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Some survivors of ebolavirus outbreaks create antibodies that may broadly neutralize those viruses–and today , scientists at Scripps Research have illuminated how these antibodies can disable the viruses so efficiently. The insights might be helpful for developing effective treatments.
Ebolavirus is a family of often-deadly viruses that includes Ebola virus and lots of lesser-known viruses like Bundibugyo virus, Sudan virus and Reston virus.
Structural biologists at Scripps Research used electron microscopy techniques to envision a set of antibodies that target a key site on those viruses called the”glycan cap” Their study showed that the antibodies work against ebolaviruses using the exact same three mechanisms to stop the virus from infecting host cells.
The research, published in Cell Reports, is a step toward the creation of an antibody-based treatment which will be useful from a wide assortment of ebolaviruses.
Ward, a professor at the Department of Integrative Structural and Computational Biology at Scripps Research, says he hopes that the work will contribute the development of a”cocktail” of therapeutic antibodies that can save lives by treating several kinds of the Ebola virus.
Ever-emergent Ebola Other species have been added to this family of viruses, such as Sudan ebolavirus and Bundibugyo ebolavirus. Ebola viruses colonize African fruit bats, often result in disease in chimpanzees and other non-human primates, and activate outbreaks in humans every few years, normally. Infected people develop a hemorrhagic syndrome that’s fatal in roughly half of untreated cases.
Vaccines against Ebola have been developed recently but have not yet been widely used. And although antibody-based remedies also have been developed, none has been shown effective against a wide assortment of ebolavirus species.
A surprisingly large proportion of those widely neutralizing antibodies target the glycan cap, a sugar-slathered website on a stalk-like protein–known as the glycoprotein–which enables Ebola viruses to enter cells.
The goal is to provide doctors in Ebola-prone regions their best weapon yet against these deadly outbreaks. The insights we have gained through our structural studies of the virus show how this may be possible.”
Andrew Ward, PhD., Scripps Research
In the new study, Murin and Ward, along with their colleagues at the James Crowe Lab at Vanderbilt University where the antibodies were isolated, used electron microscopy to analyze a set of glycan cap-targeting antibodies from survivors of various ebolaviruses. Their goal was to understand better how these antibodies target the virus so effectively.
Three ways to conquer the virus Their study suggested that the most widely effective of these glycan cap-targeting antibodies hit the identical vulnerable website on the glycan cap, letting them thwart viral infectivity in three ways.
The antibody displaces a long viral structure close to the glycan cap in a way that destabilizes the entire viral glycoprotein structure, sometimes causing it to fall apart.
Secondly, the glycan cap antibody–when it binds to its target site–can block a key event in the disease process, where an enzyme called a cathepsin cleaves off the glycan cap. Blocking this cleavage event blocks the glycoprotein’s capacity to enter cells.
Lastly, the glycan cap antibody, by displacing the loose structure near the glycan cap, enables another sort of neutralizing antibody to bind to a separate vulnerable site on the virus. Thus, a glycan cap antibody can”synergize” with another antibody to hit the virus significantly tougher than either antibody does alone.
The scientists determined the key genetic components that allow glycan-cap antibodies to thwart ebolaviruses in these three ways.
Now that they have illuminated how these broadly neutralizing antibodies work, Ward, Murin and colleagues are examining them as elements of a next-generation antibody cocktail which they hope will have the ability to take care of the Zaire, Sudan and Bundibugyo ebolaviruses.
Scripps Research Institute
Murin, C.D., et al. (2021) Convergence of a common solution for broad ebolavirus neutralization by glycan cap-directed human antibodies. Cell Reports. doi.org/10.1016/j.celrep.2021.108984.