Harcourt B H, Sanchez A, Offermann M K
Winship Cancer Center, Emory University, Atlanta, Georgia 30322, USA.
Virology. 1998 Dec 5;252(1):179-88. doi: 10.1006/viro.1998.9446.
Fatal cases of filoviral infection are accompanied by a marked immunosuppression. Endothelial cells play a vital role in the host immune response through the expression of several immunomodulatory genes in addition to the expression of the antiviral genes, 2',5'-oligoadenylate synthetase [2'-5'(A)N], and the double-stranded RNA (dsRNA)-activated protein kinase (PKR). dsRNA, an intermediate generated during viral replication and gene transcription of many viruses, leads to the induction of immunomodulatory genes in endothelial cells. In this report, we show that induction of the major histocompatibility complex class I family of genes, 2'-5'(A)N, interleukin-6 (IL-6), PKR, interferon (IFN)-regulatory factor-1, and intercellular adhesion molecule-1 (ICAM-1) by dsRNA in human umbilical vein endothelial cells is suppressed by infection with the filovirus Ebola-Zaire (EZ). In contrast, induction of IL-6 and ICAM-1 by IL-1 is intact in EZ-infected cells. Gel shift analysis demonstrates that dsRNA-induced protein binding to IFN-responsive elements is strongly suppressed by EZ-IFN, whereas NF-kappa B activation by dsRNA remains intact. We previously reported that IFN signaling is suppressed by EZ infection, and these data strongly suggest that elements shared between IFN and dsRNA signaling are being inhibited by EZ. Inhibition of IFN and dsRNA responsiveness could play a role in the immunosuppression seen in EZ infections and would play a role in the pathogenesis of disease caused by EZ.
丝状病毒感染的致死病例伴有明显的免疫抑制。内皮细胞除了表达抗病毒基因、2',5'-寡腺苷酸合成酶[2'-5'(A)N]和双链RNA（dsRNA）激活的蛋白激酶（PKR）外，还通过表达几种免疫调节基因在宿主免疫反应中发挥重要作用。dsRNA是许多病毒在复制和基因转录过程中产生的中间体，可导致内皮细胞中免疫调节基因的诱导。在本报告中，我们表明，人脐静脉内皮细胞中dsRNA诱导的主要组织相容性复合体I类基因、2'-5'(A)N、白细胞介素-6（IL-6）、PKR、干扰素（IFN）调节因子-1和细胞间黏附分子-1（ICAM-1）的诱导受到丝状病毒埃博拉-扎伊尔（EZ）感染的抑制。相比之下，IL-1诱导的IL-6和ICAM-1在EZ感染的细胞中保持完整。凝胶迁移分析表明，dsRNA诱导的蛋白与IFN反应元件的结合受到EZ-IFN的强烈抑制，而dsRNA诱导的核因子κB激活保持完整。我们之前报道过，EZ感染会抑制IFN信号传导，这些数据强烈表明，IFN和dsRNA信号传导之间共有的元件受到EZ的抑制。IFN和dsRNA反应性的抑制可能在EZ感染中出现的免疫抑制中起作用，并在EZ引起的疾病发病机制中起作用。
