缺氧诱导因子1α在流感病毒感染中的作用及其分子机制研究

Infection of Influenza A virus (IAV) can trigger exaggerated pulmonary inflammation and induce acute lung injury (ALI). Limitation of influenza virus replication and alleviation of pulmonary inflammation are the key to the treatment of influenza virus infection. Recent studies have showed that HIF1α is an essential factor for the development and repair of ALI; however, the role and concrete mechanisms of HIF1α in IAV-induced ALI remain elusive. In our preliminary experiments, we found that knockdown of HIF1α in lung epithelial cells led to down-regulation of several genes that encode the enzymes involved in the cell glycolysis pathway, autophagy enhancement and higher influenza virus replication; loss of HIF1α in macrophages impaired alternative macrophage activation; granulocyte specific Hif1α knockout mice infected with IAV developed more severe lung inflammation and had an increased mortality compared to IAV-infected control mice. Here, we hypothesized that HIF1α could affect influenza virus replication in lung epithelial cells and alternative macrophage activation which define the development and prognosis of IAV-induced ALI. Therefore, the objectives of this project will be to investigate whether and how HIF1α is implicated in the influenza virus replication and alternative macrophage activation during the IAV-induced ALI and explore novel therapeutic targets for this deadly disease.

流感病毒（IAV）感染可以诱发急性肺部炎症反应，重症导致急性肺损伤（ALI）。控制流感病毒复制与减轻肺部炎症反应是治疗流感病毒感染的关键。研究表明HIF1α是ALI炎症和修复中的关键因子，但其在流感病毒感染诱发ALI中的作用和机制尚未被阐明。我们预实验发现上皮细胞中敲低HIF1α后，糖酵解酶基因转录水平显著降低，细胞自噬作用增强，流感病毒复制增多；巨噬细胞中HIF1α缺失导致巨噬细胞II型极化诱导障碍，小鼠感染流感病毒后肺部炎症加重，死亡率增高。据此我们假设HIF1α参与流感病毒感染时上皮细胞中病毒复制和巨噬细胞II型极化，进而影响急性肺损伤。我们将在本项目深入研究HIF1α参与调控流感病毒复制及巨噬细胞II型极化的分子机制。研究结果将为流感病毒诱发ALI治疗提供新的靶点。

流感病毒（IAV）感染可以诱发急性肺部炎症反应，重症导致急性肺损伤（ALI），对社会医疗造成严重负担。控制流感病毒复制与减轻肺部炎症反应是治疗流感病毒感染的关键。缺氧诱导因子（HIF-1α）是肺部炎症和修复中的关键因子，但其在流感病毒感染诱发ALI中的作用和机制尚未被阐明。本项目主要聚焦于研究HIF-1α参与调控流感病毒复制及巨噬细胞II型极化的分子机制。利用HIF-1α特异性敲除动物模型和细胞模型进行流感病毒感染对相关机制进行研究。我们发现上皮细胞中特异性敲低HIF-1α后，显著增加小鼠流感病毒感染诱发的肺损伤和死亡率；体外上皮细胞HIF-1α缺失后，降低了流感病毒感染时细胞的糖酵解作用，进而激活AMPKα-ULK1信号通路，从而增加细胞自噬与流感病毒复制。同时巨噬细胞中HIF-1α缺失导致巨噬细胞II型极化诱导障碍，小鼠感染流感病毒后肺部炎症加重，死亡率增高；巨噬细胞中HIF-1α缺失会通过调控miR-210的转录以调控Arg1的表达，进而影响巨噬细胞的II型极化。本研究揭示了HIF-1α信号通过调节AMPKα-ULK1信号介导的肺泡二型上皮细胞细胞自噬来控制IAV复制及通过调控肺泡巨噬细胞二型极化影响肺部炎症的新机制，为IAV的致病性研究提供了新的思路。深入了解HIF-1α在流感病毒感染中的作用，有助于开发靶定宿主因子的抗流感病毒疗法。