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PLoS Pathog. 2010 Jul 1;6:e1000980. doi: 10.1371/journal.ppat.1000980.

Bid regulates the pathogenesis of neurotropic reovirus.

Author information

1
Department of Biology, Indiana University, Bloomington, Indiana, United States of America. pdanthi@indiana.edu

Abstract

Reovirus infection leads to apoptosis in both cultured cells and the murine central nervous system (CNS). NF-kappaB-driven transcription of proapoptotic cellular genes is required for the effector phase of the apoptotic response. Although both extrinsic death-receptor signaling pathways and intrinsic pathways involving mitochondrial injury are implicated in reovirus-induced apoptosis, mechanisms by which either of these pathways are activated and their relationship to NF-kappaB signaling following reovirus infection are unknown. The proapoptotic Bcl-2 family member, Bid, is activated by proteolytic cleavage following reovirus infection. To understand how reovirus integrates host signaling circuits to induce apoptosis, we examined proapoptotic signaling following infection of Bid-deficient cells. Although reovirus growth was not affected by the absence of Bid, cells lacking Bid failed to undergo apoptosis. Furthermore, we found that NF-kappaB activation is required for Bid cleavage and subsequent proapoptotic signaling. To examine the functional significance of Bid-dependent apoptosis in reovirus disease, we monitored fatal encephalitis caused by reovirus in the presence and absence of Bid. Survival of Bid-deficient mice was significantly enhanced in comparison to wild-type mice following either peroral or intracranial inoculation of reovirus. Decreased reovirus virulence in Bid-null mice was accompanied by a reduction in viral yield. These findings define a role for NF-kappaB-dependent cleavage of Bid in the cell death program initiated by viral infection and link Bid to viral virulence.

PMID:
20617182
PMCID:
PMC2895667
DOI:
10.1371/journal.ppat.1000980
[Indexed for MEDLINE]
Free PMC Article

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