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Dengue Virus Induces Novel Changes in Gene Expression of Human Umbilical Vein Endothelial Cells

Center for Infectious Disease and Vaccine Research and Department of Medicine,¹ Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655,⁵ Dengue Research Program, Banco Municipal de Sangre, Caracas, Venezuela,⁴ Brigham and Women's Hospital,² Vascular Research Division, Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115³

Received 27 January 2003/ Accepted 9 July 2003

Endothelial cells are permissive to dengue virus (DV) infection in vitro, although their importance as targets of DV infection in vivo remains a subject of debate. To analyze the virus-host interaction, we studied the effect of DV infection on gene expression in human umbilical vein endothelial cells (HUVECs) by using differential display reverse transcription-PCR (DD-RTPCR), quantitative RT-PCR, and Affymetrix oligonucleotide microarrays. DD identified eight differentially expressed cDNAs, including inhibitor of apoptosis-1, 2'-5' oligoadenylate synthetase (OAS), a 2'-5' OAS-like (OASL) gene, galectin-9, myxovirus protein A (MxA), regulator of G-protein signaling, endothelial and smooth muscle cell-derived neuropilin-like protein, and phospholipid scramblase 1. Microarray analysis of 22,000 human genes confirmed these findings and identified an additional 269 genes that were induced and 126 that were repressed more than fourfold after DV infection. Broad functional responses that were activated included the stress, defense, immune, cell adhesion, wounding, inflammatory, and antiviral pathways. These changes in gene expression were seen after infection of HUVECs with either laboratory-adapted virus or with virus isolated directly from plasma of DV-infected patients. Tumor necrosis factor alpha, OASL, and MxA and h-IAP1 genes were induced within the first 8 to 12 h after infection, suggesting a direct effect of DV infection. These global analyses of DV effects on cellular gene expression identify potentially novel mechanisms involved in dengue disease manifestations such as hemostatic disturbance.

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