Ebola virus inhibits induction of genes by double-stranded RNA in endothelial cells

Fatal cases of filoviral infection are accompanied by a marked immunosuppre ssion. Endothelial cells play a vital role in the host immune response thro ugh the expression of several immunomodulatory genes in addition to the exp ression of the antiviral genes, 2',5'-oligoadenylate synthetase [2'-5'(A)(N )], and the double-stranded RNA (dsRNA)-activated protein kinase (PKR). dsR NA, an intermediate generated during viral replication and gene transcripti on of many viruses, leads to the induction of immunomodulatory genes in end othelial cells. In this report, we show that induction of the major histoco mpatibility 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 s uppressed by infection with the filovirus Ebola-Zaire (EZ). In contrast, in duction of IL-6 and ICAM-1 by IL-1 is intact in EZ-infected cells. Gel shif t analysis demonstrates that dsRNA-induced protein binding to IFN-responsiv e elements is strongly suppressed by EZ-IFN, whereas NF-kappa B activation by dsRNA remains intact. We previously reported that IFN signaling is suppr essed by EZ infection, and these data strongly suggest that elements shared between IFN and dsRNA signaling are being inhibited by EZ Inhibition of IF N and dsRNA responsiveness could play a role in the immunosuppression seen in EZ infections and would play a role in the pathogenesis of disease cause d by EZ. (C) 1998 Academic Press.