Depletion of Bone Marrow Hematopoietic Cells in Ebola Virus-Infected Rhesus Macaques: A Possible Cause of Hematologic Abnormalities in Ebola Virus Disease.

The pathophysiology of long-recognized hematological abnormalities in Ebola virus disease (EVD) is unknown. From limited human sampling (of peripheral blood), it has been postulated that emergency hematopoiesis plays a role in severe EVD, but the systematic characterization of the bone marrow (BM) has not occurred in human disease or in nonhuman primate models. In a lethal rhesus macaque (RhM) model of EVD, sternal BMs from eighteen RhMs were characterized after intramuscular exposure to Ebola virus (EBOV) Kikwit as compared to uninfected controls (n=3). Immunohistochemistry, RNAscope in situ hybridization, transmission electron microscopy, and confocal microscopy showed that EBOV infects BM monocytes/macrophages and megakaryocytes. EBOV exposure was associated with severe BM hypocellularity, including depletion of myeloid, erythroid, and megakaryocyte hematopoietic cell populations. These depletions were negatively correlated with cell proliferation (Ki67 expression) and neither associated with BM apoptosis during disease progression. At terminal disease, BM sampled from EBOV-infected RhMs showed marked hemophagocytosis, megakaryocyte emperipolesis, and the release of immature hematopoietic cells into the sinusoids. Collectively, these data demonstrate not only direct EBOV infection of BM monocytes/macrophages and megakaryocytes but also that disease progression is associated with hematopoietic failure, notably in peripheral cytopenia. These findings inform current pathophysiologic unknowns and suggest a crucial role for bone marrow dysfunction and/or failure, including emergency hematopoiesis, as part of the natural history of severe human disease.