Tamanini Anna, Nicolis Elena, Bonizzato Alberto, Bezzerri Valentino, Melotti Paola, Assael Baroukh M, Cabrini Giulio
Laboratorio Patologia Molecolare, Centro Fibrosi Cistica, Azienda Ospedaliera-Universitaria, Piazzale Stefani 1, 37126 Verona, Italy.
J Virol. 2006 Nov;80(22):11241-54. doi: 10.1128/JVI.00721-06. Epub 2006 Sep 6.
The innate immune response to adenovirus (Ad)-derived gene transfer vectors has been shown to initiate immediately after interaction of Ad with respiratory epithelial cells, through the induction of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and JNK mitogen-activated protein kinase (MAPK), nuclear factor kappaB (NF-kappaB), and different proinflammatory genes. Ad serotypes 2 or 5 (Ad2/5) enter respiratory epithelia after initial binding of fiber with the coxsackievirus-adenovirus receptor (CAR) or, alternatively, with cell surface heparan sulfate glycosaminoglycans. Ad2/5 internalization is triggered by binding of penton base to cellular RGD-binding integrins. Here we investigated the role of the Ad5 surface domain proteins constituting the vector capsid, namely, the fiber, the penton base, and the hexon, on the transmembrane signals leading to the transcription of the different proinflammatory genes in the human respiratory A549 cell line. Interaction of Ad fiber with CAR activates both ERK1/2 and JNK MAPK and the nuclear translocation of NF-kappaB, whereas no activation was observed after exposing A549 cells to penton base and hexon proteins. Moreover, interaction of Ad fiber with CAR, but not heparan sulfate proteoglycans, promotes transcription of the chemokines interleukin-8, GRO-alpha, GRO-gamma, RANTES, and interferon-inducible protein 10. These results identify the binding of Ad5 fiber with the cellular CAR as a key proinflammatory activation event in epithelial respiratory cells that is independent of the transcription of Ad5 genes.
对腺病毒（Ad）衍生基因转移载体的先天性免疫反应已显示，在Ad与呼吸道上皮细胞相互作用后，通过诱导细胞外信号调节激酶1和2（ERK1/2）、JNK丝裂原活化蛋白激酶（MAPK）、核因子κB（NF-κB）以及不同的促炎基因，立即启动。Ad血清型2或5（Ad2/5）在纤维最初与柯萨奇病毒-腺病毒受体（CAR）结合后，或者与细胞表面硫酸乙酰肝素糖胺聚糖结合后，进入呼吸道上皮细胞。Ad2/5的内化是由五聚体基座与细胞RGD结合整合素的结合触发的。在这里，我们研究了构成载体衣壳的Ad5表面结构域蛋白，即纤维、五聚体基座和六邻体，在导致人呼吸道A549细胞系中不同促炎基因转录的跨膜信号中的作用。Ad纤维与CAR的相互作用激活了ERK1/2和JNK MAPK以及NF-κB的核转位，而在将A549细胞暴露于五聚体基座和六邻体蛋白后未观察到激活。此外，Ad纤维与CAR而非硫酸乙酰肝素蛋白聚糖的相互作用促进了趋化因子白细胞介素-8、GRO-α、GRO-γ、RANTES和干扰素诱导蛋白10的转录。这些结果表明，Ad5纤维与细胞CAR的结合是上皮呼吸道细胞中关键的促炎激活事件，且独立于Ad5基因的转录。
