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

被引:39
作者
Clarke, Penny [1 ]
Beckham, J. David [2 ]
Leser, J. Smith [1 ]
Hoyt, Cristen C. [4 ]
Tyler, Kenneth L. [1 ,2 ,3 ,4 ,5 ]
机构
[1] Univ Colorado, Denver Hlth Sci Programs, Dept Neurol, Aurora, CO 80045 USA
[2] Univ Colorado, Denver Hlth Sci Programs, Dept Med, Aurora, CO 80045 USA
[3] Univ Colorado, Denver Hlth Sci Programs, Dept Microbiol, Aurora, CO 80045 USA
[4] Univ Colorado, Denver Hlth Sci Programs, Dept Immunol, Aurora, CO 80045 USA
[5] Denver Vet Adm, Denver, CO 80220 USA
基金
美国国家卫生研究院;
关键词
NF-KAPPA-B; CENTRAL-NERVOUS-SYSTEM; PROTEIN-KINASE PATHWAYS; VIRUS TYPE-1 INFECTION; T-CELLS; UP-REGULATION; LIGAND EXPRESSION; ACTIVATION; DEATH; TRANSCRIPTION;
D O I
10.1128/JVI.02488-08
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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.
引用
收藏
页码:6161 / 6170
页数:10
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