Mechanisms and Consequences of Ebolavirus-Induced Lymphocyte Apoptosis

Ebolavirus (EBOV) is a member of the filovirus family and causes severe hemorrhagic fever, resulting in death in up to 90% of infected humans. EBOV infection induces massive bystander lymphocyte apoptosis; however, neither the cellular apoptotic pathway(s) nor the systemic implications of lymphocyte...

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Bibliographic Details
Main Authors: Bradfute, Steven B, Swanson, Paul E, Smith, Mark A, Watanabe, Eizo, McDunn, Jonathan E, Hotchkiss, Richard S, Bavari, Sina
Format: Report
Language:English
Subjects:
APOPTOSIS
CELLS(BIOLOGY)
DEATH
DEATH RECEPTOR
EBOLA
EBOLA VIRUS
ENZYMES
FILOVIRUS
GENES
HEMORRHAGIC FEVERS
HUMANS
IN VIVO ANALYSIS
INFECTIOUS DISEASES
KNOCKOUT MICE
LABORATORY ANIMALS
LIVER
LYMPHOCYTE APOPTOSIS
LYMPHOCYTES
Medicine and Medical Research
MITOCHONDRIA
PATHOGENESIS
REDUCTION
SENSE ORGANS
SURVIVAL(PERSONNEL)
TRANSCRIPTION(GENETICS)
TRANSGENIC
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Summary:Ebolavirus (EBOV) is a member of the filovirus family and causes severe hemorrhagic fever, resulting in death in up to 90% of infected humans. EBOV infection induces massive bystander lymphocyte apoptosis; however, neither the cellular apoptotic pathway(s) nor the systemic implications of lymphocyte apoptosis in EBOV infection are known. Herein we show that EBOV-induced lymphocyte apoptosis in vivo occurs via both the death receptor (extrinsic) and mitochondrial (intrinsic) pathways, as both Fas associated death domain (FADD) dominant negative transgenic mice and mice overexpressing bcl-2 were resistant to EBOV-induced lymphocyte apoptosis. Surprisingly, inhibiting lymphocyte apoptosis during EBOV infection did not result in improved animal survival. Furthermore, we show for the first time that significant hepatocyte apoptosis likely occurs in EBOV infection, and that mice lacking the proapoptotic genes bim and bid had reduced hepatocyte apoptosis and marked reduction in liver enzyme levels in plasma after infection. Collectively, these data suggest that EBOV induces multiple pro-apoptotic stimuli and that blocking lymphocyte apoptosis is not sufficient to improve survival in EBOV infection. These data suggest that hepatocyte apoptosis may play a role in the pathogenesis of EBOV infection while lymphocyte apoptosis appears to be non-essential for EBOV pathogenesis. The original document contains color images. Pub. in Journal Immunology, v184, p327-335, 2010.