Inhibition of mRNA export and dimerization of interferon regulatory factor 3 by Theiler's virus leader protein

Area of Science:

• Neurovirology
• Molecular Virology
• Immunology

Background:

• Theiler's murine encephalomyelitis virus (TMEV) causes chronic demyelinating disease and lifelong central nervous system persistence.
• The viral L protein is crucial for persistence, inhibiting type I interferon (IFN) gene transcription and altering host protein localization.

Purpose of the Study:

• To investigate the mechanisms by which the TMEV L protein affects host protein expression and IFN responses.
• To elucidate the role of L protein in viral persistence and pathogenesis.

Main Methods:

• Reporter gene assays (GFP, luciferase) to assess protein synthesis inhibition.
• Analysis of mRNA export, nucleocytoplasmic transport, and protein phosphorylation (Nup98).
• Investigation of IFN regulatory factor 3 (IRF-3) dimerization and gene transcription (IFN, chemokines, cytokines).
• In vivo studies using TMEV mutants in IFN receptor-deficient and competent mice.

Main Results:

• L protein expression globally shut off host protein synthesis by blocking cellular mRNA export, not transcription or translation.
• This mRNA export blockade correlated with Nup98 phosphorylation.
• L protein inhibited IFN gene transcription by preventing IRF-3 dimerization, affecting other cytokine/chemokine genes.
• In vivo, L protein's IFN antagonism was critical early in infection for viral fitness in IFN-competent hosts.

Conclusions:

• TMEV L protein employs distinct mechanisms to antagonize host immunity and protein synthesis: blocking mRNA export and inhibiting IRF-3-mediated transcription.
• These functions likely contribute significantly to TMEV's persistence and pathogenesis in the CNS.
• The interplay between nuclear pore complex dysfunction and IRF-3 inhibition warrants further investigation.