HIFs inhibit SARS-CoV-2 infection of lung epithelial cells

April 13, 2021—Cellular activation of hypoxia inducible factors (HIFs) by either oxygen starvation (hypoxia) or drug treatment inhibits SARS-CoV-2 entry and replication in lung epithelial cells, raising the possibility of using clinically licensed HIF activators to prevent and/or treat COVID-19.

HIF is a protein central to the body’s response to hypoxia. When oxygen is abundant, HIF is modified with hydroxyl chemical groups by the oxygen-sensing prolyl hydroxylase domain (PHD) enzymes, which target HIF for degradation. When oxygen levels are low, HIF is no longer hydroxylated by PHD enzymes and activates the expression of genes involved in responding to low oxygen, including genes regulating red blood cell production, cell metabolism, proliferation and immune regulation.

COVID-19 disease, caused by the novel coronavirus SARS-CoV-2, is characterised by low oxygen levels throughout the body. While previous studies have shown that hypoxia affects the replication of several viruses, including influenza A and HIV, it is not yet known whether hypoxia has an effect on SARS-CoV-2 infection. Understanding the interplay of hypoxia and SARS-CoV-2 infection would shed light on possible COVID-19 prevention or treatment strategies.

Peter Wing, Tom Keeley and colleagues from the laboratories of Ludwig Oxford’s Tammie Bishop and Sir Peter Ratcliffe, and the University of Oxford’s Jane McKeating demonstrate in cell culture and animal studies that activation of HIF, either by hypoxia or by pharmacological inhibition of the PHD enzymes, reduces levels of the receptor required for SARS-CoV-2 entry into host cells (ACE2) and markedly reduces the entry of SARS-CoV-2 into lung epithelial cells.

Their research, published in the journal Cell Reports, also reveals that hypoxia and PHD inhibition reduce SARS-CoV-2 replication in infected lung epithelial cells, including that of the recently emerged UK and South African variants. Taken together, these findings show that pharmacological activation of HIF inhibits several stages of the SARS-CoV-2 life cycle, including viral entry and genome replication.

The findings are promising because PHD inhibitors including Roxadustat, are clinically approved for the treatment of patients with chronic kidney disease. However, because the effects of HIF on the body are complex, further investigation in animal studies and clinical trials is needed to assess whether PHD inhibitors would have a net benefit in preventing or treating COVID-19.


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