Kim Hyun Jik, Kim Chang-Hoon, Kim Min-Ji, Ryu Ji-Hwan, Seong Sang Yeop, Kim Sujin, Lim Su Jin, Holtzman Michael J, Yoon Joo-Heon
1 Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul, Korea.
2 The Airway Mucus Institute.
Am J Respir Cell Mol Biol. 2015 Oct;53(4):525-35. doi: 10.1165/rcmb.2014-0334OC.
We studied the relative roles of Duox2-derived reactive oxygen species (ROS) in host defense against influenza A virus (IAV) infection in normal human nasal epithelial cells and mouse nasal mucosa. We found that Duox2 primarily generated ROS rapidly after IAV infection in normal human nasal epithelial cells and that knockdown of Duox2 aggravated IAV infection. In addition, Duox2-derived ROS enhancement significantly suppressed IAV infection in nasal epithelium. In particular, Duox2-derived ROS were required for the induction of retinoic acid-inducible gene (RIG)-I and melanoma differentiation-associated protein 5 (MDA5) transcription. After intranasal IAV inoculation into mice, viral infection was significantly aggravated from 3 days postinoculation (dpi) in the nasal mucosa, and the IAV viral titer was highest at 7 dpi. Both RIG-I and MDA5 messenger RNA levels increased dominantly in mouse nasal mucosa from 3 dpi; consistent with this, RIG-I and MDA5 proteins were also induced after IAV infection. RIG-I and MDA5 messenger RNA levels were induced to a lower extent in the nasal mucosa of the mice that were inoculated with Duox2 short hairpin RNA, and the IAV viral titer was significantly higher in nasal lavage. Taken together, Duox2-derived ROS are necessary for the innate immune response and trigger the induction of RIG-I and MDA5 to resist IAV infection in human nasal epithelium and mouse nasal mucosa.
我们研究了双氧化酶2（Duox2）衍生的活性氧（ROS）在正常人鼻上皮细胞和小鼠鼻黏膜抵御甲型流感病毒（IAV）感染的宿主防御中的相对作用。我们发现，在正常人鼻上皮细胞中，IAV感染后Duox2主要迅速产生活性氧，并且敲低Duox2会加重IAV感染。此外，Duox2衍生的活性氧增强显著抑制鼻上皮中的IAV感染。特别地，Duox2衍生的活性氧是诱导视黄酸诱导基因（RIG）-I和黑色素瘤分化相关蛋白5（MDA5）转录所必需的。将IAV经鼻接种到小鼠体内后，从接种后3天（dpi）起鼻黏膜中的病毒感染显著加重，并且IAV病毒滴度在7 dpi时最高。从3 dpi起，RIG-I和MDA5信使核糖核酸水平在小鼠鼻黏膜中均显著升高；与此一致的是，IAV感染后也诱导了RIG-I和MDA5蛋白。在接种了Duox2短发夹RNA的小鼠鼻黏膜中，RIG-I和MDA5信使核糖核酸水平的诱导程度较低，并且鼻灌洗中的IAV病毒滴度显著更高。综上所述，Duox2衍生的活性氧对于先天性免疫反应是必需的，并触发RIG-I和MDA5的诱导以抵抗人鼻上皮和小鼠鼻黏膜中的IAV感染。
