A role for Z-DNA binding in vaccinia virus pathogenesis

Area of Science:

• Virology
• Molecular Biology
• Structural Biology

Background:

• The N-terminal domain of the vaccinia virus E3L protein shares sequence similarity with Z-DNA binding proteins.
• This E3L domain is crucial for vaccinia virus pathogenicity in mice.
• Z-DNA is a left-handed helical conformation of DNA.

Purpose of the Study:

• To investigate the role of Z-DNA binding by the E3L protein in vaccinia virus pathogenicity.
• To determine if Z-DNA binding is essential for E3L protein's pathogenic activity.
• To explore the potential for developing antiviral agents targeting E3L's Z-DNA binding capability.

Main Methods:

• Construction of chimeric viruses with substituted Z-DNA binding domains.
• Introduction of mutations to decrease Z-DNA binding in both chimeric and wild-type E3L proteins.
• Assessment of viral pathogenicity in mice following intracranial inoculation.

Main Results:

• Chimeric viruses with Z-DNA binding domains retained lethality, while those without were not pathogenic.
• Mutations reducing Z-DNA binding in chimeras and wild-type E3L correlated with decreased pathogenicity.
• A mutation enabling Z-DNA binding in a non-pathogenic chimera rendered the virus lethal.

Conclusions:

• Z-DNA binding is essential for the pathogenic activity of the vaccinia virus E3L protein.
• These findings support the development of antiviral therapies targeting E3L's Z-DNA binding.
• This approach could be effective against variola (smallpox) virus due to its similar E3L protein.