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

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 NO-independent. 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 cross-reactive antibodies may be involved in dengue pathogenesis by causing endothelial dysfunction.