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Journal of Virology, May 2008, p. 4502-4510, Vol. 82, No. 9
0022-538X/08/$08.00+0     doi:10.1128/JVI.02349-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Theiler's Virus-Induced Intrinsic Apoptosis in M1-D Macrophages Is Bax Mediated and Restricts Virus Infectivity: a Mechanism for Persistence of a Cytolytic Virus{triangledown}

Kyung-No Son,1,2 Robert P. Becker,3 Patricia Kallio,1 and Howard L. Lipton1,2*

Departments of Neurology and Rehabilitation,1 Microbiology and Immunology,2 Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois 60612-73443

Received 30 October 2007/ Accepted 13 February 2008

Theiler's murine encephalomyelitis virus (TMEV), a member of the Cardiovirus genus in the family Picornaviridae, is a highly cytolytic virus that produces necrotic death in rodent cells except for macrophages, which undergo apoptosis. In the present study we have analyzed the kinetics of BeAn virus infection in M1-D cells, in order to temporally relate virus replication to the apoptotic signaling events. Apoptosis was associated with early exponential virus growth from 1 to 12 h postinfection (p.i.); however, ≥80% of peak infectivity was lost by 16 to 24 h p.i. The pan-caspase inhibitor qVD-OPh led to significantly higher virus yields, while zVAD-fmk completely inhibited virus replication until 10 h p.i., precluding its assessment in apoptosis. In contrast, while zVAD-fmk significantly inhibited BeAn virus replication in BHK-21 cells at 12 and 16 h p.i., virus replication at these time points was not altered by qVD-OPh. Bax translocation into mitochondria, efflux of cytochrome c into the cytoplasm, and activation of caspases 9 and 3 between ~8 and 12 h p.i. (all hallmarks of the intrinsic apoptotic pathway) were transiently inhibited by expression of Bcl-2, which is not expressed in M1-D cells. Thus, BeAn virus infection in M1-D macrophages, which restricts virus replication, provides a potential mechanism for modulating TMEV neurovirulence during persistence in the mouse central nervous system.

* Corresponding author. Mailing address: Department of Microbiology-Immunology, MC 790, University of Illinois at Chicago, 835 South Wolcott, Chicago, IL 60612-7344. Phone: (312) 996-5754. Fax: (312) 355-3581. E-mail: hlipton{at}uic.edu

{triangledown} Published ahead of print on 20 February 2008.

Journal of Virology, May 2008, p. 4502-4510, Vol. 82, No. 9
0022-538X/08/$08.00+0     doi:10.1128/JVI.02349-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Son, K.-N., Pugazhenthi, S., Lipton, H. L. (2009). Activation of Tumor Suppressor Protein p53 Is Required for Theiler's Murine Encephalomyelitis Virus-Induced Apoptosis in M1-D Macrophages. J. Virol. 83: 10770-10777 [Abstract] [Full Text]  
  • Lidsky, P. V., Romanova, L. I., Kolesnikova, M. S., Bardina, M. V., Khitrina, E. V., Hato, S. V., van Kuppeveld, F. J. M., Agol, V. I. (2009). Interactions between Viral and Prokaryotic Pathogens in a Mixed Infection with Cardiovirus and Mycoplasma. J. Virol. 83: 9940-9951 [Abstract] [Full Text]  
  • Fan, J., Son, K.-N., Arslan, S. Y., Liang, Z., Lipton, H. L. (2009). Theiler's Murine Encephalomyelitis Virus Leader Protein Is the Only Nonstructural Protein Tested That Induces Apoptosis When Transfected into Mammalian Cells. J. Virol. 83: 6546-6553 [Abstract] [Full Text]  
  • Hou, W., Kang, H. S., Kim, B. S. (2009). Th17 cells enhance viral persistence and inhibit T cell cytotoxicity in a model of chronic virus infection. JEM 206: 313-328 [Abstract] [Full Text]  


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