ACTIVATION OF ENDOTHELIAL-CELLS VIA ANTIBODY-ENHANCED DENGUE VIRUS-INFECTION OF PERIPHERAL-BLOOD MONOCYTES

Although endothelial cells have been speculated to be a target in the pathogenesis of dengue hemorrhagic fever (DHF), there has been little evidence linking dengue virus infection to any alteration in endotheli al cell function, In this study, we show that human umbilical vein end othelial cells become activated when exposed to culture fluids from de ngue virus-infected peripheral blood monocytes, Maximum activation was achieved with culture fluids from monocytes in which virus infection was enhanced by the addition of dengue virus-immune serum, thus correl ating with epidemiological evidence that prior immunity to dengue viru s is a major risk factor for DHF. Activation was strongest for endothe lial cell expression of VCAM-1 and ICAM-1. In contrast, activation of endothelial cell E-selectin expression appeared to be more transient, as indicated by its detection at 3 h, but not at 16 h, of treatment, T reatment of monocyte culture fluids with anti-tumor necrosis factor al pha (TNF-a) antibody largely abolished the activation effect (as measu red by endothelial cell expression of ICAM-1), whereas treatment with IL-1 beta receptor antagonist had a much smaller inhibitory effect on activation, Endothelial cells inoculated directly with dengue virus or with virus-antibody combinations were poorly infectable (compared to Vero cells or peripheral blood monocytes), and virus-inoculated endoth elial cells showed no increased expression of VCAM-1, ICAM-1, or E-sel ectin, Taken together, the results strongly indicate that dengue virus can modulate endothelial cell function by an indirect route, in which a key intermediary is TNF-alpha released from virus-infected monocyte s.