Hypoxia inducible factors regulate Pneumovirus replication by enhancing innate immune sensing

Using Daprodustat, a clinically approved activator of HIF signalling we demonstrated that stimulation of this pathway enhanced innate immune signalling and limited viral replication. Transcriptomic analysis showed that HIF promoted innate immune response genes in mice infected with PVM and human airway epithelial cells infected with hRSV.

Importantly, inhibition of type I interferon signalling or the RIG-I sensing pathway abrogated the antiviral activity of HIF. We uncovered a role for HIF to regulate the levels of N6-methyladenosine modification of viral RNA transcripts, resulting in the increased activation of nucleic acid sensing.