The 5' noncoding sequences from a less virulent Theiler's virus dramatically attenuate GDVII neurovirulence

Area of Science:

• Neurovirology
• Molecular Pathogenesis
• Immunology

Background:

• Theiler's murine encephalomyelitis virus (TMEV) causes neurological disease.
• GDVII and BeAn are TMEV strains with differing virulence and persistence.
• Understanding TMEV molecular pathogenesis is crucial for disease control.

Purpose of the Study:

• To investigate the molecular basis of TMEV pathogenesis using recombinant viruses.
• To determine the role of specific viral sequences in neurovirulence and persistence.

Main Methods:

• Construction of recombinant TMEV chimeras between GDVII and BeAn strains.
• Infection of mice with parental and chimeric viruses.
• Analysis of viral replication, neurovirulence, antigen distribution, histopathology, and immune responses.

Main Results:

• Chimera 2, containing BeAn 5' noncoding sequences, exhibited significantly reduced GDVII neurovirulence.
• Reduced neurovirulence correlated with slower virus growth and lower peak titers in the central nervous system.
• Chimera 2 was cleared from the CNS, unlike persistent BeAn, suggesting BeAn polyprotein or 3' sequences are vital for persistence.
• Localized, non-progressive demyelinating lesions were observed in chimera 2-infected mice.

Conclusions:

• BeAn 5' noncoding sequences attenuate GDVII neurovirulence.
• Viral persistence, potentially mediated by BeAn polyprotein or 3' sequences, is necessary for sustained demyelination.
• Non-progressive demyelination can occur without viral persistence, but progression requires it.