Up-regulation of Fas ligand expression by human cytomegalovirus immediate-early gene product 2: A novel mechanism in cytomegalovirus-induced apoptosis in human retina
Up-regulation of Fas ligand expression by human cytomegalovirus immediate-early gene product 2: A novel mechanism in cytomegalovirus-induced apoptosis in human retina
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DOI：
10.4049/jimmunol.167.7.4098
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发表时间：
2001-10-01
影响因子：
4.4
通讯作者：
Wu, CW
中科院分区：
文献类型：
--
作者：
Chiou, SH;Liu, JH;Wu, CW
人类巨细胞病毒（HCMV）是一种重要的病原体，可在免疫功能低下的个体中引起广泛的疾病。在机会性 HCMV 感染中，HCMV 视网膜炎最常见于移植受者和艾滋病患者。如果不及时治疗，通常会导致失明。 HCMV 感染如何引起视网膜发病机制的问题仍未解决。在这里，我们报告病毒立即早期基因产物 2 (IE2)，而不是 IE1，上调 HCMV 感染的人视网膜色素上皮细胞中的 Fas 配体 (FasL) 表达。在 HCMV 感染后，观察到 FasL 从病毒感染细胞向培养基中的分泌增加。这种无细胞培养基诱导表达 Fas (CD95) 的 Jurkat 细胞凋亡的能力进一步暗示 Fas-FasL 相互作用可能介导 HCMV 视网膜炎病变中的细胞死亡。为了支持这一观点，我们观察到，与未感染 HCMV 的 AIDS 患者相比，患有 HCMV 视网膜炎的 AIDS 患者的玻璃体中可溶性 FasL 水平有所增加。此外，通过原位杂交和免疫组化，我们在HCMV感染的视网膜病变的相同部位检测到FasL信号增强、病毒IE Ags和凋亡细胞的存在。这些结果强烈表明，IE2 诱导人视网膜中 FasL 表达可能是感染早期发生的一个重要事件，并最终导致与 HCMV 视网膜炎相关的个体视力丧失。
Human CMV (HCMV) is an important pathogen that causes widespread diseases in immunocompromised individuals. Among the opportunistic HCMV infections, HCMV retinitis is most common in transplant recipients and AIDS patients. It often leads to blindness if left untreated. The question as to how HCMV infection causes retinal pathogenesis remains unresolved. Here, we report that viral immediate-early gene product 2 (IE2), but not IE1, up-regulates the Fas ligand (FasL) expression in HCMV-infected human retinal pigment epithelium cells. Increased secretion of FasL from virally infected cells into cultured medium was observed upon HCMV infection. The capability of such cell-free medium to induce apoptosis of Fas (CD95)-expressing Jurkat cells further implies that Fas-FasL interaction might mediate cell death in the lesion of HCMV retinitis. To support this idea, we observed augmented soluble FasL levels in vitreous from AIDS patients with HCMV retinitis as compared with that from AIDS patients without HCMV infection. In addition, by in situ hybridization and immunohistochemistry, we detected enhanced signals of FasL, the existence of viral IE Ags and apoptotic cells at the same sites in the lesion of HCMV-infected retina. These results strongly suggest that IE2 induction of FasL expression in human retina might be an important event that takes place in the early stage of infection and finally leads to visual loss in individuals affiliated with HCMV retinitis.