Kong Kok-Fai, Delroux Karine, Wang Xiaomei, Qian Feng, Arjona Alvaro, Malawista Stephen E, Fikrig Erol, Montgomery Ruth R
Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520-8031, USA.
J Virol. 2008 Aug;82(15):7613-23. doi: 10.1128/JVI.00618-08. Epub 2008 May 28.
West Nile virus (WNV), a mosquito-borne flavivirus, has recently emerged in North America, and the elderly are particularly susceptible to severe neurological disease and death from infection with this virus. We have investigated the innate immune response of primary human macrophages to WNV in vitro and have found significant differences between the responsiveness of macrophages derived from younger donors and that from older donors. Binding of the glycosylated WNV envelope protein to the C-type lectin dendritic cell-specific intercellular adhesion molecule 3 (ICAM3) grabbing nonintegrin (DC-SIGN) leads to a reduction in the expression of Toll-like receptor 3 (TLR3) in macrophages from young donors via the signal transducer and activator of transcription 1 (STAT1)-mediated pathway. This signaling is impaired in the elderly, and the elevated levels of TLR3 result in an elevation of cytokine levels. This alteration of the innate immune response with aging may contribute to the permeability of the blood-brain barrier and suggests a possible mechanism for the increased severity of WNV infection in older individuals.
西尼罗河病毒（WNV）是一种由蚊子传播的黄病毒，最近在北美出现，老年人尤其易感染该病毒并引发严重的神经疾病甚至死亡。我们研究了原代人巨噬细胞对WNV的体外固有免疫反应，发现年轻供体来源的巨噬细胞与老年供体来源的巨噬细胞在反应性上存在显著差异。糖基化的WNV包膜蛋白与C型凝集素树突状细胞特异性细胞间黏附分子3（ICAM3）抓取非整合素（DC-SIGN）结合，通过信号转导和转录激活因子1（STAT1）介导的途径导致年轻供体巨噬细胞中Toll样受体3（TLR3）表达降低。这种信号传导在老年人中受损，TLR3水平升高导致细胞因子水平升高。随着年龄增长，固有免疫反应的这种改变可能导致血脑屏障通透性增加，并提示老年人WNV感染严重程度增加的一种可能机制。
