Triple IFN pathway deficiency sensitizes mice to human respiratory virus infection independent of human viral receptor expression.

Summary

The authors created a triple interferon-receptor knockout (IFNAR/IFNGR/IFNLR) mouse (AGL) that supports infection by multiple human respiratory viruses without human receptor expression. Findings reveal a layered interferon defense with type III IFN acting as a backup to type I/II and demonstrate the model’s value for pathogenesis and antiviral testing across diverse viral families.

Key Findings

• One-step knockout of IFNAR, IFNGR, and IFNLR (AGL mice) permits robust infection by diverse human respiratory viruses without human receptor expression.
• Type III interferon signaling functions as a secondary antiviral frontline beneath type I/II pathways.
• Proof-of-concept antiviral studies (MPXV, PIV) demonstrate the model’s translational utility for therapeutic testing.

Clinical Implications

While preclinical, the AGL model can accelerate translational pipelines by enabling in vivo efficacy and safety testing of antivirals and vaccines across multiple respiratory viruses, informing preparedness strategies.

Limitations

• Global interferon pathway ablation creates an extreme susceptibility state that does not reflect typical human immunity.
• Model may overestimate pathogenicity or tissue tropism compared with immunocompetent hosts.

Future Directions

Refine compartment- or cell-specific interferon deficiencies to model differential host defenses, expand antiviral/vaccine testing breadth, and integrate humanized immune components for better translational fidelity.