HUMAN ISOLATES OF DENGUE TYPE-1 VIRUS INDUCE APOPTOSIS IN MOUSE NEUROBLASTOMA-CELLS

Human isolates of dengue (DEN) type 1 viruses FGA/89 and BR/90 differ in their membrane fusion properties in mosquito cell lines (P. Despres et al., Virology 196:209-216, 1993). FGA/89 and BR/90 were assayed fo r their neurovirulence in newborn mice, and neurons were the major tar get cells for both DEN-1 virus strains within the central nervous syst em. To study the susceptibility of neurons to DEN virus infection, DEN virus replication was analyzed in the murine neuroblastoma cell line Neuro 2a. Infection of Neuro 2a cells with FGA/89 or BR/90 induced apo ptotic DNA degradation after 25 h of infection. Studies of DEN protein synthesis revealed that accumulation of viral proteins leads to apopt otic cell death. The apoptotic process progressed more rapidly followi ng BR/90 infection than it did after FGA/89 infection. The higher cyto toxicity of BR/90 for Neuro 2a cells was linked to an incomplete matur ation of the envelope proteins, resulting in abortive virus assembly. Accumulation of viral proteins in the endoplasmic reticulum mag induce stress and thereby activate the apoptotic pathway in mouse neuroblast oma cells.