Hypoxic and pharmacological activation of HIF inhibits SARS-CoV-2 infection of lung epithelial cells

Wing, P. A.C. et al. (2021) Hypoxic and pharmacological activation of HIF inhibits SARS-CoV-2 infection of lung epithelial cells. Cell Reports, 35(3), 109020. (doi: 10.1016/j.celrep.2021.109020) (PMID:33852916) (PMCID:PMC8020087)

Abstract

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.

• Item Type: Articles
• Additional Information: The McKeating laboratory is funded by a Wellcome Investigator Award (IA) 200838/Z/16/Z, UK Medical Research Council (MRC) project grant MR/R022011/1, and the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China (grant number: 2018-I2M-2-002). The Ratcliffe laboratory is funded by the Oxford Branch of the Ludwig Institute for Cancer Research; Wellcome IA 106241/Z/14/Z; the Francis Crick Institute, which receives core funding from Cancer Research UK (FC001501), UK MRC (FC001501), and Wellcome (FC001501); and the Paradifference Foundation. P.J.R., E.J.H., and T.B. are additionally funded by the COVID-19 Research Response Fund, University of Oxford. S.K. is funded by the Clarendon scholarships fund and the Christopher Welch Trust. The Davis laboratory is funded by Wellcome IA 209412/Z/17/Z and Wellcome Strategic Awards 091911/B/10/Z and 107457/Z/15/Z. J.Y.L. is funded by the Medial Sciences Graduate Studentship, University of Oxford. The Hinks laboratory is funded by grants from Wellcome (104553/z/ 14/z and 211050/Z/18/z) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre; the views expressed are those of the authors and not those of the NHS or NIHR.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Castello, Professor Alfredo and Noerenberg, Dr Marko
• Authors: Wing, P. A.C., Keeley, T. P., Zhuang, X., Lee, J. Y., Prange-Barczynska, M., Tsukuda, S., Morgan, S. B., Harding, A. C., Argles, I. L.A., Kurlekar, S., Noerenberg, M., Thompson, C. P., Huang, K.-Y. A., Balfe, P., Watashi, K., Castello, A., Hinks, T. S.C., James, W., Ratcliffe, P. J., Davis, I., Hodson, E. J., Bishop, T., and McKeating, J. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Cell Reports
• Publisher: Cell Press
• ISSN: 2211-1247
• ISSN (Online): 2211-1247
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Cell Reports 35(3):109020
• Publisher Policy: Reproduced under a Creative Commons License