Natural history of Ebola virus disease in rhesus monkeys shows viral variant emergence dynamics and tissue-specific host responses

Authors: NORMANDIN, ERICA - Broad Institute Of Mit/harvard; TRIANA, SERGIO - Broad Institute Of Mit/harvard; RAJU, SIDDHARTH - Broad Institute Of Mit/harvard; LAN, TAMMY - Broad Institute Of Mit/harvard; LAGERBORG, KIM - Broad Institute Of Mit/harvard; RUDY, MELISSA - Broad Institute Of Mit/harvard; ADAMS, GORDON - Broad Institute Of Mit/harvard; DERUFF, KATHERINE - Broad Institute Of Mit/harvard; LOGUE, JAMES - National Institutes Of Health (NIH); LIU, DAVID - National Institutes Of Health (NIH); STREBINGER, DANIEL - Broad Institute Of Mit/harvard; RAO, ARYA - Columbia University - New York; MESSER, KATELYN - Broad Institute Of Mit/harvard; SACKS, MOLLY - Broad Institute Of Mit/harvard; ADAMS, RICKY - National Institutes Of Health (NIH); JANOSKO, KRISZTINA - Broad Institute Of Mit/harvard; KOTLIAR, DYLAN - Broad Institute Of Mit/harvard; SHAH, RICKEY - Broad Institute Of Mit/harvard; CROZIER, IAN - Frederick National Laboratory For Cancer Research; RINN, JOHN - University Of Colorado; MELE, MARTA - Consultant; HONKO, ANNA - National Institutes Of Health (NIH); ZHANG, FENG - Broad Institute Of Mit/harvard; BABADI, MEHRTASH - Broad Institute Of Mit/harvard; LUBAN, JEREMY - Broad Institute Of Mit/harvard; BENNETT, RICHARD - National Institutes Of Health (NIH); SHALEK, ALEX - Broad Institute Of Mit/harvard; BARKAS, NIKOLAOS - Broad Institute Of Mit/harvard; LIN, AARON - Broad Institute Of Mit/harvard; Hensley, Lisa; SABETI, PARDIS - Broad Institute Of Mit/harvard; SIDDLE, KATHERINE - Broad Institute Of Mit/harvard

Submitted to: Cell Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/15/2023
Publication Date: 11/21/2023
Citation: Normandin, E., Triana, S., Raju, S.S., Lan, T.C., Lagerborg, K., Rudy, M., Adams, G.C., Deruff, K.C., Logue, J., Liu, D., Strebinger, D., Rao, A., Messer, K.S., Sacks, M., Adams, R.D., Janosko, K., Kotliar, D., Shah, R., Crozier, I., Rinn, J.L., Mele, M., Honko, A.N., Zhang, F., Babadi, M., Luban, J., Bennett, R.S., Shalek, A.K., Barkas, N., Lin, A.E., Hensley, L.E., Sabeti, P.C., Siddle, K.J. 2023. Natural history of Ebola virus disease in rhesus monkeys shows viral variant emergence dynamics and tissue-specific host responses. Cell Genomics. 3(12). https://doi.org/10.1016/j.xgen.2023.100440.
DOI: https://doi.org/10.1016/j.xgen.2023.100440

Interpretive Summary: This paper explored the responses that occur in the bone marrow during infection with Ebola virus. Ebola virus is a hemorrhagic fever virus causing severe disease in humans and nonhuman primates. Closely related viruses have also been demonstrated to cause disease in pigs. How the virus causes such severe disease remains unknown. This paper documents that changes that occur over the course of the infection. The work will help researchers identify how the virus causes such severe disease and how the immune system tries to fight the infection and provides the first insight into how the virus affects the bone marrow.

Technical Abstract: The pathophysiology of long-recognized hematologic abnormalities in Ebolavirus (EBOV) 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 model of EVD, 18 sternal BM samples exposed to the Kikwit strain of EBOV were compared to those from 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 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 current pathophysiologic unknowns and suggest a crucial role for BM dysfunction and/or failure, including emergency hematopoiesis, as part of the natural history of severe human disease.