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J Virol, January 1998, p. 823-829, Vol. 72, No. 1
Unité des Arbovirus et Virus des
Fièvres Hémorragiques1 and
Unité de la Rage,2 Institut
Pasteur, 75724 Paris, France, and
Departamento Bioquimica e
Biologia Molecular, Instituto Oswaldo Cruz, 21045-900 Rio de
Janeiro, R.J., Brazil3
Received 15 August 1997/Accepted 3 October 1997
Apoptosis has been suggested as a mechanism by which dengue (DEN)
virus infection may cause neuronal cell death (P. Desprès, M. Flamand, P.-E. Ceccaldi, and V. Deubel, J. Virol. 70:4090-4096, 1996). In this study, we investigated whether apoptotic cell death occurred in the central nervous system (CNS) of neonatal mice inoculated intracerebrally with DEN virus. We showed that serial passage of a wild-type human isolate of DEN virus in mouse brains selected highly neurovirulent variants which replicated more
efficiently in the CNS. Infection of newborn mice with these
neurovirulent variants produced fatal encephalitis within 10 days after
inoculation. Virus-induced cell death and oligonucleosomal DNA
fragmentation were observed in mouse brain tissue by day 9. Infected
mouse brain tissue was assayed for apoptosis by in situ terminal
deoxynucleotidyl transferase-mediated dUTP nick end labeling and for
virus replication by immunostaining of viral antigens and in situ
hybridization. Apoptotic cell death and DEN virus replication were
restricted to the neurons of the cortical and hippocampal regions.
Thus, DEN virus-induced apoptosis in the CNS was a direct result of virus infection. In the murine neuronal cell line Neuro 2a,
neuroadapted DEN virus variants showed infection patterns similar to
those of the parental strain. However, DEN virus-induced apoptosis in these cells was more pronounced after infection with the neurovirulent variants than after infection with the parental strain.
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Apoptosis in the Mouse Central Nervous System in
Response to Infection with Mouse-Neurovirulent Dengue Viruses
*
Corresponding author. Mailing address: Unité des
Arbovirus et Virus des Fièvres Hémorragiques, Institut
Pasteur, 25, rue du Dr. Roux, 75724 Paris, France. Phone: 33-140613563. Fax: 33-145688780. E-mail: pdespres{at}pasteur.fr.
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