Respiratory Syncytial Virus G Protein CX3C Motif Impairs Human Airway Epithelial and Immune Cell Responses
Respiratory Syncytial Virus G Protein CX3C Motif Impairs Human Airway Epithelial and Immune Cell Responses
复制标题
DOI：
10.1128/jvi.01741-13
复制
发表时间：
2013-12-01
影响因子：
5.4
通讯作者：
Anderson, Larry J.
中科院分区：
文献类型：
--
作者：
Chirkova, Tatiana;Boyoglu-Barnum, Seyhan;Anderson, Larry J.
呼吸道合胞病毒（RSV）是婴幼儿严重下呼吸道感染的主要病因，也会导致老年人以及心脏、肺部或免疫系统受损者患病。尽管RSV感染的发病率很高，但目前还没有高效的治疗方法或疫苗。RSV的G蛋白在疾病进程中起重要作用。G蛋白中一个保守的CX3C趋化因子样基序可能与疾病的发病机制有关。通过这个基序，G蛋白与多种免疫细胞上存在的CX3CR1结合，并影响对RSV的免疫反应，正如在RSV感染的小鼠模型中所显示的那样。然而，对于RSV的CX3C - CX3CR1相互作用在人类疾病中的作用知之甚少。在这项研究中，我们使用一种人RSV感染的体外模型，该模型由人外周血单个核细胞（PBMC）组成，这些细胞通过可渗透膜与人呼吸道上皮细胞（A549）隔开，A549细胞感染了具有完整CX3C基序（CX3C）或突变基序（CX4C）的RSV。我们发现，CX4C病毒在A549细胞中诱导更高水平的I型/III型干扰素（IFN），使人浆细胞样树突状细胞（pDC）和单核细胞产生更多的干扰素 -α和肿瘤坏死因子 -α（TNF -α），并使效应/记忆T细胞亚群中干扰素 -γ的产生增加。用抗G单克隆抗体（MAb）的F(ab')(2)片段处理感染CX3C病毒的细胞，该片段可阻断与CX3CR1的结合，其结果与CX4C病毒相似。我们的数据表明，RSV G蛋白的CX3C基序会损害人类先天性和适应性免疫反应，可能对疫苗和抗病毒药物的研发具有重要意义。
Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory infection in infants and young children and causes disease in the elderly and persons with compromised cardiac, pulmonary, or immune systems. Despite the high morbidity rates of RSV infection, no highly effective treatment or vaccine is yet available. The RSV G protein is an important contributor to the disease process. A conserved CX3C chemokine-like motif in G likely contributes to the pathogenesis of disease. Through this motif, G protein binds to CX3CR1 present on various immune cells and affects immune responses to RSV, as has been shown in the mouse model of RSV infection. However, very little is known of the role of RSV CX3C-CX3CR1 interactions in human disease. In this study, we use an in vitro model of human RSV infection comprised of human peripheral blood mononuclear cells (PBMCs) separated by a permeable membrane from human airway epithelial cells (A549) infected with RSV with either an intact CX3C motif (CX3C) or a mutated motif (CX4C). We show that the CX4C virus induces higher levels of type I/III interferon (IFN) in A549 cells, increased IFN-alpha and tumor necrosis factor alpha (TNF-alpha) production by human plasmacytoid dendritic cells (pDCs) and monocytes, and increased IFN-gamma production in effector/memory T cell subpopulations. Treatment of CX3C virus-infected cells with the F(ab')(2) form of an anti-G monoclonal antibody (MAb) that blocks binding to CX3CR1 gave results similar to those with the CX4C virus. Our data suggest that the RSV G protein CX3C motif impairs innate and adaptive human immune responses and may be important to vaccine and antiviral drug development.