Thogoto virus ML protein is a potent inhibitor of the interferon regulatory factor-7 transcription factor

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Thogoto virus (THOV) is a tick-borne orthomyxovirus.
• THOV possesses a viral suppressor of the RNA virus-sensing interferon (IFN) system, the ML protein.
• Understanding viral immune evasion mechanisms is crucial for antiviral strategies.

Purpose of the Study:

• To investigate the role of the THOV ML protein in suppressing the host type I IFN response.
• To elucidate the molecular mechanism by which ML antagonizes IFN induction.
• To identify the specific host factors targeted by ML.

Main Methods:

• Infection of primary mouse embryo fibroblasts and plasmacytoid dendritic cells with wild-type and ML-deficient THOV.
• Reporter gene assays to measure IFN regulatory factor (IRF) activation (IRF3 and IRF7).
• Co-immunoprecipitation assays to study protein-protein interactions between ML and IRF7, and TRAF6.
• Analysis of IRF7 nuclear translocation.

Main Results:

• THOV lacking ML strongly induces type I IFN, while wild-type THOV suppresses it.
• ML inhibits reporter gene expression dependent on IRF3 and IRF7.
• ML directly interacts with IRF7, preventing its dimerization and association with TRAF6.
• ML does not affect the nuclear translocation of IRF7.

Conclusions:

• The THOV ML protein is a key virulence factor that antagonizes the host type I IFN response.
• ML specifically targets IRF family members, inhibiting their activation upstream of nuclear translocation.
• ML acts by preventing IRF7 dimerization and subsequent TRAF6 association, thereby suppressing IFN induction.