The Ebola virus glycoprotein sequence can vary up to 50% between Ebola virus species, presenting a challenge to develop pan-Ebola therapeutics or vaccines. Erica Ollmann Saphire discusses her work on antibodies that neutralize all Ebola virus species and the changing nature of the structural biology toolkit used to study them.
Julie's Biggest Takeaways
While recombinant protein technologies have facilitated many structural studies, these studies often produce a snapshot of protein interactions and functions. Newer technologies allow in-cell imaging and examine dynamic protein interactions and functions over different times and in different cellular locations.
The presence of 2 Ebola virus glycoprotein versions can confound viral studies, particularly with regards to understanding the immune response. The full-length version (GP) is incorporated as a trimer into the viral envelope to mediate viral entry while the truncated, secreted version (sGP) is secreted as a dimer and has an unknown function. sGP may act as a decoy for the immune system or as a modulator of viral pathogenesis. It’s unclear whether the antibody response to sGP helps or hinders patient response to GP and viral neutralization.
The GP genes of different Ebola virus species can differ by up to 50%, which is one reason why antibody-based treatments are often specific to a single species of Ebola virus. ADI-15878 was discovered by Saphire and colleagues from the serum of an airlifted healthcare worker, and is one of a few antibodies that neutralizes across Ebola species. ADI-15878 and the other pan-Ebola neutralizing antibodies bind GP in what is described as the “waist” of the protein, and they bind quaternary epitopes - those that bridge across more than one GP monomer of the trimeric structure.
A large study comparing over 200 antibodies against Ebola virus conducted in labs across the world and using multiple assay systems showed that the feature of antibodies cross-reacting between GP and sGP was not predictive for efficacy or ability to neutralize, emphasizing the work yet to be done to understand the role of sGP during infection.
“Ebola has only 7 genes. Lassa virus has only 4. A lot of other viruses that people work with, similarly, 4, 6, only a handful of genes. There’s just a very limited number of protein molecules that these make. One of the fundamental questions of the lab is: how can so few tools do so many things?”
“You only learn so much when you study a single monoclonal therapeutically. Really what is practical and useful in an outbreak setting will probably be a vaccine. A vaccine elicits a polyclonal resapsons. A natural infection elicits a polyclonal response. We need to understand how these antibodies are acting in concert.”
“This is what’s exciting about being a structural biologist and a virologist now, compared to when I was a beginning student: before, we would solve the structure and it would explain what everyone already thought, but we put a picture to it. Now, we have the ability to use that structure as a road map, to say here’s the structure, here’s how it work, here’s how you can modify it, here’s how you can make a better vaccine.”
“There is nothing more intellectually satisfying to me in the world than a density map….if you know the X/Y/Z coordinates in space of every atom in that protein, and the B value by which it moved from that spot, you can learn anything you wanted to know about that molecule. That map was beauty and truth wrapped up in one fantastic experiment. That was the moment I knew “I’m going to do this, this is my career, I’m going to solve structures.”
“Study what you want and what you’re most interested in. You’ll get a lot of advice from a lot of people. All the advice you get is based on one person’s experience which may be quite limited and it may not apply to you.
Links for This Episode
- MTM Listener Survey (thanks!).
- Ollmann-Saphire Lab Site.
- Protein Database.
- Isolation of Potent Neutralizing Antibodies from a Survivor of the 2014 Ebola Virus Outbreak. Science 2016.
- Systemic Analysis of Monoclonal Antibodies against Ebola Virus GP Defines Features that Contribute to Protection. Cell 2018.
- Structural Basis of Pan-Ebolavirus Neutralization by a Human Antibody against a Conserved, yet Cryptic Epitope. mBio 2018.
- Tenacious Researchers Identify a Weakness in All Ebolaviruses. mBio 2018.
- HOM Tidbit: How “Lassa,” a small Nigerian Town, was Stigmatized by having a Killer Virus Named after it.
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