Lassa lashed: X-ray vaccine clue

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  • Published: Jun 15, 2017
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Lassa lashed: X-ray vaccine clue

Lethal Lassa

The molecular structure of a Lassa virus protein provides the blueprints for vaccine design. (Credit: Ollmann Saphire Lab/The Scripps Research Institute)

Lassa fever can be lethal, it is a severe hemorrhagic disease caused by a single-stranded RNA virus in the arenavirus family. There is currently no vaccine. But that might soon change thanks to work by Kathryn Hastie and Erica Ollmann Saphire at The Scripps Research Institute (TSRI).They and their colleagues have solved the structure of the proteins that allow Lassa virus to enter human cells. Generally, it is 50 to 70% fatal but up to 90 percent fatal in pregnant women, a vaccine is vital.

Writing in the journal Science, the team explains reveals details of a key piece of the viral structure, the surface glycoprotein, which is present on all lethal arenaviruses. The new structure could be used as a template for designing a vaccine against the disease.

“This was a tenacious effort - over a decade - to conquer a global threat,” explains Ollmann Saphire. Hastie joined Ollmann Saphire’s lab as a graduate student in 2007 and proclaimed that wanted to solve the structure of the assembled arenavirus glycoprotein. Ultimately, she planned to determine the structure using X-ray crystallography and thus map the targets on the virus where antibodies might attack. Unfortunately, Lassa virus glycoproteins would prove to be far too unstable for crystals to be wrought. There was another problem; in the viral replication cycle Lassa’s glycoprotein is split into two subunits. “We had to figure out how to get the subunits to be sufficiently clipped and where to put the staple to make sure they stayed together,” Hastie explains.

Host binding

The team worked closely with the laboratory at the Kenema Government Hospital in Sierra Leone and was able to obtain antibodies from survivors of Lassa fever. These antibodies could then be used to deactivate samples of the virus and have already been demonstrated as giving protection to lab animal. These are the kinds of antibodies researchers are hoping to elicit with a future Lassa virus vaccine. “Studying Lassa is critically important," Ollmann Saphire says. "Hundreds of thousands of people are infected with the virus every year, and it is the viral hemorrhagic fever that most frequently comes to the United States and Europe.”

It took several years before Hastie saw promising results in her work. She created mutant versions of important parts of the molecule and engineered a version of the Lassa virus surface glycoprotein that was stable. She then used this glycoprotein model as an attractor for antibodies from patient samples that would show the ability to bind to the glycoprotein and so neutralize the virus. Ultimately, the X-ray structure would show that the glycoprotein has two parts, whimsically it resembles an ice-cream cone loaded with ice-cream. In this analogy, the subunit GP2 forms the cone, and GP1 sits on top like a scoop of ice-cream. The two sub-units work together when they encounter a host cell. GP1 binds to a host cell receptor, and GP2 starts the fusion process to enter that cell.

Ice-cream tripod

The structure also revealed that the system has a dangling structure on GP1 (a dribble of ice-cream running down the cone, if you like). It is this “dribble” that sticks the two subunits together in their pre-fusion state. Hastie went on to show that three of the GP1-GP2 pairs come together in a trimer forming a tripod-like structure, which is apparently unique to Lassa virus. Other viral trimers, such as those present in influenza and HIV, form poles not tripods.

"It was great to see exactly how Lassa was different from other viruses," says Hastie, 10 years after starting the project. "It was a tremendous relief to finally have the structure."

It is that tripod arrangement that opens up a path to a vaccine. The scientists found that 90 percent of the effective antibodies in Lassa patients targeted the spot where the three GP subunits come together. These antibodies locked the subunits together, preventing the virus from gearing up to enter a host cell. A future vaccine would work best if it triggered production of antibodies that target that site.

Related Links

Science, 2017, 356, 923-928: "Structural basis for antibody-mediated neutralization of Lassa virus"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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