Deficiency of HIF-1 alpha enhances influenza A virus replication by promoting autophagy in alveolar type II epithelial cells
Deficiency of HIF-1 alpha enhances influenza A virus replication by promoting autophagy in alveolar type II epithelial cells
复制标题
HIF-1 α 的缺乏通过促进 II 型肺泡上皮细胞的自噬来增强甲型流感病毒的复制
DOI：
10.1080/22221751.2020.1742585
复制
发表时间：
2020
影响因子：
13.2
通讯作者：
Su Xiao
中科院分区：
文献类型：
--
作者：
Zhao Caiqi;Chen Jie;Cheng Lianping;Xu Kaifeng;Yang Yiyu;Su Xiao
甲型流感病毒（IAV）感染可引起肺部炎症反应加剧，导致急性肺损伤（ALI）。限制IAV复制和减轻肺部炎症是治疗流感病毒感染的两个重要策略。近年来的研究表明，低氧诱导因子-1 α（HIF-1α）在急性肺损伤的发生、发展和修复中起重要作用，但其在IAV诱导的急性肺损伤中的作用及其机制尚不清楚。在这里，我们证明了感染IAV的肺上皮细胞特异性Hif 1 α基因敲除小鼠发生了更多的肺IAV复制和严重的肺部炎症，与感染IAV的对照小鼠相比，这导致死亡率增加。此外，在A549细胞（人肺泡II型上皮细胞系）中敲低HIF 1A促进IAV在体外的复制。从机制上讲，HIF 1A的敲低通过调节糖酵解相关酶的转录来减少糖酵解，随后激活AMPKα-ULK 1信号通路。有趣的是，AMPKα-ULK 1信号促进自噬并增强IAV复制。总之，肺上皮细胞中HIF-1α的缺乏减少了糖酵解并增强了AMPKα-ULK 1介导的自噬，最终促进了IAV的复制。这些发现加深了我们对HIF-1α在调节IAV复制中的作用的理解，并为我们提供了对抗流感感染的新的治疗靶点。
Infection of influenza A virus (IAV) can trigger exaggerated pulmonary inflammation and induce acute lung injury (ALI). Limiting IAV replication and alleviation of pulmonary inflammation are two important therapeutic strategies for influenza virus infection. Recent studies have shown that hypoxia inducible factor-1α (HIF-1α) is an essential factor for the development and repair of ALI; however, the role and the underlying mechanisms of HIF-1α in IAV-induced ALI remain elusive. Here, we demonstrated that lung epithelial cell-specificHif1αknockout mice infected with IAV developed more lung IAV replication and severe lung inflammation, which led to increased mortality compared to IAV-infected control mice. Moreover, knockdown ofHIF1Ain A549 cells (human alveolar type II epithelial cell line) promoted IAV replicationin vitro. Mechanistically, knockdown ofHIF1Areduced glycolysis by regulating transcription of glycolysis-related enzymes, which subsequently activated the AMPKα-ULK1 signalling pathway. Interestingly, AMPKα-ULK1 signalling promoted autophagy and augmented IAV replication. Taken together, deficiency of HIF-1α in lung epithelial cells reduces glycolysis and enhances AMPKα-ULK1-mediated autophagy, which finally facilitates IAV replication. These findings have deepened our understanding of the role of HIF-1α in regulating IAV replication and provided us novel therapeutic targets for combating influenza infection.