Death receptor-mediated apoptotic signaling is activated in the brain following infection with west nile virus in the absence of a peripheral immune response

Penny Clarke, J. Smith Leser, Eamon D. Quick, Kalen R. Dionne, J. David Beckham, Kenneth L. Tyler

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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.

Original languageEnglish
Pages (from-to)1080-1089
Number of pages10
JournalJournal of virology
Volume88
Issue number2
DOIs
StatePublished - Jan 2014

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