Hypoxia inducible factors regulate Pneumovirus replication by enhancing innate immune sensing

This study explores the role of the hypoxic inducible factor (HIF) signalling pathway in
limiting pneumoviral infections, such as respiratory syncytial virus (hRSV) and pneumonia
virus of mice (PVM). 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.