Hypoxia inducible factors regulate pneumovirus replication by enhancing innate immune sensing

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• Immune mechanisms in pneumoviral infections remain unclear.
• Hypoxia-inducible factor (HIF) signaling's role in antiviral immunity is under investigation.

Purpose of the Study:

• To investigate the impact of HIF activation on pneumoviral infection and immune responses.
• To explore daprodustat's antiviral effects and underlying mechanisms.

Main Methods:

• Pharmacological activation of HIF using daprodustat in mouse models (PVM) and human cell cultures (hRSV).
• Transcriptomic analysis to assess immune gene expression.
• Investigation of type I interferon and RIG-I signaling pathways.
• Analysis of N6-methyladenosine modification on viral RNA.

Main Results:

• Daprodustat limited viral replication in PVM-infected mice and hRSV-infected cells.
• HIF activation upregulated innate immune genes, including ISG15.
• Antiviral effects were dependent on type I interferon and RIG-I signaling.
• Daprodustat enhanced viral RNA sensing and reduced viral RNA methylation via RNA demethylases.

Conclusions:

• HIF signaling plays a crucial role in antiviral immunity against pneumoviruses.
• Daprodustat's mechanism involves enhanced viral RNA sensing and modified RNA processing.
• HIF activation presents a potential therapeutic avenue for pneumoviral infections.