Culley Fiona J, Pennycook Alasdair M J, Tregoning John S, Dodd Jonathan S, Walzl Gerhard, Wells Timothy N, Hussell Tracy, Openshaw Peter J M
Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, St Mary's Campus, Norfolk Place, London W2 1PG, United Kingdom.
J Virol. 2006 Aug;80(16):8151-7. doi: 10.1128/JVI.00496-06.
CCL5/RANTES is a key proinflammatory chemokine produced by virus-infected epithelial cells and present in respiratory secretions of asthmatics. To examine the role of CCL5 in viral lung disease, we measured its production during primary respiratory syncytial virus (RSV) infection and during secondary infection after sensitizing vaccination that induces Th2-mediated eosinophilia. A first peak of CCL5 mRNA and protein production was seen at 18 to 24 h of RSV infection, before significant lymphocyte recruitment occurred. Treatment in vivo with Met-RANTES (a competitive chemokine receptor blocker) throughout primary infection decreased CD4+ and CD8+ cell recruitment and increased viral replication. In RSV-infected, sensitized mice with eosinophilic disease, CCL5 production was further augmented; Met-RANTES treatment again reduced inflammatory cell recruitment and local cytokine production. A second wave of CCL5 production occurred on day 7, attributable to newly recruited T cells. Paradoxically, mice treated with Met-RANTES during primary infection demonstrated increased cellular infiltration during reinfection. We therefore show that RSV induces CCL5 production in the lung and this causes the recruitment of RSV-specific cells, including those making additional CCL5. If this action is blocked with Met-RANTES, inflammation decreases and viral clearance is delayed. However, the exact effects of chemokine modulation depend critically on time of administration, a factor that may potentially complicate the use of chemokine blockers in inflammatory diseases.
CCL5/调节激活正常T细胞表达和分泌的因子是一种关键的促炎趋化因子，由病毒感染的上皮细胞产生，存在于哮喘患者的呼吸道分泌物中。为了研究CCL5在病毒性肺部疾病中的作用，我们检测了其在原发性呼吸道合胞病毒（RSV）感染期间以及诱导Th2介导的嗜酸性粒细胞增多的致敏疫苗接种后的二次感染期间的产生情况。在RSV感染18至24小时时，在显著的淋巴细胞募集发生之前，观察到CCL5 mRNA和蛋白质产生的第一个峰值。在整个原发性感染期间用Met-RANTES（一种竞争性趋化因子受体阻滞剂）进行体内治疗可减少CD4+和CD8+细胞募集，并增加病毒复制。在患有嗜酸性粒细胞疾病的RSV感染致敏小鼠中，CCL5的产生进一步增加；Met-RANTES治疗再次减少了炎症细胞募集和局部细胞因子产生。在第7天出现了第二波CCL5产生，这归因于新募集的T细胞。矛盾的是，在原发性感染期间用Met-RANTES治疗的小鼠在再次感染期间表现出细胞浸润增加。因此，我们表明RSV诱导肺部产生CCL5，这导致募集RSV特异性细胞，包括那些产生额外CCL5的细胞。如果用Met-RANTES阻断这种作用，炎症会减轻，但病毒清除会延迟。然而，趋化因子调节的确切效果严重取决于给药时间，这一因素可能会使趋化因子阻滞剂在炎症性疾病中的使用变得复杂。
