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Journal of Virology, July 2007, p. 6984-6992, Vol. 81, No. 13
0022-538X/07/$08.00+0     doi:10.1128/JVI.00467-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Novel Strategy for Treatment of Viral Central Nervous System Infection by Using a Cell-Permeating Inhibitor of c-Jun N-Terminal Kinase{triangledown}

J. David Beckham,1 Robin J. Goody,2 Penny Clarke,2 Christophe Bonny,5 and Kenneth L. Tyler1,2,3,4*

Departments of Medicine,1 Neurology,2 Microbiology, University of Colorado Health Sciences Center, Denver, Colorado 80262,3 Denver Veteran Affairs Medical Center, Denver, Colorado 80220,4 Xigen SA, Rue des Terreaux 17, CH-1003 Lausanne, Switzerland5

Received 5 March 2007/ Accepted 21 April 2007

Viral encephalitis is a major cause of morbidity and mortality worldwide, yet there is no proven efficacious therapy for most viral infections of the central nervous system (CNS). Many of the viruses that cause encephalitis induce apoptosis and activate c-Jun N-terminal kinase (JNK) following infection. We have previously shown that reovirus infection of epithelial cell lines activates JNK-dependent apoptosis. We now show that reovirus infection resulted in activation of JNK and caspase-3 in the CNS. Treatment of reovirus-infected mice with a cell-permeating peptide that competitively inhibits JNK activity resulted in significantly prolonged survival of intracerebrally infected mice following an otherwise lethal challenge with T3D (100x 50% lethal dose). Protection correlated with reduced CNS injury, reduced neuronal apoptosis, and reduced c-Jun activation without altering the viral titer or viral antigen distribution. Given the efficacy of the inhibitor in protecting mice from viral encephalitis, JNK inhibition represents a promising and novel treatment strategy for viral encephalitis.

* Corresponding author. Mailing address: Dept. Neurology (B182), University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262. Phone: (303) 393-2874. Fax: (303) 393-4686. E-mail: ken.tyler{at}uchsc.edu

{triangledown} Published ahead of print on 2 May 2007.

Journal of Virology, July 2007, p. 6984-6992, Vol. 81, No. 13
0022-538X/07/$08.00+0     doi:10.1128/JVI.00467-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Clarke, P., Beckham, J. D., Leser, J. S., Hoyt, C. C., Tyler, K. L. (2009). Fas-Mediated Apoptotic Signaling in the Mouse Brain following Reovirus Infection. J. Virol. 83: 6161-6170 [Abstract] [Full Text]  
  • Beckham, J. D., Tuttle, K., Tyler, K. L. (2009). Reovirus Activates Transforming Growth Factor {beta} and Bone Morphogenetic Protein Signaling Pathways in the Central Nervous System That Contribute to Neuronal Survival following Infection. J. Virol. 83: 5035-5045 [Abstract] [Full Text]  
  • Danthi, P., Kobayashi, T., Holm, G. H., Hansberger, M. W., Abel, T. W., Dermody, T. S. (2008). Reovirus Apoptosis and Virulence Are Regulated by Host Cell Membrane Penetration Efficiency. J. Virol. 82: 161-172 [Abstract] [Full Text]  


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