Inducible Expression of Inflammatory Chemokines in Respiratory Syncytial Virus-Infected Mice: Role of MIP-1α in Lung Pathology

Lower respiratory tract disease caused by respiratory syncytial virus (RSV) is characterized by profound airway mucosa inflammation, both in infants with naturally acquired infection and in experimentally inoculated animal models. Chemokines are central regulatory molecules in inflammatory, immune, and infectious processes of the lung. In this study, we demonstrate that intranasal infection of BALB/c mice with RSV A results in inducible expression of lung chemokines belonging to the CXC (MIP-2 and IP-10), CC (RANTES, eotaxin, MIP-1β, MIP-1α, MCP-1, TCA-3) and C (lymphotactin) families. Chemokine mRNA expression occurred as early as 24 h following inoculation and persisted for at least 5 days in mice inoculated with the highest dose of virus (10(7) PFU). In general, levels of chemokine mRNA and protein were dependent on the dose of RSV inoculum and paralleled the intensity of lung cellular inflammation. Immunohisthochemical studies indicated that RSV-induced expression of MIP-1α, one of the most abundantly expressed chemokines, was primarily localized in epithelial cells of the alveoli and bronchioles, as well as in adjoining capillary endothelium. Genetically altered mice with a selective deletion of the MIP-1α gene (−/− mice) demonstrated a significant reduction in lung inflammation following RSV infection, compared to control littermates (+/+ mice). Despite the paucity of infiltrating cells, the peak RSV titer in the lung of −/− mice was not significantly different from that observed in +/+ mice. These results provide the first direct evidence that RSV infection may induce lung inflammation via the early production of inflammatory chemokines.

由呼吸道合胞病毒（respiratory syncytial virus, RSV）引发的下呼吸道疾病，无论在自然感染的婴幼儿群体还是经实验接种的动物模型中，均以显著的气道黏膜炎症为核心特征。趋化因子（Chemokines）是调控肺部炎症、免疫应答及感染进程的核心分子。本研究证实，以呼吸道合胞病毒A型（RSV A）滴鼻感染BALB/c小鼠，可诱导肺部表达隶属于CXC、CC及C家族的趋化因子，其中CXC家族包含MIP-2与IP-10，CC家族涵盖RANTES、嗜酸性粒细胞趋化因子（eotaxin）、MIP-1β、MIP-1α、MCP-1及TCA-3，C家族则为淋巴细胞趋化蛋白（lymphotactin）。趋化因子的mRNA表达最早可于病毒接种后24小时出现，在接种最高病毒剂量（10^7 PFU）的小鼠体内，该表达至少持续5天。总体而言，趋化因子mRNA与蛋白的表达水平随RSV接种剂量变化而改变，且与肺部细胞炎症的严重程度呈平行关联。免疫组化研究显示，作为表达丰度最高的趋化因子之一，RSV诱导的MIP-1α表达主要定位于肺泡与细支气管上皮细胞，以及相邻的毛细血管内皮细胞。与同窝野生型对照小鼠（+/+小鼠）相比，MIP-1α基因选择性敲除的基因修饰小鼠（-/-小鼠）在RSV感染后，肺部炎症程度显著降低。尽管该敲除小鼠的肺部浸润细胞数量较少，但其肺部的RSV峰值滴度与+/+对照小鼠并无显著差异。本研究结果首次提供了直接证据，表明RSV感染可通过早期产生炎性趋化因子诱导肺部炎症。