Defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in Ebola virus-infected patients

Abstract

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.

Ebola virus: The role of macrophages and dendritic cells in the pathogenesis of Ebola hemorrhagic fever

“…Blood samples from fatally infected African patients also show reduced lymphocyte counts and biochemical markers of apoptosis, suggesting that a similar process occurs in humans (Baize et al, 1999).…”

How Ebola and Marburg viruses battle the immune system

“…The first suggestions of this concept came from the observed clinical manifestations of advanced filoviral diseases in humans 38 and monkeys 39 , in which there were pronounced indications of apoptotic death of lymphocyte populations in peripheral blood and lymph nodes. Because contraction -the loss of some 95% of cells that had proliferated in response to antigenic stimulation -is a normal part of immune homeostasis 40 , it was unclear at first the degree to which these observations were exaggerated in filoviruses compared with other acute infections.…”

“…Returning to the particular case of filoviruses and the acute diseases that they cause, recent investigations in individuals and non-human primates infected with filoviruses have demonstrated the gradual disappearance and deletion of CD8 + T cells and NK cells 38,50 . That little or no immune response to the virus is observed in humans and non-human primates before they succumb to disease 4,6,51 is consistent with the incapacity of infected DCs to regulate their CD40 and CD86 molecules, and the coincident failure of DCs to secrete IL-12 and other cytokines 20,23 .…”

“…Worse, on receiving co-inhibitory signals, these cells might contribute to the production of copious amounts of IFNγ, which can induce more B7-H1 (REF. 58) and thus facilitate further cellular anergy and subsequent NK-cell deletion 38,50 . Conversely, as filovirally infected DCs retain an immature phenotype, these cells could be eliminated by the NK-cell-dependent NKp30 trigger receptor 59 .…”

Status and challenges of filovirus vaccines

“…Within 6-8 days of fever, hemorrhagic complications can develop, and patients develop increasingly severe symptoms including severe weight loss, delirium, shock, liver failure, massive hemorrhaging, and multi-organ dysfunction. For ZEBOV, clinical signs include elevated liver enzymes, pronounced decreases in peripheral blood lymphocyte counts, especially CD8 T cells, and elevations in inflammatory cytokines [31][32][33][34]. Thrombocytopenia is reported as well as decreases in platelet counts and development of disseminated intravascular coagulation in some but not all fatal cases.…”