Increased dengue virus-infected endothelial cell apoptosis caused by antibodies against nonstructural protein 1.

Abstract

Vascular dysfunction is a hallmark of severe dengue haemorrhagic fever (‎DHF)‎ in dengue virus (‎DENV)‎ infection. Both viral infection and immunopathogenesis are involved in the vasculopathy of DHF. We previously showed that antibodies against DENV nonstructural protein 1 (‎NS1)‎ may cross-react with endothelial cells. A further study demonstrated the pathogenic role of anti-NS1 antibodies on endothelial dysfunction by inducing cell death and inflammation. In this study, we investigated the effect of anti- NS1 antibodies on DENV-infected human endothelial cells. We found increased binding activity of anti-NS1 antibodies to endothelial cells after DENV infection. Either DENV infection or anti-NS1 treatment caused endothelial cell apoptosis. Importantly, co-treatment with anti-NS1 antibodies increased DENV-induced endothelial cell apoptosis. The generation of nitric oxide (‎NO)‎ could be detected in anti-NS1-stimulated, but not DENV-infected, endothelial cells. Furthermore, anti-NS1-induced endothelial cell apoptosis was NO-dependent, whereas DENV infection-induced apoptosis was NOindependent. These results suggest an additive effect but distinct mechanisms between anti-NS1 antibodies and DENV in endothelial cell damage. These findings indicate that both viral infection and crossreactive antibodies may be involved in dengue pathogenesis by causing endothelial dysfunction.