Research published in PLOS
Pathogens clarifies the mechanism by which Ebola is able to cause excessive
bleeding and inflammation in human hosts. The research, conducted using tissue
culture, involved human cells that were exposed to GP proteins isolated from
infected cells, and it suggests novel possibilities for drug therapy against
Ebola.
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| Figure 8 from the research paper. |
The study suggests that infected cells shed glycoproteins after
they are cleaved from surface membranes by a cellular protease called TACE.
After cleavage-induced shedding, GP proteins encounter and stimulate dendritic
cells and macrophages that produce a diverse combination of inflammatory cytokines.
In turn, these cytokines activate other dendritic cells and macrophages that also
release immunological messengers, ultimately prompting widespread inflammation.
Additionally, shed glycoproteins stimulate endothelial cells
(blood vessel cells) to increase permeability and reduce coagulation (which
facilitates bleeding), and shed GP proteins bind to antibodies, preventing them
from neutralizing the actual virus. Inflammation and permeability improve the
virus’s ability to access and infiltrate target cells; after macrophage and
dendritic cell infection, viral replication intensifies in liver cells
(hepatocytes) and white blood cells purified in the spleen (splenocytes), leading
to organ failure.
Together, these factors contribute to the pathogenicity of
Ebola virus.
The researchers continued their investigation by treating
macrophages and dendritic cells with antibodies against TLR4—a human toll-like
receptor that is previously known to mediate the immune response and be
activated by shed GP proteins. After treatment with the antibodies, shed
glycoprotein bound dendritic cells and macrophages less successfully.
The results of this study clarify the pathway by which the
Ebola virus triggers disease, and it points to TLR4 as a potential drug target
for attenuating the pathogenic effects of Ebola. Future avenues of study
include validating these results within an animal model and, if successful, in
clinical trials.
-Luis Garcia
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