNA 复制，表明病毒生命周期中的进入后步骤对氧气敏感。这项研究强调了 HIF 信号在调节 SARS-CoV-2 感染的多个方面的重要性，并提出了 HIF 脯氨酰羟化酶抑制剂在预防或治疗 COVID-19 中的潜在用途。
