Clinical and immunological correlates of vasodilatory shock among Ebola virus infected nonhuman primates in a critical care model
Sydney R Stein, Andrew P Platt, Heather L Teague, Scott M Anthony, Rebecca J Reeder, Kurt Cooper, Russell Byrum, David J Drawbaugh, David X Liu, Tracey L Burdette, Kyra Hadley, Bobbi Barr, Seth Warner, Francisco Rodriguez-Hernandez, Cristal Johnson, Phil Stanek, Joseph Hischak, Heather Kendall, Louis M Huzella, Jeffrey R Strich, Richard Herbert, Marisa St. Claire, Kevin M Vannella, Michael R Holbrook, Daniel S Chertow- Infectious Diseases
- Immunology and Allergy
Abstract
Background
Existing nonhuman primate models of Ebola virus infection have not fully characterized the physiology of shock and its association with daily virological, clinical, and immunological parameters. We implemented a nonhuman primate critical care model to study the progression and nature of shock following Ebola virus infection relative to viremia, organ dysfunction, coagulopathy, and daily high-dimensional circulating immune cell phenotyping.
Methods
Two rhesus macaques were inoculated intramuscularly with a target dose of 1000 plaque forming units of Ebola virus, Makona variant. Supportive critical care was initiated on study day 3 including mechanical ventilation, invasive hemodynamic monitoring, fluid and electrolyte management, empiric antibiotics, and stress-dose steroids. High dimensional spectral cytometry was used to broadly phenotype neutrophils and peripheral blood mononuclear cells daily.
Results
Ebola virus infection induced progressive vasodilatory shock with preserved cardiac function after an exponential rise in viremia beginning on day 5 post infection. Multi-organ dysfunction began day 6 post infection coincident with a nadir in circulating neutrophils. Consumptive coagulopathy and anemia were observed by days 7 to 8 post infection concurrent with irreversible shock which preceded death. The monocyte repertoire began shifting at D4 with a decline in circulating classical monocytes and expansion of double negative monocytes followed by upregulation of the hemoglobin scavenger CD163 and collapse of the monocyte repertoire concurrent with viremia. Among lymphocytes a selective loss of CXCR3 positive B and T cells, expansion of naïve B cells, and activation of NK cells follows the onset of viremia.
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 multi-organ failure.