Apoptosis induced in vitro and in vivo during infection by Ebola and Marburg viruses.
Induction of apoptosis has been documented during infection with a number of different viruses. In this study, we used transmission electron microscopy (TEM) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling to investigate the effects of Ebola and Marburg viruses on apoptosis of different cell populations during in vitro and in vivo infections. Tissues from 18 filovirus-infected nonhuman primates killed in extremis were evaluated. Apoptotic lymphocytes were seen in all tissues examined. Filoviral replication occurred in cells of the mononuclear phagocyte system and other well-documented cellular targets by TEM and immunohistochemistry, but there was no evidence of replication in lymphocytes. With the exception of intracytoplasmic viral inclusions, filovirus-infected cells were morphologically normal or necrotic, but did not exhibit ultrastructural changes characteristic of apoptosis. In lymph nodes, filoviral antigen was co-localized with apoptotic lymphocytes. Examination of cell populations in lymph nodes showed increased numbers of macrophages and concomitant depletion of CD8+ T cells and plasma cells in filovirus-infected animals. This depletion was particularly striking in animals infected with the Zaire subtype of Ebola virus. In addition, apoptosis was demonstrated in vitro in lymphocytes of filovirus-infected human peripheral blood mononuclear cells by TEM. These findings suggest that lymphopenia and lymphoid depletion associated with filoviral infections result from lymphocyte apoptosis induced by a number of factors that may include release of various chemical mediators from filovirus-infected or activated cells, damage to the fibroblastic reticular cell conduit system, and possibly stimulation by a viral protein.
Geisbert
T W
TW
Pathology Division, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland 21702-5011, USA. tom.geisbert@amedd.army.mil
Hensley
L E
LE
Gibb
T R
TR
Steele
K E
KE
Jaax
N K
NK
Jahrling
P B
PB
D000818:Animals; D017209:Apoptosis; D029043:Ebolavirus / Q000472:pathogenicity* / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000648:ultrastructure / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008198:Lymph Nodes / Q000648:ultrastructure / Q000821:virology; D029024:Marburgvirus / Q000472:pathogenicity* / Q000648:ultrastructure; D008854:Microscopy, Electron; D009000:Monocytes / Q000648:ultrastructure / Q000821:virology; D011323:Primates