Interferon Signaling-Dependent Contribution of Glycolysis to Rubella Virus Infection

Area of Science:

• Immunology
• Virology
• Cell Biology

Background:

• Interferons (IFNs) are crucial for innate and adaptive immunity.
• Type I and Type III IFNs play distinct roles in antiviral defense.

Purpose of the Study:

• To investigate the roles of type I and type III IFN receptors in rubella virus (RuV) infection.
• To elucidate the interplay between IFN signaling and cellular metabolism during RuV infection.

Main Methods:

• Loss-of-function analysis using A549 respiratory epithelial cells with knockouts (KO) of type I IFN receptor (IFNAR) and/or type III IFN receptor (IFNLR1).
• Assessment of RuV genome replication and viral protein synthesis.
• Extracellular flux analysis to evaluate cellular bioenergetics (glycolysis and mitochondrial respiration).
• Treatment with 2-deoxy-D-glucose (2-DG) to assess the role of glycolysis.

Main Results:

• Complete knockout of both IFNAR and IFNLR1 receptors significantly enhanced RuV genome replication and viral protein synthesis compared to control and IFNAR KO cells.
• Type III IFN signaling influenced the generation of IFN-beta during RuV infection; extracellular IFN-beta was undetectable in IFNAR/IFNLR1 KO cells.
• RuV-infected IFNAR/IFNLR1 KO cells showed increased glycolysis, while mitochondrial respiration remained comparable across cell types.
• 2-DG treatment increased viral protein synthesis in control cells but had no effect on IFNAR/IFNLR1 KO cells, indicating an IFN signaling-dependent role for glycolysis.

Conclusions:

• Type III IFN signaling positively regulates IFN-beta generation during RuV infection.
• Glycolysis contributes to RuV infection in an IFN signaling-dependent manner.
• Type III IFNs exhibit antiviral activity against RuV, and their absence, along with type I IFNs, significantly enhances viral replication.