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

Abstract

The pathophysiology of long-recognized hematologic abnormalities in Ebolavirus (EBOV) disease is unknown. From limited human sampling (of peripheral blood), it has been postulated that emergency hematopoiesis plays a role in severe EBOV disease, but the bone marrow (BM) has not been systematically characterized in human disease or in nonhuman primate models. In a rhesus macaque model of fatal EBOV disease, 18 sternal BM samples exposed to the Kikwit strain of EBOV were compared to those from uninfected controls (n = 3). On IHC analysis, RNAscope in situ hybridization, transmission electron microscopy, and confocal microscopy, BM monocytes/macrophages and megakaryocytes were EBOV infected. EBOV exposure was associated with severe BM hypocellularity, including depletion of myeloid, erythroid, and megakaryocyte hematopoietic cells. These depletions were negatively correlated with cell proliferation (Ki67 expression) and were not associated with BM apoptosis during disease progression. In EBOV-infected rhesus macaques with terminal disease, BM 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 pathophysiologic unknowns and suggest a crucial role for BM dysfunction and/or failure, including emergency hematopoiesis, in the natural history of severe human disease.