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

Cell Rep. 2021 Apr 20;35(3):109020. doi: 10.1016/j.celrep.2021.109020. Epub 2021 Apr 5.

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.

Keywords: hypoxia, HIF, SARS-CoV-2, HIF prolyl hydroxylase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • COVID-19 / drug therapy
  • COVID-19 / metabolism*
  • COVID-19 / pathology
  • Caco-2 Cells
  • Cell Hypoxia / drug effects
  • Chlorocebus aethiops
  • Epithelial Cells / metabolism*
  • Epithelial Cells / virology
  • Glycine / analogs & derivatives*
  • Glycine / pharmacology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Isoquinolines / pharmacology*
  • Lung / metabolism*
  • Lung / virology
  • Mice
  • SARS-CoV-2 / physiology*
  • Vero Cells
  • Virus Internalization / drug effects*
  • Virus Replication / drug effects*

Substances

  • FG-4592
  • HIF1A protein, human
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Isoquinolines
  • Glycine