Influenza virus infection causes considerable morbidity and mortality, but current therapies have limited efficacy. We hypothesized that investigating the metabolic signaling during infection may help to design innovative antiviral approaches. Using bronchoalveolar lavages of infected mice, we here demonstrate that influenza virus induces a major reprogramming of lung metabolism. We focused on mitochondria-derived succinate that accumulated both in the respiratory fluids of virus-challenged mice and of patients with influenza pneumonia. Notably, succinate displays a potent antiviral activity in vitro as it inhibits the multiplication of influenza A/H1N1 and A/H3N2 strains and strongly decreases virus-triggered metabolic perturbations and inflammatory responses. Moreover, mice receiving succinate intranasally showed reduced viral loads in lungs and increased survival compared to control animals. The antiviral mechanism involves a succinate-dependent posttranslational modification, that is, succinylation, of the viral nucleoprotein at the highly conserved K87 residue. Succinylation of viral nucleoprotein altered its electrostatic interactions with viral RNA and further impaired the trafficking of viral ribonucleoprotein complexes. The finding that succinate efficiently disrupts the influenza replication cycle opens up new avenues for improved treatment of influenza pneumonia.

中文翻译：

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宿主琥珀酸盐通过病毒核蛋白的琥珀酰化和细胞核滞留抑制流感病毒感染

流感病毒感染导致相当大的发病率和死亡率，但目前的治疗效果有限。我们假设研究感染期间的代谢信号可能有助于设计创新的抗病毒方法。使用受感染小鼠的支气管肺泡灌洗液，我们在此证明流感病毒诱导肺代谢的主要重编程。我们专注于线粒体衍生的琥珀酸，这种琥珀酸在病毒攻击小鼠和流感肺炎患者的呼吸液中积累。值得注意的是，琥珀酸盐在体外显示出有效的抗病毒活性因为它抑制流感 A/H1N1 和 A/H3N2 病毒株的繁殖，并强烈降低病毒引发的代谢扰动和炎症反应。此外，与对照动物相比，鼻内接受琥珀酸的小鼠肺部病毒载量减少，存活率增加。抗病毒机制涉及高度保守的K87残基处病毒核蛋白的琥珀酸依赖性翻译后修饰，即琥珀酰化。病毒核蛋白的琥珀酰化改变了其与病毒 RNA 的静电相互作用，并进一步损害了病毒核糖核蛋白复合物的运输。琥珀酸盐有效破坏流感复制周期的发现为改进流感肺炎的治疗开辟了新途径。