RSAD2/VIPERIN and CMPK2 coordinate an immunometabolic response to Epstein-Barr Virus

Area of Science:

• Virology
• Immunology
• Cell Biology

Background:

• Epstein-Barr Virus (EBV) infection and reactivation in B-lymphocytes are controlled by host antiviral genes.
• Interferon-Stimulated Genes (ISGs) play a significant role in antiviral responses.

Purpose of the Study:

• To identify key ISGs modulating EBV expression and cellular response.
• To elucidate the roles of RSAD2 and CMPK2 in EBV infection and reactivation.

Main Methods:

• Gene expression analysis (upregulation of RSAD2 and CMPK2 during EBV infection).
• Gene depletion studies (RSAD2 and CMPK2 knockdown).
• Transcriptomic analysis to identify shared pathways.
• Metabolomic analysis to assess metabolic changes.

Main Results:

• RSAD2 and CMPK2 are upregulated during EBV infection and reactivation.
• RSAD2 depletion reduced cell viability and limited EBV reactivation.
• CMPK2 depletion promoted EBV lytic gene expression during latency.
• Both genes converge on immunometabolic pathways including IFN signaling, mitochondrial function, and UPR.
• RSAD2 and CMPK2 knockdown affected key signaling molecules (IRAK1, TRAF6, TAK1, NF-κB).
• Metabolomic analysis revealed remodeling of nucleotide metabolism, glycolysis, and fatty acid biosynthesis.
• RSAD2 is essential for the formation of antiviral ribonucleotide ddhCTP during lytic reactivation.

Conclusions:

• RSAD2 and CMPK2 form a coordinated ER-Mitochondria-Interferon signaling axis.
• This axis shapes EBV reactivation and host immune control.
• A novel immunometabolic regulatory mechanism modulates viral latency and reactivation.