Interferon Regulatory Factor 3 Exacerbates the Severity of COVID-19 in Mice.

Summary

In K18-ACE2 mice, IRF3 deficiency protected against severe SARS-CoV-2 disease, lowering mortality and disease scores without reducing lung viral load. IRF3 amplified IFN-β and inflammatory cytokines, indicating a detrimental inflammatory role in severe COVID-19.

Key Findings

• IRF3-deficient K18-ACE2 mice had reduced mortality (84.6% vs. 100%) and lower disease scores following SARS-CoV-2 infection.
• Lung viral loads were similar regardless of IRF3 presence, indicating disease severity was not due to impaired viral control.
• IRF3 increased pulmonary IFN-β and altered cytokine profiles, linking IRF3 activation to harmful inflammation.

Clinical Implications

Therapies dampening IRF3 signaling or modulating type I IFN timing might reduce hyperinflammation in severe COVID-19/ARDS without compromising viral clearance.

Limitations

• K18-ACE2 model may overexpress ACE2 and not fully recapitulate human disease.
• Mouse findings require validation in human tissues and clinical contexts.

Future Directions

Evaluate IRF3/IFN pathway modulators in preclinical ARDS/COVID models and investigate IRF3 activity signatures in patients to guide therapeutic timing.