Department of Molecular Biology in College of Basic Medical Sciences and Institute of Pediatrics in The First Hospital of Jilin University, Jilin University, Changchun, Jilin, China.
Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.
Immunology. 2019 May;157(1):37-51. doi: 10.1111/imm.13045. Epub 2019 Feb 27.
The excessive activation of interferon regulatory factor 7 (IRF7) promotes the development of acute lung injury (ALI) caused by influenza A virus (IAV). However, the deficiency of IRF7 increases the susceptibility to deadly IAV infection in both humans and mice. To test whether the attenuation rather than the abolishment of IRF7 activity in local infectious sites could alleviate IAV-induced ALI, we established IAV-infected mouse model and trachea/lung-tissue culture systems, and designed two IRF7-interfering oligodeoxynucleotides, IRF7-rODN M1 and IRF7-rODN A1, based on the mouse and human consensus sequences of IRF7-binding sites of Ifna/IFNA genes, respectively. In the model mice, we found a close relationship between the IAV-induced ALI and the level/activity of IRF7 in local infectious sites, and also found that the reduced IRF7 level or activity in the lungs of mice treated with IRF7-rODN M1 led to decreased mRNA levels of Ifna genes, reduced neutrophil infiltration in the lungs and prolonged survival of mice. Furthermore, we found that the effects of IRF7-rODN M1 on alleviating IAV-induced ALI could be correlated to the reduced translocation of IRF7, caused by the IRF7-rODN M1, from cytosol to nucleus in IAV-infected cells. These data suggest that the proper attenuation of IRF7 activity in local infectious sites could be a novel approach for treating IAV-induced ALI.
干扰素调节因子 7（IRF7）的过度激活可促进甲型流感病毒（IAV）引起的急性肺损伤（ALI）的发展。然而，IRF7 的缺乏会增加人类和小鼠对致命性 IAV 感染的易感性。为了测试局部感染部位 IRF7 活性的减弱而非消除是否可以减轻 IAV 诱导的 ALI，我们建立了 IAV 感染的小鼠模型和气管/肺组织培养系统，并基于鼠和人干扰素-α/IFNA 基因的 IRF7 结合位点的共识序列，分别设计了两种 IRF7 干扰寡脱氧核苷酸（IRF7-rODN M1 和 IRF7-rODN A1）。在模型小鼠中，我们发现 IAV 诱导的 ALI 与局部感染部位 IRF7 的水平/活性之间存在密切关系，并且还发现用 IRF7-rODN M1 处理的小鼠肺部 IRF7 水平或活性降低会导致 Ifna 基因的 mRNA 水平降低、肺部中性粒细胞浸润减少以及小鼠存活时间延长。此外，我们发现 IRF7-rODN M1 减轻 IAV 诱导的 ALI 的作用可能与 IRF7-rODN M1 引起的 IRF7 从细胞质向细胞核的易位减少有关，这在 IAV 感染的细胞中。这些数据表明，局部感染部位 IRF7 活性的适当减弱可能是治疗 IAV 诱导的 ALI 的一种新方法。
