Exchange Proteins Directly Activated by cAMP and Their Roles in Respiratory Syncytial Virus Infection
Exchange Proteins Directly Activated by cAMP and Their Roles in Respiratory Syncytial Virus Infection
复制标题
DOI：
10.1128/jvi.01200-18
复制
发表时间：
2018-11-01
影响因子：
5.4
通讯作者：
Bao, Xiaoyong
中科院分区：
文献类型：
--
作者：
Choi, Eun-Jin;Ren, Yuping;Bao, Xiaoyong
呼吸道合胞病毒（RSV）是幼儿和高危成人呼吸道感染的主要原因。然而，目前还没有针对这种病毒感染的具体治疗方法。在这项研究中，我们发现一种直接由环腺苷酸激活的交换蛋白（EPAC）可以作为RSV的潜在治疗靶点。在下部和上部上皮细胞中，用EPAC抑制剂（ESI-09）而不是蛋白激酶A抑制剂（H89）处理显著抑制RSV复制和促炎性细胞因子/趋化因子诱导。此外，属于NF-κ B和IRF家族的RSV激活的转录因子也被ESI-09抑制。通过亚型特异性基因敲除，我们发现EPAC 2，而不是EPAC 1，在控制RSV复制和病毒诱导的宿主反应中起主导作用。使用EPAC 2敲除和EPAC 2特异性抑制剂的实验支持EPAC 2的这种作用。因此，EPAC 2是一个有前途的治疗靶点，以调节RSV复制和相关的炎症。重要性RSV是一个严重的公共卫生问题，因为它与细支气管炎，肺炎和哮喘恶化。目前没有有效的治疗方法或疫苗，许多关于RSV诱导的肺部疾病的分子机制仍然是未知的。该项目旨在阐明一种名为EPAC 2的蛋白质在RSV复制和先天性炎症反应中的重要和新功能。我们的研究结果将为开发抗RSV感染的新药理学策略提供重要的见解，从而降低RSV相关的发病率和死亡率。
Respiratory syncytial virus (RSV) is the leading cause of respiratory infection in young children and high-risk adults. However, a specific treatment for this viral infection is not currently available. In this study, we discovered that an exchange protein directly activated by cyclic AMP (EPAC) can serve as a potential therapeutic target for RSV. In both lower and upper epithelial cells, treatment with EPAC inhibitor (ESI-09), but not protein kinase A inhibitor (H89), significantly inhibits RSV replication and proinflammatory cytokine/chemokine induction. In addition, RSV-activated transcriptional factors belonging to the NF-kappa B and IRF families are also suppressed by ESI-09. Through isoform-specific gene knockdown, we found that EPAC2, but not EPAC1, plays a dominant role in controlling RSV replication and virus-induced host responses. Experiments using both EPAC2 knockout and EPAC2-specific inhibitor support such roles of EPAC2. Therefore, EPAC2 is a promising therapeutic target to regulate RSV replication and associated inflammation.IMPORTANCE RSV is a serious public health problem, as it is associated with bronchiolitis, pneumonia, and asthma exacerbations. Currently no effective treatment or vaccine is available, and many molecular mechanisms regarding RSV-induced lung disease are still significantly unknown. This project aims to elucidate an important and novel function of a protein, called EPAC2, in RSV replication and innate inflammatory responses. Our results should provide an important insight into the development of new pharmacologic strategies against RSV infection, thereby reducing RSV-associated morbidity and mortality.