Innate Immune Responses to RSV Infection Facilitated by OGG1, an Enzyme Repairing Oxidatively Modified DNA Base Lesions.
Innate Immune Responses to RSV Infection Facilitated by OGG1, an Enzyme Repairing Oxidatively Modified DNA Base Lesions.
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OGG1（一种修复氧化修饰 DNA 碱基损伤的酶）促进对 RSV 感染的先天免疫反应
DOI：
10.1159/000524186
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发表时间：
2022
影响因子：
5.3
通讯作者：
中科院分区：
文献类型：
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作者：
呼吸道合胞病毒 (RSV) 感染导致发病和死亡的主要原因是过度的先天免疫反应 (IIR)，其中活性氧 (ROS) 发挥着关键作用。然而，这些过程的机制尚未完全了解。我们假设 IIR 基因的表达受 ROS 生成的表观遗传样标记 7,8-二氢-8-氧代（d）鸟嘌呤（8-oxo(d)Gua）和 8-氧代鸟嘌呤 DNA 糖基化酶 1 (OGG1) 控制。在这里，我们报道ROS不仅产生螺旋内8-oxo(d)Gua，而且还通过酶促作用使RSV感染的人气道上皮细胞和小鼠肺中的OGG1失效。 OGG1与基因调控序列中的8-oxo(d)Gua结合促进IIR基因的表达，从而加剧实验动物的肺部炎症、组织学变化和体重减轻。 OGG1 底物结合的药理抑制可降低 RSV 诱导的趋化因子和细胞因子的表达，并显着减轻临床症状。机制研究结果表明，OGG1 在 8-oxo(d)Gua 启动子区域的结合通过 RSV 感染的肺和气道上皮细胞中的瞬时协同相互作用调节转录因子的负载。其他碱基特异性 DNA 修复蛋白没有影响。总的来说，这项研究确定了 ROS 产生的 DNA 碱基损伤和同源修复蛋白作为 RSV 诱导的旺盛炎症的决定因素所发挥的前所未有的作用。药物抑制 OGG1 与其 DNA 底物的相互作用可能代表了预防/干预呼吸道病毒感染的新策略。
The primary cause of morbidity and mortality from infection with respiratory syncytial virus (RSV) is the excessive innate immune response(s) (IIR) in which reactive oxygen species (ROS) play key role(s). However, the mechanisms for these processes are not fully understood. We hypothesized that expressions of IIR genes are controlled by the ROS-generated epigenetic-like mark 7,8-dihydro-8-oxo(d)guanine (8-oxo(d)Gua) and 8-oxoguanine DNA glycosylase1 (OGG1). Here, we report that ROS not only generates intrahelical 8-oxo(d)Gua, but also enzymatically disables OGG1 in RSV-infected human airway epithelial cells and mouse lungs. OGG1 bound to 8-oxo(d)Gua in gene regulatory sequences promotes expression of IIR genes, and consequently exacerbates lung inflammation, histological changes, and body weight loss of experimental animals. Pharmacological inhibition of OGG1 substrate binding decreased expression of RSV-induced chemokine and cytokines and significantly lessened clinical symptoms. Results of mechanistic studies show that OGG1 binding at 8-oxo(d)Gua promoter regions modulated loading of transcription factors via transient cooperative interactions in RSV-infected lungs and airway epithelial cells. Other base specific DNA repair proteins had no effects. Collectively, this study identifies unprecedented roles of ROS-generated DNA base lesion(s) and cognate repair protein as a determinant of RSV-induced exuberant inflammation. Pharmaceutical inhibition of OGG1 interaction with its DNA substrate may represent a novel strategy in prevention/intervention of respiratory viral infections.
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影响因子：
7.4
作者：
Hajas, Gyorgy;Bacsi, Attila;Aguilerra-Aguirre, Leopoldo;German, Peter;Radak, Zsolt;Sur, Sanjiv;Hazra, Tapas K.;Boldogh, Istvan
通讯作者：
Boldogh, Istvan
影响因子：
14.9
作者：
Amente, Stefano;Di Palo, Giacomo;Majello, Barbara
通讯作者：
Majello, Barbara
酶失活的 OGG1 与 DNA 结合并引导碱基切除修复朝向基因转录
影响因子：
4.8
作者：
Hao, Wenjing;Wang, Jing;Ba, Xueqing
通讯作者：
Ba, Xueqing
影响因子：
6.4
作者：
Haeberle, HA;Takizawa, R;Garofalo, RP
通讯作者：
Garofalo, RP
影响因子：
--
作者：
Brasier, Allan R;Boldogh, Istvan
通讯作者：
Boldogh, Istvan