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Synopsis: New concepts about immunologic responses in humans that determine survival or death from Ebola virus are presented. Recovery from Ebola is related to a progressive set of humoral and cellular responses.
Source: Baize S, et al. Defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in Ebola virus-infected patients. Nat Med 1999;5: 423-426.
Ebola is a word that has come to signify one of the most feared of infectious diseases: contagious, horrifying in its manifestations, and rapidly fatal for its victims. Work to delineate the pathogenesis of Ebola is worthy in its own right in confronting this emerging infectious disease, but investigative work also offers the prospect of a model for investigating novel pathogens.
Research has progressed on both fronts regarding Ebola over the past decade. The current contribution by Baize and Leroy (equal contributors) and associates advances new concepts about immunologic responses in humans that determine survival or death.
Specimens for the study were collected during two Ebola outbreaks, the first occurring in February 1996 in Mayibout, an isolated tropical village in northeast Gabon, the second six months later in Booué, about 500 miles from Mayibout. Mortality was 66% in Mayibout and 75% in Booué. Collection of samples from the epidemics was accomplished in heroic fashion, although samples from the Mayibout group of patients was unfortunately incomplete.
The central question of the study was: what factors related to survival in Ebola infection? It turns out that recovery is related to a progressive set of humoral as well as cellular responses. Regarding humoral response, IgM and IgG responses were brisk in certain individuals but, for survival, needed to be followed by activation of cytotoxic cells as antigen was being cleared from the blood. Death, conversely, was associated with poor IgG response and inadequate activation of T cells that underwent premature intravascular apoptosis.
All survivors made markedly more IgG and IgM antibody response to nucleoprotein than nonsurvivors and many survivors continued to make an IgG response to viral protein (VP) 40 and VP35 in the recovery period as measured by Western Blot determination. The discrepancies in IgG and IgM responses between groups were seen as early as 2-3 days and were markedly discrepant at the time of death (survivors vs nonsurvivors).
A large number of cytokine and lymphocyte responses were measured (in 4 survivors and 4 nonsurvivors, respectively), all assayed by RT-PCR of mRNA: IL-2, IL-4, IFN gamma, CD3, CD8, CD28, Fas, FasL, perforin, and Bcl-2. In the nonsurvivors, none made any mRNA indicative of cellular activation whereas in the survivors FasL, perforin, CD28, and IFN-gamma all were measurable. Additionally, T-cell receptor Vß repertoire changes were absent in the last days of fatal infection.
Baize et al also cleverly discovered that intravascular apoptosis of lymphocytes was characteristic in fatal cases. In fact, as measured by DNA fragmentation and release of specific nuclear matrix proteins, apoptosis was "massive" and progressed relentlessly during the last five days of life.
The early immunologic response in Ebola virus infection, thus, determines clinical outcome. When defective, lack of crucial humoral and cellular responses allows progression of programmed cell death that produces a fatal syndrome now familar to clinicians and also mimicked (destruction of lymphocytes in lymph node, spleen, and bone marrow) in monkies infected with Ebola virus. Recovery, on the other hand, is associated with a well-orchestrated sequence of humoral responses followed by activated cytotoxic T-cells.
Short articles in Nature Medicine, a new journal now in only its fifth year of publication, are unusual because the background, results, and discussion sections flow in one central leading section. A methods section follows at the end. Yet, as in this article, there is a wealth of information packed into these short articles.
In this offering from research groups in Paris and Lyon, we glean an extensive amount of insight into one of the most feared emerging infections. The outbreaks studied in this report date back several years when Ebola was most prominent in the news. Although the media coverage has abated, new alerts suggest a new outbreak, again in the country formerly known as Zaire, now called the Democratic Republic of Congo. Forty-six people have died since January 1999 in response to what was first thought to be Ebola, but now appears to be marburg virus infection. The illness was first seen in gold miners but is now spreading to the community.1
What are the major findings of this study? Well, the title says it all. We learn that survival from Ebola virus is associated with rapid destruction of lymphocytes intravascularly by programmed cell death. The normal response is blunting of apoptosis—the programmed cell death—that occurs with efficient humoral response to specific viral proteins, followed by a cytotoxic T-cell response that probably clears residual viral antigen, thus blocking apoptosis. The ending of early IgG and IgM responses in survivors suggest that an amnestic response is occurring, possibly associated with earlier exposure to cross-reacting viruses, perhaps like the gold miner outbreak described above.
What we do not learn from this article is why lymphocytic apoptosis brings with it the hemorrhagic demise of Ebola’s victims. Perhaps with deranged cytokine responses as infection progresses, intravascular coagulation occurs in response to lymphocytic dysregulation, although this is my speculation.
This work from France holds promise since it uncovers the need for an early, effective humoral response. Now that we know those proteins to which an IgG and IgM response is needed, vaccine development can progress. A section of Nature Medicine called "NEWS & VIEWS" features a perspective on Ebola and this paper by Gary Nabel, MD, a noted investigator from the University of Michigan. Nabel has most recently been appointed to the crucial post of Head, AIDS Vaccine Center. So we will likely see the fruits of his leadership in his new position against another pathogen originating in central Africa, human immunodeficiency virus (HIV).
1. ProMED Digest 1999;99:101.
a. Massive apoptosis of lymphocytes
b. Rapid rise in IgG antibody titer
c. Rapid rise in IgM antibody titer
d. Increased cellular mRNA for interferon gamma