Ebola Virus Inhibits Induction of Genes by Double-Stranded RNA in Endothelial Cells

Abstract

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-κB 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.