Ebola virus is very pathogenic in humans. It induces an acute hemorrhagic fever that leads to death in about 70% of patients. We compared the immune responses of patients who died from Ebola virus disease with those who survived during two large outbreaks in 1996 in Gabon. In survivors, early and increasing levels of IgG, directed mainly against the nucleoprotein and the 40-kDa viral protein, were followed by clearance of circulating viral antigen and activation of cytotoxic T cells, which was indicated by the upregulation of FasL, perforin, CD28 and gamma interferon mRNA in peripheral blood mononuclear cells. In contrast, fatal infection was characterized by impaired humoral responses, with absent specific IgG and barely detectable IgM. Early activation of T cells, indicated by mRNA patterns in peripheral blood mononuclear cells and considerable release of gamma interferon in plasma, was followed in the days preceding death by the disappearance of T cell-related mRNA (including CD3 and CD8). DNA fragmentation in blood leukocytes and release of 41/7 nuclear matrix protein in plasma indicated that massive intravascular apoptosis proceeded relentlessly during the last 5 days of life. Thus, events very early in Ebola virus infection determine the control of viral replication and recovery or catastrophic illness and death.

SUMMARY Ebola virus subtype Zaire (Ebo‐Z) induces acute haemorrhagic fever and a 60–80% mortality rate in humans. Inflammatory responses were monitored in victims and survivors of Ebo‐Z haemorrhagic fever during two recent outbreaks in Gabon. Survivors were characterized by a transient release in plasma of interleukin‐1β (IL‐1β), IL‐6, tumour necrosis factor‐α (TNFα), macrophage inflammatory protein‐1α (MIP‐1α) and MIP‐1β early in the disease, followed by circulation of IL‐1 receptor antagonist (IL‐1RA) and soluble receptors for TNFα (sTNF‐R) and IL‐6 (sIL‐6R) towards the end of the symptomatic phase and after recovery. Fatal infection was associated with moderate levels of TNFα and IL‐6, and high levels of IL‐10, IL‐1RA and sTNF‐R, in the days before death, while IL‐1β was not detected and MIP‐1α and MIP‐1β concentrations were similar to those of endemic controls. Simultaneous massive activation of monocytes/macrophages, the main target of Ebo‐Z, was suggested in fatal infection by elevated neopterin levels. Thus, presence of IL‐1β and of elevated concentrations of IL‐6 in plasma during the symptomatic phase can be used as markers of non‐fatal infection, while release of IL‐10 and of high levels of neopterin and IL‐1RA in plasma as soon as a few days after the disease onset is indicative of a fatal outcome. In conclusion, recovery from Ebo‐Z infection is associated with early and well‐regulated inflammatory responses, which may be crucial in controlling viral replication and inducing specific immunity. In contrast, defective inflammatory responses and massive monocyte/macrophage activation were associated with fatal outcome.