Chen Yin, Hamati Edward, Lee Pak-Kei, Lee Wai-Ming, Wachi Shinichiro, Schnurr David, Yagi Shigeo, Dolganov Gregory, Boushey Homer, Avila Pedro, Wu Reen
Center for Comparative Respiratory Biology and Medicine, Genomic and Biomedical Sciences Facility, Suite 6510, University of California at Davis, One Shields Ave., Davis, CA 95616, USA.
Am J Respir Cell Mol Biol. 2006 Feb;34(2):192-203. doi: 10.1165/rcmb.2004-0417OC. Epub 2005 Oct 6.
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 Affymetrix 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.
鼻病毒（RV）感染是普通感冒和哮喘发作的主要原因。由于上皮细胞层是RV感染的主要靶标，我们推测RV诱导的气道疾病与气道上皮基因表达的扰动有关。在本研究中，将分化良好的原代人气道上皮细胞用RV16（主要组）或RV1B（次要组）感染。通过Affymetrix基因芯片分析RV感染和模拟感染对照细胞的转录基因谱，并通过实时RT-PCR分析确认基因表达的变化。感染后24小时，鉴定出两种病毒诱导的48个基因。这些基因中的大多数与IFN途径相关，并且已被证明具有抗病毒功能。实际上，在RV16感染后检测到IFN-β分泌的显著刺激。IFN-β特异性中和抗体和Janus激酶途径的特异性抑制剂均显著阻断RV诱导基因的诱导。进一步的研究表明，2-氨基嘌呤，一种双链RNA依赖性蛋白激酶的特异性抑制剂，可以阻断IFN-β的产生和RV诱导的基因表达。因此，IFN-β依赖性途径是双链RNA启动途径的一部分，该途径负责RV诱导的基因表达。与其在抗病毒基因诱导中的不可或缺的作用一致，该信号通路的失活显著增强了病毒产生。由于病毒产量的增加与RV诱导的气道疾病的严重程度相关，本研究中上皮抗病毒信号通路的发现将有助于我们理解RV诱导的感冒和哮喘发作的发病机制。
