Influenza hijacks circulating myeloid cells to inflict Type-I Interferon-fueled damage in the heart
Infections by influenza A viruses remain a threat to human health. Although much of the virus's pathogenesis is confined to the lung, there is evidence that IAV inflames and damages other organs, including the heart. Our understanding of how this occurs, however, is lacking. Here, we identify a hijacked heart-lung axis, whereby influenza infects a relatively minor and ontologically unusual monocyte which preferentially migrates to the heart, differentiates into a cardiac macrophage, and disseminate the virus exclusively to cardiomyocytes, which then support active viral replication. The arrival of influenza in the heart initiates TLR3-dependent IFN-I production by myeloid cells, which signal through the IFN-I receptor (IFNAR1) on cardiomyocytes to cause damage and compromise heart function. Therapeutically dampening IFNAR1 on cardiomyocytes or limiting monocyte accumulation protects the heart while allowing for anti-viral immunity in the lung. Our results uncover an axis for intervention to mitigate cardiovascular risk following influenza infection. Overall design: All experiments were performed on sex- and age-matched mice between the ages of 5 and 12 weeks. In certain experiments, where indicated, aged mice were used. A group of mice were infected with Influenza A virus. Heart tissues from a group of infected and uninfected mice were extracted and single-nuclear RNA-seq (10X Genomics) was performed.