Bid Regulates the Pathogenesis of Neurotropic Reovirus

PLoS Pathogens

Geoffrey H. Holm¹  Pranav Danthi¹  Sandra S. Zinkel²  Andrea J. Pruijssers²  Angela K. Berger³  Terence S. Dermody³ 

[1] Department of Biology, Indiana University, Bloomington, Indiana, United States of America;Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America;Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America

关键词: Apoptosis;    Transcription factors;    Apoptotic signaling cascade;    Central nervous system;    Mitochondria;    Viral replication;    Brain damage;    Immune serum;   

DOI  :  10.1371/journal.ppat.1000980

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Reovirus infection leads to apoptosis in both cultured cells and the murine central nervous system (CNS). NF-κB-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-κB 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-κB 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-κB-dependent cleavage of Bid in the cell death program initiated by viral infection and link Bid to viral virulence.

【 授权许可】

CC BY