Mechanisms and Consequences of Ebolavirus-Induced Lymphocyte Apoptosis
ARMY MEDICAL RESEARCH INST OF INFECTIOUS DISEASES FORT DETRICK MD
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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 pathways 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.
- Medicine and Medical Research