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

 Highlights

  • •
    Severe IAV infection imparts a long-lasting decline in cardiac function
  • •
    Atypical GMP-independent CD319+ pro-DC3s transport infectious IAV to cardiomyocytes
  • •
    Direct IFN-I signaling on cardiomyocytes drives cardiac dysfunction
  • •
    mod-mRNA delivery of dominant-negative IFNAR1 on cardiomyocytes ameliorates damage

Summary

Abundant evidence has correlated influenza infection with cardiovascular disease, yet mechanisms linking infection with the heart remain poorly understood. Here, we show that influenza infection damaged the human and murine heart. In mice, we showed that shortly after pulmonary infection, the virus infected a circulating myeloid pro-dendritic cell 3 (pro-DC3) that expressed high concentrations of the chemokine receptor CCR2. The heart, which produces abundant CCL2, preferentially attracted infected pro-DC3. In the myocardium, the virus escaped pro-DC3, infected cardiomyocytes, and triggered production of type-I interferon (IFN-I). Engagement of the IFN-I receptor (IFNAR1) on cardiomyocytes caused tissue damage and compromised heart function. Genetically and therapeutically dampening IFNAR1 exclusively in cardiomyocytes protected the heart while preserving anti-viral immunity in the lung. Our results identify a series of host-pathogen interactions that propagate tissue damage and uncover an axis for intervention to mitigate cardiovascular risk following viral infection.

Read full article at:
https://www.sciencedirect.com/science/article/abs/pii/S1074761325005679



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