Influenza A virus (IAV) is a lytic RNA virus that triggers receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated pathways of apoptosis and mixed lineage kinase domain-like pseudokinase (MLKL)-dependent necroptosis in infected cells. ZBP1 initiates RIPK3-driven cell death by sensing IAV RNA and activating RIPK3. Here, we show that replicating IAV generates Z-RNAs, which activate ZBP1 in the nucleus of infected cells. ZBP1 then initiates RIPK3-mediated MLKL activation in the nucleus, resulting in nuclear envelope disruption, leakage of DNA into the cytosol, and eventual necroptosis. Cell death induced by nuclear MLKL was a potent activator of neutrophils, a cell type known to drive inflammatory pathology in virulent IAV disease. Consequently, MLKL-deficient mice manifest reduced nuclear disruption of lung epithelia, decreased neutrophil recruitment into infected lungs, and increased survival following a lethal dose of IAV. These results implicate Z-RNA as a new pathogen-associated molecular pattern and describe a ZBP1-initiated nucleus-to-plasma membrane “inside-out” death pathway with potentially pathogenic consequences in severe cases of influenza.

甲型流感病毒（IAV）是一种裂解性RNA病毒，可在感染细胞中触发受体相互作用的丝氨酸/苏氨酸蛋白激酶3（RIPK3）介导的凋亡途径和混合谱系激酶域样假激酶（MLKL）依赖性坏死病。ZBP1通过感应IAV RNA并激活RIPK3来引发RIPK3驱动的细胞死亡。在这里，我们表明复制IAV会生成Z-RNA，从而激活被感染细胞核中的ZBP1。然后，ZBP1在核中启动RIPK3介导的MLKL活化，导致核被膜破坏，DNA泄漏到细胞质中并最终坏死。核MLKL诱导的细胞死亡是嗜中性粒细胞的有效激活剂，嗜中性粒细胞是一种已知类型，可在强毒IAV疾病中引起炎症病理。因此，MLKL缺陷小鼠表现出减少的肺上皮细胞核破坏，致死剂量的IAV可以减少中性粒细胞向感染肺部的募集，并提高生存率。这些结果暗示Z-RNA是一种新的病原体相关分子模式，并描述了ZBP1启动的核到质膜“由内而外”的死亡途径，在严重的流感病例中具有潜在的病原学后果。