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.

甲型流感病毒（influenza A viruses）感染仍是威胁人类健康的公共卫生隐患。尽管该病毒的多数致病进程局限于肺部，但已有研究证实，甲型流感病毒（influenza A viruses，下文简称IAV）可诱发包括心脏在内的多器官炎症与损伤。然而，目前学界对这一跨器官致病机制的认知仍存在空白。本研究鉴定出一条被病毒劫持的心-肺信号轴：流感病毒会侵染一类相对罕见且发育学上非常规的单核细胞，这类细胞会优先迁移至心脏，分化为心脏巨噬细胞，并将病毒特异性散播至心肌细胞，随后心肌细胞将支持病毒的活跃复制。流感病毒定植心脏后，会触发髓系细胞产生依赖于Toll样受体3（TLR3）的I型干扰素（IFN-I）；这类干扰素通过心肌细胞表面的I型干扰素受体（IFNAR1）传递信号，最终造成心肌损伤并损害心脏功能。在治疗策略上，抑制心肌细胞表面的IFNAR1或限制单核细胞向心脏聚集，既可实现心脏保护，又能保留肺部的抗病毒免疫应答能力。本研究结果揭示了一条可用于干预流感感染后心血管并发症的潜在靶点通路。整体实验设计：所有实验均使用性别与年龄匹配的5至12周龄小鼠开展。部分标注实验中采用老年小鼠。将一组小鼠接种甲型流感病毒，分别提取感染组与未感染组小鼠的心脏组织，进行单细胞核RNA测序（single-nuclear RNA-seq，10X Genomics）。