Rhinovirus induces airway epithelial gene expression through double-stranded RNA and IFN-dependent pathways
Rhinovirus induces airway epithelial gene expression through double-stranded RNA and IFN-dependent pathways
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DOI：
10.1165/rcmb.2004-0417oc
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发表时间：
2006-02-01
影响因子：
6.4
通讯作者：
Wu, R
中科院分区：
文献类型：
--
作者：
Chen, Y;Hamati, E;Wu, R
鼻病毒(RV)感染是普通感冒和哮喘加重的主要原因。由于上皮细胞层是RV感染的主要靶点，我们推测RV诱导的呼吸道疾病与呼吸道上皮基因表达的紊乱有关。在这项研究中，高分化的原代人呼吸道上皮细胞被RV16(主要组)或RV1B(次要组)感染。用Affy-Metrix基因芯片分析RV感染和模拟感染对照细胞的转录基因表达谱，并通过实时定量RT-PCR分析基因表达的变化。在感染后24小时，鉴定了两种病毒诱导的48个基因。这些基因中的大多数与干扰素途径有关，并已被证明具有抗病毒功能。事实上，在RV16感染后，检测到显著的干扰素-β分泌刺激。针对干扰素-β的中和抗体和Janus激酶途径的特异性抑制剂都显著地阻断了轮状病毒诱导基因的诱导。进一步的研究表明，2-氨基嘌呤，一种特异性的抑制双链RNA依赖的蛋白激酶，可以同时阻断干扰素-β的产生和轮状病毒诱导的基因表达。因此，干扰素-β依赖途径是双链RNA启动途径的一部分，该途径负责轮状病毒诱导的基因表达。与其在诱导抗病毒基因中不可或缺的作用一致，该信号通路的失活显著地促进了病毒的产生。由于病毒产量的增加与RV诱导的呼吸道疾病的严重程度相关，本研究中发现的上皮性抗病毒信号通路将有助于我们理解RV诱导的感冒和哮喘加重的发病机制。
Rhinovirus (RV) infection is the major cause of common colds and of asthma exacerbations. Because the epithelial cell layer is the primary target of RV infection, we hypothesize that RV-induced airway disease is associated with the perturbation of airway epithelial gene expression. In this study, well differentiated primary human airway epithelial cells were infected with either RV16 (major group) or RV1B (minor group). Transcriptional gene profiles from RV-infected and mock-infected control cells were analyzed by Affy-metrix Genechip, and changes of the gene expression were confirmed by real-time RT-PCR analysis. At 24 h after infection, 48 genes induced by both viruses were identified. Most of these genes are related to the IFN pathway, and have been documented to have antiviral functions. Indeed, a significant stimulation of IFN-beta secretion was detected after RV16 infection. Neutralizing antibody specific to IFN-beta and a specific inhibitor of the Janus kinase pathway both significantly blocked the induction of RV-inducible genes. Further studies demonstrated that 2-aminopurine, a specific inhibitor double-stranded RNA-dependent protein kinase, could block both IFN-beta production and RV-induced gene expression. Thus, IFN-beta-dependent pathway is a part of the double-stranded RNA-initiated pathway that is responsible for RV-induced gene expression. Consistent with its indispensable role in the induction of antiviral genes, deactivation of this signaling pathway significantly enhanced viral production. Because increase of viral yield is associated with the severity of RV-induced airway illness, the discovery of an epithelial antiviral signaling pathway in this study will contribute to our understanding of the pathogenesis of RV-induced colds and asthma exacerbations.