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Journal of Virology, March 2005, p. 2743-2753, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.2743-2753.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Nonstructural Protein {sigma}1s Is a Determinant of Reovirus Virulence and Influences the Kinetics and Severity of Apoptosis Induction in the Heart and Central Nervous System

Cristen C. Hoyt,1 Sarah M. Richardson-Burns,2 Robin J. Goody,3 Bridget A. Robinson,3 Roberta L. DeBiasi,3,4 and Kenneth L. Tyler1,2,3,5,6,7*

Departments of Immunology,1 Neurology,3 Pediatrics,4 Microbiology,5 Medicine,2 Program in Neurosciences, University of Colorado Health Sciences Center,6 Denver Veterans Affairs Medical Center, Denver, Colorado7

Received 25 May 2004/ Accepted 11 October 2004

The mechanisms by which viruses kill susceptible cells in target organs and ultimately produce disease in the infected host remain poorly understood. Dependent upon the site of inoculation and strain of virus, experimental infection of neonatal mice with reoviruses can induce fatal encephalitis or myocarditis. Reovirus-induced apoptosis is a major mechanism of tissue injury, leading to disease development in both the brain and heart. In cultured cells, differences in the capacity of reovirus strains to induce apoptosis are determined by the S1 gene segment, which also plays a major role as a determinant of viral pathogenesis in both the heart and the central nervous system (CNS) in vivo. The S1 gene is bicistronic, encoding both the viral attachment protein sigma-1 and the nonstructural protein sigma-1-small ({sigma}1s). Although {sigma}1s is dispensable for viral replication in vitro, we wished to investigate the expression of {sigma}1s in the infected heart and brain and its potential role in reovirus pathogenesis in vivo. Two-day-old mice were inoculated intramuscularly or intracerebrally with either {sigma}1s– or {sigma}1s+ reovirus strains. While viral replication in target organs did not differ between {sigma}1s– and {sigma}1s+ viral strains, virus-induced caspase-3 activation and resultant histological tissue injury in both the heart and brain were significantly reduced in {sigma}1s– reovirus-infected animals. These results demonstrate that {sigma}1s is a determinant of the magnitude and extent of reovirus-induced apoptosis in both the heart and CNS and thereby contributes to reovirus pathogenesis and virulence.

* Corresponding author. Mailing address: Department of Neurology (B-182), University of Colorado Health Sciences Center, 4200 E. 9th Ave., Denver, CO 80262. Phone: (303) 393-2874. Fax: (303) 393-4686. E-mail: Ken.Tyler{at}uchsc.edu.

Journal of Virology, March 2005, p. 2743-2753, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.2743-2753.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Beckham, J. D., Goody, R. J., Clarke, P., Bonny, C., Tyler, K. L. (2007). Novel Strategy for Treatment of Viral Central Nervous System Infection by Using a Cell-Permeating Inhibitor of c-Jun N-Terminal Kinase. J. Virol. 81: 6984-6992 [Abstract] [Full Text]  
  • Coffey, C. M., Sheh, A., Kim, I. S., Chandran, K., Nibert, M. L., Parker, J. S. L. (2006). Reovirus Outer Capsid Protein {micro}1 Induces Apoptosis and Associates with Lipid Droplets, Endoplasmic Reticulum, and Mitochondria.. J. Virol. 80: 8422-8438 [Abstract] [Full Text]  
  • Liu, M., Vakharia, V. N. (2006). Nonstructural protein of infectious bursal disease virus inhibits apoptosis at the early stage of virus infection.. J. Virol. 80: 3369-3377 [Abstract] [Full Text]  


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