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Journal of Virology, July 2000, p. 6425-6432, Vol. 74, No. 14
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Sindbis Virus Entry into Cells Triggers Apoptosis by Activating Sphingomyelinase, Leading to the Release of Ceramide

Jia-Tsrong Jan,1,dagger Subroto Chatterjee,2 and Diane E. Griffin1,*

W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21205,1 and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 212872

Received 24 November 1999/Accepted 12 April 2000

Sindbis virus (SV) causes acute encephalomyelitis by infecting and inducing the death of neurons. Induction of apoptosis occurs during virus entry and involves acid-induced conformational changes in the viral surface glycoproteins and sphingomyelin (SM)-dependent fusion of the virus envelope with the endosomal membrane. We have studied neuroblastoma cells to determine how this entry process triggers cell death. Acidic sphingomyelinase was activated during entry followed by activation of neutral sphingomyelinase, SM degradation, and a sustained increase in ceramide. Ceramide-induced apoptosis and SV-induced apoptosis could be inhibited by treatment with Z-VAD-fmk, a caspase inhibitor, and by overexpression of Bcl-2, an antiapoptotic cellular protein. Acid ceramidase, expressed in a recombinant SV, decreased intracellular ceramide and protected cells from apoptosis. The data suggest that acid-induced SM-dependent virus fusion initiates the apoptotic cascade by inducing SM degradation and ceramide release.

* Corresponding author. Mailing address: Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, 615 N. Wolfe St., Baltimore, MD 21205. Phone: (410) 955-3459. Fax: (410) 955-0105. E-mail: dgriffin{at}jhsph.edu.

dagger Present address: Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China.

Journal of Virology, July 2000, p. 6425-6432, Vol. 74, No. 14
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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