Pathogenesis of Ebola hemorrhagic fever in primate models: evidence that hemorrhage is not a direct effect of virus-induced cytolysis of endothelial cells.
Ebola virus (EBOV) infection causes a severe and often fatal hemorrhagic disease in humans and nonhuman primates. Whether infection of endothelial cells is central to the pathogenesis of EBOV hemorrhagic fever (HF) remains unknown. To clarify the role of endothelial cells in EBOV HF, we examined tissues of 21 EBOV-infected cynomolgus monkeys throughout time, and also evaluated EBOV infection of primary human umbilical vein endothelial cells and primary human lung-derived microvascular endothelial cells in vitro. Results showed that endothelial cells were not early cellular targets of EBOV in vivo, as viral replication was not consistently observed until day 5 after infection, a full day after the onset of disseminated intravascular coagulation. Moreover, the endothelium remained relatively intact even at terminal stages of disease. Although human umbilical vein endothelial cells and human lung-derived microvascular endothelial cells were highly permissive to EBOV replication, significant cytopathic effects were not observed. Analysis of host cell gene response at 24 to 144 hours after infection showed some evidence of endothelial cell activation, but changes were unremarkable considering the extent of viral replication. Together, these data suggest that coagulation abnormalities associated with EBOV HF are not the direct result of EBOV-induced cytolysis of endothelial cells, and are likely triggered by immune-mediated mechanisms.
Geisbert
Thomas W
TW
United States Army Medical Institute of Infectious Diseases, Fort Detrick, MD 21702-5011, USA. tom.geisbert@amedd.army.mil
Young
Howard A
HA
Jahrling
Peter B
PB
Davis
Kelly J
KJ
Larsen
Tom
T
Kagan
Elliott
E
Hensley
Lisa E
LE
D000818:Animals; D001798:Blood Proteins / Q000032:analysis; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004198:Disease Susceptibility; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000821:virology; D011464:Epoprostenol / Q000378:metabolism; D019142:Hemorrhagic Fever, Ebola / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D012709:Serum Albumin / Q000032:analysis; D014158:Transcription, Genetic
D001798:Blood Proteins; D018925:Chemokines; D016207:Cytokines; D012333:RNA, Messenger; D012709:Serum Albumin; D011464:Epoprostenol