Determinants in the envelope E protein and viral RNA helicase NS3 that influence the induction of apoptosis in response to infection with dengue type 1 virus.
One mechanism by which dengue (DEN) virus may cause cell death is apoptosis. In this study, we investigated whether the genetic determinants responsible for acquisition by DEN type 1 (DEN-1) virus of mouse neurovirulence interfere with the induction of apoptosis. Neurovirulent variant FGA/NA d1d was generated during the adaptation of the human isolate of DEN-1 virus strain FGA/89 to grow in newborn mouse brains and mosquito cells in vitro [Desprès, P. Frenkiel, M. -P. Ceccaldi, P.-E. Duarte Dos Santos, C. and Deubel, V. (1998) J. Virol., 72: 823-829]. Genetic determinants possibly responsible for mouse neurovirulence were studied by sequencing the entire genomes of both DEN-1 viruses. Three amino acid differences in the envelope E protein and one in the nonstructural NS3 protein were found. The cytotoxicity of the mouse-neurovirulent DEN-1 variant was studied in different target cells in vitro and compared with the parental strain. FGA/NA d1d was more pathogenic for mouse neuroblastoma cells and attenuated for human hepatoma cells. Changes in virus replicative functions and virus assembly may account, in a large part, for the differences in the induction of apoptosis. Our data suggest that identified amino acid substitutions in the envelope E protein and viral RNA helicase NS3 may influence DEN-1 virus pathogenicity by altering viral growth.
Duarte dos Santos
C N
CN
Departmento de Bioquimica e Biologia Molecular, Laboratorio de Expressao e Regulaçao Genica, Rio de Janeiro, R.J., Brazil.
Frenkiel
M P
MP
Courageot
M P
MP
Rocha
C F
CF
Vazeille-Falcoz
M C
MC
Wien
M W
MW
Rey
F A
FA
Deubel
V
V
Desprès
P
P
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002460:Cell Line; D002522:Chlorocebus aethiops; D009033:Culicidae; D003716:Dengue Virus / Q000201:enzymology / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity*; D004847:Epithelial Cells / Q000473:pathology / Q000821:virology; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008561:Membrane Fusion; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000473:pathology / Q000821:virology; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D020365:RNA Helicases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012367:RNA, Viral / Q000096:biosynthesis; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000096:biosynthesis / Q000378:metabolism; D014774:Virulence; D014779:Virus Replication
D006023:Glycoproteins; D012367:RNA, Viral; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C072281:E protein TH Sman, Dengue virus; D020365:RNA Helicases