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 o f different viruses. In this study, we used transmission electron microscop y (TEM) and terminal deoxynucleotidyl transferase-mediated deoxyuridine tri phosphate 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 kille d in extremis were evaluated. Apoptotic lymphocytes were seen in all tissue s examined. Filoviral replication occurred in cells of the mononuclear phag ocyte system and other well-documented cellular targets by TEM and immunohi stochemistry, but there was no evidence of replication in lymphocytes. With the exception of intracytoplasmic viral inclusions, filovirus-infected cel ls were morphologically normal or necrotic, but did not exhibit ultrastruct ural changes characteristic of apoptosis. In lymph nodes, filoviral antigen was co-localized with apoptotic lymphocytes. Examination of cell populatio ns in lymph nodes showed increased numbers of macrophages and concomitant d epletion 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 i n lymphocytes of filovirus-infected human peripheral blood mononuclear cell s by TEM. These findings suggest that lymphopenia and lymphoid depletion as sociated with filoviral infections result from lymphocyte apoptosis induced by a number of factors that may include release of various chemical mediat ors from filovirus-infected or activated cells, damage to the fibroblastic reticular cell conduit system, and possibly stimulation by a viral protein.