Prevention of Immune Cell Apoptosis as Potential Therapeutic Strategy for Severe Infections

Janie Parrino; Richard S. Hotchkiss; Mike Bray

Disclosures

Emerging Infectious Diseases. 2007;13(2):191-198. 

In This Article

Lymphocyte Apoptosis in Ebola Hemorrhagic Fever

In addition to occurring during common forms of sepsis, a marked increase in lymphocyte apoptosis has been observed in such exotic illnesses as Ebola hemorrhagic fever. When transferred to humans from an unidentified animal reservoir, Ebola virus replicates rapidly in macrophages and dendritic cells, causing intense inflammation, high viremia, and spread of infection to multiple organs, with fever, coagulation abnormalities, and shock.[10] Case fatality rates have reached 90% in outbreaks in central Africa.

Limited data from patients and more extensive data from laboratory animals indicate that massive lymphocyte apoptosis occurs during Ebola hemorrhagic fever and may contribute to the high death rate. Thus, the few patients who survive infection develop antibodies to the virus during the second week of illness, while fatally infected persons apparently undergo terminal immunosuppression similar to that seen with septic shock.[11,12] A small study of blood samples from patients in Gabon showed that fatal cases of Ebola hemorrhagic fever were characterized by extensive intravascular apoptosis, particularly of T cells, beginning at least 5 days before death, with a decrease and eventual disappearance of Bcl-2 mRNA expression.[11] In survivors, by contrast, Bcl-2 mRNA was identified in circulating cells during T-cell activation. Importantly, a similar loss of Bcl-2 has been reported in circulating lymphocytes of patients with sepsis.[4]

Because of the difficulty of performing clinical research under the conditions of an Ebola outbreak, the pathogenesis of lethal infection has been elucidated principally through intensive studies in nonhuman primates, which develop uniformly lethal illness resembling fatal hemorrhagic fever in humans. Lymphocytes in these animals remain free of viral infection but nevertheless undergo extensive apoptosis, with early development of lymphopenia and depletion of circulating natural killer cells and CD4+ and CD8+ lymphocytes.[13] Massive lymphocyte apoptosis is also observed histologically in lymph nodes, spleen, and other lymphoid tissues, beginning by day 3 postinfection. A model of Ebola virus infection in mice has demonstrated extensive lymphocytolysis in lymph nodes, spleen, and thymus, with histologic features suggestive of apoptosis.[14] Lymphocyte apoptosis has also been demonstrated in vitro in cultures of Ebola virus-infected peripheral blood mononuclear cells, which suggests that infected monocytes release substances that induce apoptosis in neighboring lymphocytes.[15]

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