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Journal of Virology, January 2008, p. 161-172, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.01739-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Reovirus Apoptosis and Virulence Are Regulated by Host Cell Membrane Penetration Efficiency{triangledown}

Pranav Danthi,1,2 Takeshi Kobayashi,1,2 Geoffrey H. Holm,1,2 Mark W. Hansberger,2,3 Ty W. Abel,4 and Terence S. Dermody1,2,3*

Departments of Pediatrics,1 Microbiology and Immunology,3 Pathology,4 Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, Tennessee 372322

Received 9 August 2007/ Accepted 17 October 2007

Apoptosis plays an important role in the pathogenesis of reovirus encephalitis and myocarditis in infected animals. Differences in apoptosis efficiency displayed by reovirus strains are linked to the viral µ1-encoding M2 gene segment. Studies using pharmacologic inhibitors of reovirus replication demonstrate that apoptosis induction by reovirus requires viral disassembly in cellular endosomes but not RNA synthesis. Since the µ1 protein functions to pierce endosomal membranes during this temporal window, these findings point to an important role for µ1 in activating signaling pathways that lead to apoptosis. To understand mechanisms used by µ1 to induce apoptosis, a panel of µ1 mutant viruses generated by reverse genetics was analyzed for the capacities to penetrate host cell membranes, activate proapoptotic signaling pathways, evoke cell death, and produce encephalitis in newborn mice. We found that single amino acid changes within the {delta} region of µ1 reduce the efficiency of membrane penetration. These mutations also diminish the capacities of reovirus to activate proapoptotic transcription factors NF-{kappa}B and IRF-3 and elicit apoptosis. Additionally, we observed that following intracranial inoculation, an apoptosis-deficient µ1 mutant is less virulent in newborn mice in comparison to the wild-type virus. These results indicate a critical function for the membrane penetration activity of µ1 in evoking prodeath signaling pathways that regulate reovirus pathogenesis.

* Corresponding author. Mailing address: Lamb Center for Pediatric Research, D7235 MCN, Vanderbilt University School of Medicine, Nashville, TN 37232. Phone: (615) 343-9943. Fax: (615) 343-9723. E-mail: terry.dermody{at}vanderbilt.edu

{triangledown} Published ahead of print on 24 October 2007.

Journal of Virology, January 2008, p. 161-172, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.01739-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Douville, R. N., Su, R.-C., Coombs, K. M., Simons, F. E. R., HayGlass, K. T. (2008). Reovirus Serotypes Elicit Distinctive Patterns of Recall Immunity in Humans. J. Virol. 82: 7515-7523 [Abstract] [Full Text]  


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