Ebola viral infections are highly lethal, with a fatality rate approaching 90% for some variants. Understanding the molecular basis of this high lethality may lead to treatments for the virus.
This is relevant to humans who live in Ebola-prone locations. One hopes that the research is also relevant to gorillas; Western lowland gorilla populations have been decimated by the virus to such an extent that they are now critically endangered.
Paul Bates (University of Pennsylvania, United States) and coworkers have found that the Ebola virus sterically shields and functionally inactivates certain surface proteins of the cells it infects. This enables infected cells to avoid destruction by the immune system, facilitating continuing viral propagation.
The Ebola question.
Viruses propagate by entering a cell and hijacking the genetic replication machinery to create more copies of themselves. Once the cell has outlived its viral propagation function, the newly synthesized viruses exit to infect other cells.
The human immune system can normally recognize infected cells and target them for destruction. Many viruses can partially protect their host cells from the immune system, but it seems that Ebola is particularly adept at this behavior, by a largely unknown mechanism.
What's known so far is that the Ebola virus encodes for two glycoproteins, one of which disrupts cell attachment. Experiments suggest that Ebola-infected cells display fewer proteins on the cell surface that are critical for immune recognition; the identity of the repressed proteins depends on the type of infected cell.
If scientists can elucidate the molecular-level mechanism of how Ebola-infected cells evade the immune system, it may contribute to a treatment for the virus. This is the goal of Bates and coworkers.
Shielding resolves an inconsistency.
The scientists' main result is that the Ebola virus does not hinder the production of certain immune-relevant cell surface proteins. In fact, the proteins are instead sterically shielded, i.e. "hidden" from view, thereby hindering cellular (and thus viral) destruction by the immune system.
By flow cytometry, a common technique for sorting cells and diagnosing blood diseases, cell surface proteins appear to be reduced by between a factor of 10 to 50 when they are infected by the Ebola virus. However, when the cells are chewed up and the proteins analyzed by Western blot (a protein detection and quantitation technique), consistent and significant changes in protein levels are not observed.
This inconsistency suggests that either the Western blot is detecting more proteins than are actually there (unlikely), or that flow cytometry isn't detecting the relevant proteins (more likely). A third technique is needed to conclusively resolve the discrepancy; the scientists chose direct cellular visualization via fluorescence microscopy.
After standard histological treatment (most notably permeabilizing the cell membrane, i.e. exposing the cell surface proteins), the scientists observed plenty of fluorescence (proteins) in the membranes of cells infected by the Ebola virus. Subsequent analysis of these permeabilized cells by flow cytometry exposed the formerly hidden cell surface proteins.
Histological treatment had no effect on apparent protein expression in cells not infected by Ebola. What is it about Ebola-infected cells that ordinarily hides cell surface proteins?
Chemically removing some of the cell surface glycoprotein present on cells infected by Ebola, in a gentle manner that does not permeabilize the cells, exposed the formerly hidden cell surface proteins. Chemically (gently) removing the sugar units of the glycoprotein, instead of the entire protein, effected the same results, suggesting that the sugar units of the glycoprotein are a major contributor to steric shielding.
Furthermore, this steric shielding reduced the cell-mediated immune response to Ebola-infected cells, even though the immune cells were fully activated. This confirms that steric shielding has functional consequences for infected cell clearance from the body.
Towards treating Ebola.
Perhaps a treatment for Ebola could involve deshielding the immune-relevant surface proteins of cells infected by Ebola, by either biochemical targeting or preventing the Ebola glycoprotein from inserting itself in the cell membrane. I don't have the necessary background to specifically propose how to do this.
Such research directions are also relevant to HIV and certain cancers, hypothesized to evade the immune response (HIV) or metastasize (cancer) due to a loss of cellular adhesion.
NOTE: The scientists' research was funded by the Public Health Service.
for more information:
Francica, J. R., Varela-Rohena, A., Medvec, A., Plesa, G., Riley, J. L., & Bates, P. (2010). Steric Shielding of Surface Epitopes and Impaired Immune Recognition Induced by the Ebola Virus Glycoprotein PLoS Pathogens, 6 (9) DOI: 10.1371/journal.ppat.1001098