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 apoptosis in EBOV infection are known. In this study, we show data suggesting that EBOV-induced lymphocyte apoptosis in vivo occurs via both the death receptor (extrinsic) and mitochondrial (intrinsic) pathways, as both Fas-associated death domain 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 hepatocyte apoptosis likely occurs in EBOV infection, and that mice lacking the proapoptotic genes Bim and Bid had reduced hepatocyte apoptosis and liver enzyme levels postinfection. Collectively, these data suggest that EBOV induces multiple proapoptotic 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, whereas lymphocyte apoptosis appears to be nonessential for EBOV disease progression.
Bradfute
Steven B
SB
United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA.
Swanson
Paul E
PE
Smith
Mark A
MA
Watanabe
Eizo
E
McDunn
Jonathan E
JE
Hotchkiss
Richard S
RS
Bavari
Sina
S
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000096:biosynthesis; D000072224:Bcl-2-Like Protein 11; D029043:Ebolavirus / Q000502:physiology; D005434:Flow Cytometry; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000473:pathology* / Q000821:virology; D020287:In Situ Nick-End Labeling; D008214:Lymphocytes / Q000473:pathology* / Q000821:virology; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C494815:Bid protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2