Retinoic acid-inducible gene I mediates early antiviral response and toll-like receptor 3 expression in respiratory syncytial virus-infected airway epithelial cells
Retinoic acid-inducible gene I mediates early antiviral response and toll-like receptor 3 expression in respiratory syncytial virus-infected airway epithelial cells
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DOI：
10.1128/jvi.01740-06
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发表时间：
2007-02-01
影响因子：
5.4
通讯作者：
Brasier, Allan R.
中科院分区：
文献类型：
--
作者：
Liu, Ping;Jamaluddin, Mohammad;Brasier, Allan R.
呼吸道合胞病毒（RSV）是引起婴幼儿严重下呼吸道感染的最常见的病毒性病原体之一。受感染的宿主细胞以不同的细胞类型特异性方式检测和响应RNA病毒，包括视黄酸诱导基因I （RIG-I）依赖和toll样受体（TLR）依赖途径。由于这两种途径在识别RSV感染中的相对作用尚不清楚，因此我们在本研究中考察了它们的作用。我们发现rig - 1解旋酶在感染后12小时内结合RSV转录本。短干扰RNA （siRNA）介导的rig - 1“敲低”显著抑制感染后9小时早期核因子κ B （nf - κ B）和干扰素反应因子3 （IRF3）的激活。与这一发现一致，rsv诱导的β干扰素（ifn - β）、干扰素诱导蛋白10 （IP-10）、趋化因子配体5 （CCL-5）和ifn刺激基因15 （ISG15）的表达水平在rig -i沉默细胞的感染早期下降，但在后期（18 h p.i）没有下降。相比之下，sirna介导的TLR3敲低不影响rsv诱导的NF-kappa B结合，但在感染后期抑制ifn - β、IP-10、CCL-5和ISG15的表达。进一步的研究表明，TLR3敲低可通过阻断NF-kappa B/RelA在丝氨酸残基276处的活化磷酸化而显著降低NF-kappa B/RelA的转录。我们进一步发现，RSV感染后TLR3的诱导受受感染气道上皮细胞分泌的rig - i依赖性IFN- β的调节，并由IFN反应刺激元件（ISRE）和其近端启动子中的信号转导和转录激活子（STAT）位点介导。总之，这些发现表明rig - 1和TLR3在介导rsv诱导的先天免疫反应中具有不同的时间作用，这与控制nf - κ B激活的不同途径相耦合。
Respiratory syncytial virus (RSV) is one of the most common viral pathogens causing severe lower respiratory tract infections in infants and young children. Infected host cells detect and respond to RNA viruses using different mechanisms in a cell-type- specific manner, including retinoic acid-inducible gene I (RIG-I)dependent and Toll-like receptor (TLR)-dependent pathways. Because the relative contributions of these two pathways in the recognition of RSV infection are unknown, we examined their roles in this study. We found that RIG-I helicase binds RSV transcripts within 12 h of infection. Short interfering RNA (siRNA) -mediated RIG-I "knockdown" significantly inhibited early nuclear factor-kappa B (NF-kappa B) and interferon response factor 3 (IRF3) activation 9 h postinfection (p.i.). Consistent with this finding, RSV-induced beta interferon (IFN-beta), interferon-inducible protein 10 (IP-10), chemokine ligand 5 (CCL-5), and IFN-stimulated gene 15 (ISG15) expression levels were decreased in RIG-I-silenced cells during the early phase of infection but not at later times (18 h p.i.). In contrast, siRNA-mediated TLR3 knockdown did not affect RSV-induced NF-kappa B binding but did inhibit IFN-beta, IP-10, CCL-5, and ISG15 expression at late times of infection. Further studies revealed that TLR3 knockdown significantly reduced NF-kappa B/RelA transcription by its ability to block the activating phosphorylation of NF-kappa B/RelA at serine residue 276. We further found that TLR3 induction following RSV infection was regulated by RIG-I-dependent IFN-beta secreted from infected airway epithelial cells and was mediated by both IFN response-stimulated element (ISRE) and signal transducer and activator of transcription (STAT) sites in its proximal promoter. Together these findings indicate distinct temporal roles of RIG-I and TLR3 in mediating RSV-induced innate immune responses, which are coupled to distinct pathways controlling NF-kappa B activation.