Metabolic reprogramming tips vaccinia virus infection outcomes by stabilizing interferon-γ induced IRF1

Area of Science:

• Immunology
• Cell Biology
• Metabolism

Background:

• Interferon (IFN)-induced activities, including interferon-stimulated genes (ISGs), are crucial for immune responses and infection outcomes.
• Aberrant ISG expression in diseases suggests regulatory layers beyond primary interferon signaling.
• Metabolic differences, particularly in glucose vs. galactose utilization, characterize tissue identity and influence virus susceptibility.

Purpose of the Study:

• To investigate the impact of distinct metabolic conditions (aerobic glycolysis via glucose vs. oxidative phosphorylation via galactose) on interferon-stimulated gene (ISG) expression.
• To explore how these metabolic states modulate the protein levels of key ISGs, such as IRF1 and IFITM3, in response to interferon stimulation.
• To determine the functional consequences of metabolic regulation of ISGs on viral replication.

Main Methods:

• Cultured human, mouse, and cat cells in media favoring either glucose (aerobic glycolysis) or galactose (oxidative phosphorylation).
• Stimulated cells with interferons (IFN-α, IFN-γ) and analyzed ISG RNA and protein expression.
• Utilized proteasome inhibition and IRF1 knockout (KO) models to assess regulatory mechanisms and viral replication dynamics.
• Infected cells with vaccinia virus (a poxvirus) and measured viral titers and protein expression under different metabolic and interferon conditions.

Main Results:

• Extended interferon priming led to divergent ISG protein expression: IRF1 was upregulated in IFN-γ/glucose, while IFITM3 increased in galactose.
• Glucose/galactose regulation of IFN-γ-induced IRF1 was conserved across species and dependent on proteasome activity.
• Glucose/IFN-γ treatment reduced vaccinia virus replication, an effect dependent on IRF1; this effect was lost in galactose media.
• A late-stage viral replication block affecting herpes- and poxvirus titers, but not protein expression, was associated with glucose/galactose conditions.

Conclusions:

• A novel regulatory layer for the ISG protein IRF1, mediated by glucose and galactose metabolism, has been identified.
• Metabolic sensing of nutrient availability by immune cells may rapidly adapt antiviral responses through embedded subprograms within the interferon pathway.
• These findings highlight the interplay between cellular metabolism and innate immunity, impacting viral control.