In 2016 West Africa experienced the largest and most deadly
outbreak of Ebola virus (EBOV) in history. Ebola virus disease (EDV) is
associated with rapid acute infection consisting of fever, fatigue, headache,
myalgia, and gastrointestinal distress 3-13 days after exposure. Due to the
limited number of outbreaks, high mortality rate, and limited technology
present in sub-Saharan countries affected by Ebola virus, there is presently
very little data on the immune response elicited by infection. In this study
researchers at the University of Medical Center Hamburg-Eppendorf (UK), were
able to analyze the response of immune cells in a single recovering patient.
This patient, who’s blood was take 37 and 46 days post EVD symptom onset,
provided an fascinating case study of lymphocyte dynamics as the patient was
able to clear the virus without being administered experimental drugs. By
carrying out an analysis of immune response following Ebola infection,
researchers aimed to increase scientific understanding of key cellular factors
that affect host cell survival, protection, and the development of persistent
Ebola strains.
It is important to note that
although the blood samples taken were from the patient after infection was
cleared, researchers quantitatively observed an above average amount of
cytotoxic T-cells accompanying persistent immune activation. T cells, like B
cells, are lymphocytes, which make up the adaptive immune system, have a memory
capacity that allows specific recognition of viral antigens from previous
encounters to prevent future infection. In order to measure the expansion of lymphocytes
in the recovering patients blood in the presence of EBOV, researchers incubated
samples of patients blood with isolated Ebola proteins. After lymphocytes were
allowed to bind to Ebola virus peptides, the cells were stained and analyzed
for antigen-experienced T cell activation. The results of the assay indicate
significantly increased CD8+ T cell activation in both the main population and
effector memory population, which had previously come in contact with EBOV.
CD4+ T cells also showed slightly increased T-cell activation. Levels of plasmablast
B cells, capable of producing large quantities of infection fighting antibodies,
were also slightly increased, and Ebola virus specific neutralizing antibodies
were detected.
A comparison of T cell stimulation upon incubation with Ebola antigens |
Percentage of single and double cytokine producing T cells stimulated by different Ebola virus antigens |
This increase in CD8+ T cells,
which initiate cell death and produce cytokines upon interacting infected
cells, was identified to be among T cells expressing tumor necrosis factor
alpha (TNFα), Interferon-γ (IFNγ). TNFα expressing T cells showed the largest
increase in production and were associated with stimulation from Ebola GP1. A
smaller proportion of T cells expressing both TNFα and IFNγ were stimulated by an Ebola
peptides SP and GP2. This analysis was carried out Intracellular Cytokine
Staining and ELIspot technique, which monitor cellular immune response through
cytokine induction. The amount of IFNγ produced by T cells with antigen
experience was considered modest by researchers, and was attributed mainly to
the considerably late analysis of blood serum at day 37 and 46 post infection.
It is important to note that this
study, while entirely specific to one individual patient who survived Ebola
virus disease, provides important initial insights in to a previously uncharacterized
immune response to Ebola virus. The main findings of the study suggest that the
adaptive immune system was stimulated by initial Ebola infection, and that
memory B cells, CD4+ T cells, and CD8+ cells participated in an activate immune
response in the presence of Ebola peptides. Specifically, CD8+ T cells
producing TNFα were the largest subset of lymphocytes produced in the
convalescing patient upon reintroduction to viral antigens. While antigen
specific immunity may be key to surviving Ebola virus infection, this study
does little to illuminate how the immune system responds to initial infection,
as it studies blood of a patient 37 and 46 days after the onset of the first
symptoms of EVD. Similarly, many of the initial defensive anti-viral functions
of the immune cells may not have presented for observation in this study
because of the time frame. However, it is possible that the presence and
activation potential of T-cell found in this patient’s blood indicate the
continued presence of virus hidden in the body. The main criticism of this
paper is that it is often contradicted by other small sample size studies of
the immune systems of patients who cleared Ebola virus. The researchers
recognize the incongruences and attribute them to the lack of scientific
information available due to outbreak sizes and resources. Further
investigation in to the pattern of adaptive immune behavior both to initial
Ebola virus infection and in patients who have cleared the infection is
necessary.
Source Paper:
Dahlke C, et al.
Comprehensive Characterization of Cellular Immune Responses Following Ebola
Virus Infection. J Infect Dis. (2016)doi: 10.1093/infdis/jiw508
Other Resources:
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RT, Jr., et al. Clinical Management of Ebola Virus Disease in the United States
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Davis CW, et al. Human Ebola virus infection results in
substantial immune
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3. Agrati C, Castilletti C,
Casetti R, et al. Longitudinal characterization of dysfunctional T cell-activation
during human acute Ebola infection. Cell Death Dis 2016; 7:e2164.
4. Ellebedy AH, Jackson KJ,
Kissick HT, et al. Defining antigen-specific plasmablast and memory B cell
subsets in human blood after viral infection or vaccination. Nat Immunol
5. Kreuels B, Wichmann D, Emmerich P,
et al. A case of severe Ebola virus infection complicated by gram-negative
septicemia. N Engl J Med 2014; 371:2394-401.
6. Luczkowiak J, Arribas JR, Gomez S,
et al. Specific neutralizing response in plasma from convalescent patients of
Ebola Virus Disease against the West Africa Makona variant of Ebola virus.
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Figures taken directly from source paper.
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