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 lymphocyt...

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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:
Anatomy and Physiology
APOPTOSIS
CELLS(BIOLOGY)
DEATH
EBOLA VIRUS
GENES
HEMORRHAGIC FEVERS
IN VIVO ANALYSIS
INFECTIOUS DISEASES
LIVER
LYMPHOCYTES
Medicine and Medical Research
Microbiology
MITOCHONDRIA
PATHOGENESIS
SENSE ORGANS
STIMULI
SURVIVAL(PERSONNEL)
TRANSCRIPTION(GENETICS)
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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. 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. The Journal of Immunology, 2010, 184: 327-335. Pub. in the Journal of Immunology, v184, p327-335, 2010. ISSN-0022-1767, ISSN-1550-6606. This research was supported in part by an appointment to the Postgraduate Research Participation Program at the U.S. Army Medical Research Institute for Infectious Disease administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and U.S. Army Medical Research and Materiel Command (to S.B.B.). This research was supported in part by Defense Threat Reduction Agency Grants 1-06-C-0037 (to R.S.H.) and 4.10022_08_RD_B (to S.B.). The Journal of Immunology, 2010, 184: 327?335.. The original document contains color images.