Pseudorabies Virus DNA Polymerase Processivity Factor UL42 Inhibits Type I IFN Response by Preventing ISGF3-ISRE...

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Alphaherpesviruses establish persistent infections by evading host innate immunity, particularly type I interferon (IFN-I) responses.
• The molecular mechanisms underlying this immune evasion are not fully understood.

Purpose of the Study:

• To investigate the role of alphaherpesvirus UL42 protein in antagonizing the type I interferon signaling pathway.
• To elucidate the mechanism by which UL42 interferes with IFN-I-induced immune responses.

Main Methods:

• Ectopic expression of UL42 in porcine macrophage and human HeLa cells.
• Assessing IFN-α-mediated activation of the IFN-stimulated response element (ISRE).
• Investigating UL42 interaction with ISRE and ISG factor 3 (ISGF3) using mutagenesis of UL42 DNA-binding sites.
• Knockdown of UL42 in pseudorabies virus (PRV) infection models.

Main Results:

• UL42 protein from PRV and HSV-1 significantly suppresses IFN-α-induced ISRE activation and downstream IFN-stimulated gene (ISG) expression.
• UL42 directly binds to ISRE, preventing ISGF3 binding and subsequent gene transcription.
• Four conserved DNA-binding sites in UL42 are crucial for ISRE interaction and viral immune evasion.
• UL42 knockdown in PRV attenuates viral antagonism of the IFN response.

Conclusions:

• Alphaherpesvirus UL42 protein antagonizes IFN-I signaling by disrupting the ISGF3-ISRE complex, facilitating viral immune evasion.
• UL42 represents a novel molecular target for antiviral therapies against alphaherpesvirus infections.