Saturday, November 29, 2014

Ebola Pathogenesis: GP Protein Shedding

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.

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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