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Abstract

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Therapeutics of Ebola hemorrhagic fever: Whole-genome transcriptional analysis of successful disease mitigation

Ebola virus (EBOV), a member of the Filoviridae, causes severe and often lethal hemorrhagic fever in humans and nonhuman primates by dysregulation of the normal host immune responses and the development of coagulopathies. Previous studies indicate that recombinant nematode anticoagulant protein c2 (rNAPc2) is capable of decreasing pathogenesis in animal models; it has been hypothesized that decreasing hypercoagulation is correlated with increased survival. To determine the effect of anticoagulants on the temporal gene expression profile of EBOV-infected macaques, animals were administered either rNAPc2 or anti-sepsis drug recombinant human protein C (rhAPC), two unique anticoagulants that work directly on the blood coagulation pathway.

We found that the genome-wide transcriptional response of blood leukocytes to EBOV infection is characteristic of infected animals, and is associated with a unique expression profile dependent on treatment or disease outcome (survival). The temporal profile was similar to earlier studies, and showed the typical early-infection up-regulation of innate immune response; overall immune response to EBOV infection was similar regardless of treatment. Although a unique treatment-associated response was not observed, the results suggest that controlling coagulopathy during early infection can notably impact disease outcome, as evidenced by a clear effect of treatment on genes associated with blood coagulation.

Of particular interest is the predictive signature that distinguishes between surviving and non-responding animals, which can be detected during early infection. This signature suggests that it is feasible to identify unique sets of biomarkers that can detect early pathogenesis and predict disease severity and outcome.