title: The proapoptotic Bcl-2 protein Bax plays an important role in the pathogenesis of reovirus encephalitis.
abstract: Encephalitis induced by reovirus serotype 3 (T3) strains results from the apoptotic death of infected neurons. Extrinsic apoptotic signaling is activated in reovirus-infected neurons in vitro and in vivo, but the role of intrinsic apoptosis signaling during encephalitis is largely unknown. Bax plays a key role in intrinsic apoptotic signaling in neurons by allowing the release of mitochondrial cytochrome c. We found Bax activation and cytochrome c release in neurons following infection of neonatal mice with T3 reoviruses. Bax(-/-) mice infected with T3 Abney (T3A) have reduced central nervous system (CNS) tissue injury and decreased apoptosis, despite viral replication that is similar to that in wild-type (WT) Bax(+/+) mice. In contrast, in the heart, T3A-infected Bax(-/-) mice have viral growth, caspase activation, and injury comparable to those in WT mice, indicating that the role of Bax in pathogenesis is organ specific. Nonmyocarditic T3 Dearing (T3D)-infected Bax(-/-) mice had delayed disease and enhanced survival compared to WT mice. T3D-infected Bax(-/-) mice had significantly lower viral titers and levels of activated caspase 3 in the brain despite unaffected transneuronal spread of virus. Cytochrome c and Smac release occurred in some reovirus-infected neurons in the absence of Bax; however, this was clearly reduced compared to levels seen in Bax(+/+) wild-type mice, indicating that Bax is necessary for efficient activation of proapoptotic mitochondrial signaling in infected neurons. Our studies suggest that Bax is important for reovirus growth and pathogenesis in neurons and that the intrinsic pathway of apoptosis, mediated by Bax, is important for full expression of disease, CNS tissue injury, apoptosis, and viral growth in the CNS of reovirus-infected mice.
authors.affiliation: Department of Microbiology, University of Colorado School of Medicine Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Berens
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Tyler
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000473:pathology; D018792:Encephalitis, Viral / Q000473:pathology / Q000821:virology*; D006651:Histocytochemistry; D054884:Host-Pathogen Interactions; D051379:Mice; D018345:Mice, Knockout; D008853:Microscopy; D008969:Molecular Sequence Data; D012087:Reoviridae / Q000472:pathogenicity*; D012088:Reoviridae Infections / Q000821:virology*; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000378:metabolism*
chemical_list: C494827:Bax protein, mouse; D051028:bcl-2-Associated X Protein