The Effect of Human bcl-2 and bcl-X Genes on Dengue Virus-Induced Apoptosis in Cultured Cells

Abstract

Infection of dengue viruses (DENs) can cause human dengue fever, hemorrhagic fever, or shock syndrome. Although DEN-induced apoptosis has been implicated in pathogenesis of the DEN-related diseases, the underlying mechanism remains largely unexplored. In this study, we investigated the effect of ectopic expression of human bcl-2 and bcl-X genes on DEN-induced apoptosis in cultured cells. We employed a human isolate of DEN serotype 2 (DEN-2), PL046, which not only caused cell-cycle arrest in the G1 phase but also induced apoptosis in infected baby hamster kidney (BHK-21) cells, murine neuroblastoma N18 cells, and human neuronal NT-2 cells. Our results reveal that overexpression of bcl-2 in fibroblast-like BHK-21 cells, although not inhibiting virus yields, delayed the process of DEN-induced apoptosis, thereby permitting surviving cells to become persistently infected. In contrast, stable bcl-2 expression in neuronal N18 cells failed to block DEN-induced apoptosis. On the other hand, Bcl-XL, expressed predominantly in the nervous system, appeared to delay DEN's killing effect in neuronal N18 cells but not in fibroblast-like BHK-21 cells. In addition, inducible expression bcl-Xs, despite its proapoptotic property in other reported system, was found to merely accelerate cell death in DEN-infected N18 but not in infected BHK-21 cells. Thus, through studying the effect of human bcl-2-related genes, our results suggest that DEN infection may trigger target cells to undergo morphologically similar but biochemically distinct apoptotic pathways in a cell-specific manner.