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Journal of Virology, June 2009, p. 6161-6170, Vol. 83, No. 12
0022-538X/09/$08.00+0     doi:10.1128/JVI.02488-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Fas-Mediated Apoptotic Signaling in the Mouse Brain following Reovirus Infection{triangledown}

Penny Clarke,1* J. David Beckham,2 J. Smith Leser,1 Cristen C. Hoyt,4,{dagger} and Kenneth L. Tyler1,2,3,4,5

Departments of Neurology,1 Medicine,2 Microbiology,3 Immunology, University of Colorado Denver Health Sciences Programs, Anschutz Medical Campus, Aurora, Colorado 80045,4 Denver Veterans Administration, Denver, Colorado 802205

Received 3 December 2008/ Accepted 20 March 2009

Type 3 (T3) reovirus strains induce apoptotic neuronal cell death and lethal encephalitis in infected mice. T3 strain Dearing (T3D)-induced apoptosis in primary neuronal cultures occurs by a Fas-mediated mechanism and requires the activation of caspase 8. We now show that Fas mRNA is upregulated in the brains of mice infected with encephalitic reovirus T3D and T3 strain Abney (T3A) but not following infection with nonencephalitic reovirus type 1 strain Lang. Fas is upregulated in regions of the brain that are injured during infection with T3 reovirus strains and colocalizes with virus antigen in individual neurons. In contrast, levels of FasL mRNA induced by encephalitic and nonencephalitic reovirus strains do not differ significantly. Caspase 8, the initiator caspase associated with Fas-mediated apoptosis, is activated in the cortex and hippocampal regions of both T3D- and T3A-infected mice. Furthermore, Bid cleavage and the activation of caspase 9 in the brains of T3D-infected mice suggest that the caspase 8-dependent activation of mitochondrial apoptotic signaling contributes to virus-induced apoptosis. We have previously shown that the inhibition of c-Jun N-terminal kinase (JNK) signaling blocks T3D-induced apoptosis and improves the outcome of virus-induced encephalitis. We now show that the reovirus-induced upregulation of Fas requires JNK signaling, thereby providing a link between reovirus-induced death receptor signaling and mitogen-activated protein kinase pathways and a potential mechanism for the therapeutic action of JNK inhibition.

* Corresponding author. Mailing address: Department of Neurology, University of Colorado Denver Health Sciences Programs, Campus Mail Stop B182, Research Complex 2, 12700 E. 19th Avenue, Aurora, CO 80045. Phone: (303) 724-4333. Fax: (303) 724-4329. E-mail: Penny.Clarke{at}uchsc.edu

{triangledown} Published ahead of print on 25 March 2009.

{dagger} Present address: Abbott Laboratories, Santa Clara, CA.

Journal of Virology, June 2009, p. 6161-6170, Vol. 83, No. 12
0022-538X/09/$08.00+0     doi:10.1128/JVI.02488-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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