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. 2011 Nov;204 Suppl 3(Suppl 3):S991-9.
doi: 10.1093/infdis/jir336.

Host response dynamics following lethal infection of rhesus macaques with Zaire ebolavirus

Hideki Ebihara  1 , Barry Rockx, Andrea Marzi, Friederike Feldmann, Elaine Haddock, Douglas Brining, Rachel A LaCasse, Don Gardner, Heinz Feldmann
Affiliations

Host response dynamics following lethal infection of rhesus macaques with Zaire ebolavirus

Hideki Ebihara et al. J Infect Dis. 2011 Nov.

Abstract

To gain further insight into the interdependent pathogenic processes in Ebola hemorrhagic fever (EHF), we have examined the dynamics of host responses in individual rhesus macaques infected with Zaire ebolavirus over the entire disease course. Examination of coagulation parameters revealed that decreased coagulation inhibitor activity triggered severe coagulopathy as indicated by prolonged coagulation times and decreased fibrinogen levels. This has been proposed as one of the significant mechanisms underlying disseminated intravascular coagulation in EHF patients. Furthermore, monitoring of expression levels for cytokines/chemokines suggested a mixed anti-inflammatory response syndrome (MARS), which indicates that a catastrophic uncontrolled immunological status contributes to the development of fatal hemorrhagic fever. These results highlight the pathological analogies between EHF and severe sepsis and not only contribute to our understanding of the pathogenic process, but will also help to establish novel postexposure treatment modalities.

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Figures

Figure 1.
Figure 1.
Disease progression in rhesus macaques following Zaire ebolavirus (ZEBOV) infection. Three rhesus macaques (subjects 14, 15, and 16) were infected via intramuscular injection with 1000 focus-forming units of ZEBOV (Mayinga strain). Clinical examination and sample collections were performed daily until animals were euthanized. (A) Disease progression and clinical presentations. Dagger: euthanasia, when clinical signs indicated terminal disease according to an endpoint-scoring sheet. (B) Total white blood cell (WBC) and lymphocyte (LY) counts. (C) Differential neutrophil (NE) and LY counts. (D) Platelet (PLT) counts. (E) Viremia. Viral infectivity titration was performed on Vero E6 cells by use of a median tissue culture infective dose (TCID50) assay. Infectivity titers are presented as log10 TCID50/mL.
Figure 2.
Figure 2.
Development of coagulation abnormalities in rhesus macaques during Zaire ebolavirus (Mayinga strain) infection. (A) Prothrombin time (PT). (B) Activated partial thromboplastin time (aPTT). (C) Thrombin time (TT). (D) Fibrinogen concentration in plasma. (E) Plasma protein C coagulation inhibitor activity. The y-axis describes values as percentage of normal human coagulation inhibitor activity. (F) Plasma protein S coagulation inhibitor activity. The y-axis describes values as percentage of normal human coagulation inhibitor activity.
Figure 3.
Figure 3.
Kinetics of plasma proinflammatory cytokine and chemokine levels in rhesus macaques following Zaire ebolavirus (Mayinga strain) infection. (A) IL-1β, (B) IL-6, (C) TNF-α, (D) MIP-1α. IL, interleukin; MIP, macrophage inflammatory protein; TNF, tumor necrosis factor.
Figure 4.
Figure 4.
Kinetics of plasma proinflammatory cytokine and chemokine levels activating T cells in rhesus macaques following Zaire ebolavirus (Mayinga strain) infection. (A) IFN-γ, (B) IL-12/23 p40, (C) IL-15, (D) IL-18. IFN, interferon; IL, interleukin.
Figure 5.
Figure 5.
Kinetics of plasma anti-inflammatory mediators, and soluble CD40 ligand (sCD40L) levels in rhesus macaques following Zaire ebolavirus (Mayinga strain) infection. (A) IL-10, (B) IL-13, (C) IL-1 receptor antagonist (IL-1ra), (D) sCD40L. IL, interleukin.
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