title: Death receptor-mediated apoptotic signaling is activated in the brain following infection with West Nile virus in the absence of a peripheral immune response.
abstract: Apoptosis is an important mechanism of West Nile virus (WNV) pathogenesis within the central nervous system (CNS). The signaling pathways that result in WNV-induced apoptotic neuronal death within the CNS have not been established. In this study, we identified death receptor (DR)-induced apoptosis as a pathway that may be important in WNV pathogenesis, based on the pattern of differential gene expression in WNV-infected, compared to uninfected, brains. Reverse transcription-PCR (RT-PCR) and Western blotting confirmed that genes involved in DR-induced apoptotic signaling are upregulated in the brain following WNV infection. Activity of the DR-associated initiator caspase, caspase 8, was also increased in the brains of WNV-infected mice and occurred in association with cleavage of Bid and activation of caspase 9. These results demonstrate that DR-induced apoptotic signaling is activated in the brain following WNV infection and suggest that the caspase 8-dependent cleavage of Bid promotes intrinsic apoptotic signaling within the brains of infected animals. Utilization of a novel ex vivo brain slice culture (BSC) model of WNV encephalitis revealed that inhibition of caspase 8 decreases virus-induced activation of caspase 3 and tissue injury. The BSC model allows us to examine WNV-induced pathogenesis in the absence of a peripheral immune response. Thus, our results indicate that WNV-induced neuronal injury in the brain is mediated by DR-induced apoptosis signaling and can occur in the absence of infiltrating immune cells. However, astrocytes and microglia were activated in WNV-infected BSC, suggesting that local immune responses influence WNV pathogenesis.
authors.affiliation: Department of Neurology, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Penny
authors.initials: P
authors.lastname: Clarke
authors.forename: J Smith
authors.initials: JS
authors.lastname: Leser
authors.forename: Eamon D
authors.initials: ED
authors.lastname: Quick
authors.forename: Kalen R
authors.initials: KR
authors.lastname: Dionne
authors.forename: J David
authors.initials: JD
authors.lastname: Beckham
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Tyler
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000166:cytology* / Q000201:enzymology / Q000276:immunology / Q000821:virology; D053148:Caspase 3 / Q000235:genetics / Q000276:immunology; D053181:Caspase 8 / Q000235:genetics / Q000276:immunology; D053453:Caspase 9 / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D017933:Peripheral Nervous System / Q000201:enzymology / Q000276:immunology* / Q000821:virology; D053218:Receptors, Death Domain / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D014901:West Nile Fever / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D014902:West Nile virus / Q000235:genetics / Q000502:physiology*
chemical_list: D053218:Receptors, Death Domain; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9