Clinical and Immunologic Correlates of Vasodilatory Shock Among Ebola Virus–Infected Nonhuman Primates in a Critical Care Model

• Published in: The Journal of infectious diseases Vol. 228; no. Supplement_7; pp. S635 - S647
• Main Authors: Stein, Sydney R, Platt, Andrew P, Teague, Heather L, Anthony, Scott M, Reeder, Rebecca J, Cooper, Kurt, Byrum, Russell, Drawbaugh, David J, Liu, David X, Burdette, Tracey L, Hadley, Kyra, Barr, Bobbi, Warner, Seth, Rodriguez-Hernandez, Francisco, Johnson, Cristal, Stanek, Phil, Hischak, Joseph, Kendall, Heather, Huzella, Louis M, Strich, Jeffrey R, Herbert, Richard, St. Claire, Marisa, Vannella, Kevin M, Holbrook, Michael R, Chertow, Daniel S
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 15.11.2023
• Subjects: Animal models; Animals; Cell activation; Critical Care; CXCR3 protein; Cytometry; Ebola virus; Ebolavirus; Hemorrhagic Fever, Ebola; Humans; Leukocytes (neutrophilic); Leukocytes, Mononuclear; Lymphocytes B; Lymphocytes T; Macaca mulatta; Monocytes; Natural killer cells; Neutrophils; Pathophysiology; Peripheral blood mononuclear cells; Phenotypes; Shock; Viremia; Viruses; Ebola virus; pathogenesis; nonhuman primate; intensive care; filovirus
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiad374

Abstract Background Existing models of Ebola virus infection have not fully characterized the pathophysiology of shock in connection with daily virologic, clinical, and immunologic parameters. We implemented a nonhuman primate critical care model to investigate these associations. Methods Two rhesus macaques received a target dose of 1000 plaque-forming units of Ebola virus intramuscularly with supportive care initiated on day 3. High-dimensional spectral cytometry was used to phenotype neutrophils and peripheral blood mononuclear cells daily. Results We observed progressive vasodilatory shock with preserved cardiac function following viremia onset on day 5. Multiorgan dysfunction began on day 6 coincident with the nadir of circulating neutrophils. Consumptive coagulopathy and anemia occurred on days 7 to 8 along with irreversible shock, followed by death. The monocyte repertoire began shifting on day 4 with a decline in classical and expansion of double-negative monocytes. A selective loss of CXCR3-positive B and T cells, expansion of naive B cells, and activation of natural killer cells followed viremia onset. Conclusions Our model allows for high-fidelity characterization of the pathophysiology of acute Ebola virus infection with host innate and adaptive immune responses, which may advance host-targeted therapy design and evaluation for use after the onset of multiorgan failure.