Developing Broad-Spectrum Antivirals Using Porcine and Rhesus Macaque Models

Area of Science:

• Immunology
• Virology

Background:

• Human ISG15 deficiency confers stable, low-level antiviral protection.
• Murine ISG15 pathway differs from humans, necessitating alternative models for antiviral development.

Purpose of the Study:

• To identify animal models that recapitulate human ISG15 deficiency for developing ISG15-targeting antivirals.
• To investigate the role of the ISG15/USP18 axis in controlling type I interferon signaling across species.

Main Methods:

• Comparative analysis of ISG15 and USP18 function in canine, porcine, rhesus macaque, and human systems.
• Assessment of interferon-stimulated gene (ISG) expression and antiviral protection in ISG15-knockout porcine and rhesus cells.

Main Results:

• Canine, porcine, and rhesus ISG15, similar to human ISG15, stabilize USP18, a type I interferon (IFN-I) inhibitor.
• ISG15-knockout porcine and rhesus cells showed enhanced ISG expression and protection against vesicular stomatitis Indiana virus compared to wild-type cells.
• Demonstrated interspecies variability in the ISG15/USP18 axis's control over IFN-I signaling.

Conclusions:

• ISG15-deficient porcine and rhesus macaques serve as valuable models for studying ISG15 function and developing broad-spectrum antivirals.
• The ISG15/USP18 axis exhibits diverse regulatory roles in IFN-I signaling across species, highlighting therapeutic potential.