The segmented flavivirus ALSV-encoded nucleoprotein VP2 inhibits type I interferon production by targeting RIG-I

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Alongshan virus (ALSV) is a tick-borne segmented flavivirus causing human infections.
• ALSV antagonizes type I interferon (IFN-I) antiviral responses, but mechanisms are unclear.
• Understanding ALSV immune evasion is crucial for developing intervention strategies.

Purpose of the Study:

• To elucidate the mechanisms by which ALSV suppresses host IFN-I production.
• To identify specific ALSV viral proteins involved in antagonizing IFN-I signaling.
• To investigate the molecular interactions of ALSV proteins with host innate immune pathways.

Main Methods:

• ALSV infection of host cells and stimulation with poly(I:C).
• Systematic evaluation of individual ALSV viral proteins' effects on Toll-like receptor-mediated IFN-I production.
• Co-immunoprecipitation assays to detect protein-protein interactions.
• Western blotting and autophagy inhibitors to assess protein degradation pathways.

Main Results:

• ALSV infection significantly suppressed poly(I:C)-induced IFN-I production.
• Viral proteins VP2 and VP3 inhibited RIG-I-mediated IFN-I production.
• NSP2 and VP1b inhibited MDA5-mediated IFN-I production.
• Viral nucleoprotein VP2 directly interacts with RIG-I and promotes its autophagy-dependent degradation, impairing innate immune sensing.

Conclusions:

• ALSV employs multiple viral proteins to disrupt RIG-I and MDA5-mediated IFN-I production.
• VP2 is a key antagonist that degrades RIG-I via autophagy, hindering host antiviral response.
• These findings advance understanding of segmented flavivirus immune evasion and suggest targeting RIG-I as a therapeutic strategy.