Influenza hijacks myeloid cells to inflict type-I interferon-fueled damage in the heart.

Summary

This mechanistic study shows that influenza-infected CCR2+ pro-DC3 myeloid cells home to the heart, where the virus spreads to cardiomyocytes and activates IFNAR1 signaling to drive tissue injury and functional impairment. Cardiomyocyte-specific dampening of IFNAR1 protects the heart without compromising pulmonary antiviral immunity.

Key Findings

• CCR2high circulating pro-DC3 myeloid cells become infected after pulmonary influenza and are chemoattracted to the CCL2-rich heart.
• Infected pro-DC3 release virus in the myocardium, leading to cardiomyocyte infection, IFN-I production, and IFNAR1-dependent tissue injury and dysfunction.
• Cardiomyocyte-specific genetic/therapeutic dampening of IFNAR1 protects cardiac tissue without impairing lung antiviral immunity.

Clinical Implications

Suggests that transient, cardiomyocyte-targeted modulation of IFN-I signaling could prevent cardiac complications of influenza while preserving antiviral defenses; informs risk stratification and therapeutic development.

Limitations

• Preclinical nature limits immediate translation; optimal timing and safety of IFNAR1 modulation in humans remain unknown.
• Specificity to influenza strains and generalizability to other respiratory viruses require further study.

Future Directions

Evaluate cardiomyocyte-targeted IFNAR1/cGAS–STING pathway modulation in large animal models; identify biomarkers (e.g., CCR2+ pro-DC3 signatures) for early cardiac risk stratification in influenza.