They have discovered a key discovery that allows them to block measles virus infection.

Scientists at the Vaccine Innovation Center at the La Jolla Institute for Immunology (LJI) in the US are working to develop vaccines. new vaccines and treatments for measles that stop this fusion process. Researchers recently used an imaging technique called cryo-electron microscopy to show in unprecedented detail how a powerful antibody can neutralize a virus before it completes the fusion process, as reported in the journal Science.

“What’s interesting about this study is that we captured snapshots of the fusion process in action,” explains LJI Professor, President and CEO Erika Ollmann Sapphire, who led the scientific study together with Matteo Porotto, Professor of Molecular Viral Pathogenesis (in Pediatrics ). ) at Columbia University, also in the USA. “This series of images is like a flip book where we see snapshots of the entire development process of the fusion protein, but then we see the antibody binding it before it can complete the final step of the fusion process. We expect that other antibodies against other viruses will do the same, but images like these have never been seen before.“.

In fact, this work may be important for more than just measles. The measles virus is just one member of a larger family of paramyxoviruses that also includes the deadly Nipah virus. Nipah virus is known to less contagious but causes a much higher mortality rate than measles.

“What we learn about the fusion process may have medical implications for Nipah, parainfluenza viruses and Hendra virus,” says first author of the study and LJI postdoctoral fellow David Zila.All of these viruses have pandemic potential.“.

In this context, the LJI team needed to develop a version of the measles fusion glycoprotein (a harmless fragment of the virus) that was stable enough to be visualized using a cryo-electron microscope. To do this, Zaila worked closely with scientists from Porotto’s lab at Columbia University in the US.

Porotto’s team has discovered several strange mutations in a variant of measles that affects the central nervous system of people. This mutated version there were some weak points in its fused glycoprotein structure. To compensate, the virus evolved special stabilizing mutations. “The virus has to mutate to reach the brain, but then it needs stabilizing mutations to compensate,” Porotto recalls.

With these discoveries at Columbia, Zyla had a practical plan to create a fusion glycoprotein with the same stabilizing mutations. This new fusion glycoprotein could be mass produced in cell culture and was robust enough for structural studies. “We obtained extremely good glycoprotein yields.which also allowed us to carry out structural biology, biochemical and biophysical studies,” says Zyla.

The researchers then began capturing images using the LJI cryo-electron microscopy core. The new images showed the fusion glycoprotein “in complex” with mAb 77.

The researchers found that mAb 77 stopped the virus mid-fusion, when the fusion glycoprotein had already partially “folded” into the correct conformation for complete membrane fusion. Finally, the researchers were able to see exactly how mAb 77 joined the pieces of the fusion glycoprotein to prevent viral infection. “FIt’s amazing to see what this intermediate step in the synthesis process actually looks like.“Mentions Zil.

Now that they know how mAb 77 works, the researchers hope the antibody could be used as part of a treatment cocktail protect people from measles or treat people with active measles infection.

In a subsequent experiment, the researchers demonstrated that mAb 77 provided significant protection against measles in cotton rat models of measles virus infection. Cotton rats pretreated with mAb 77 before exposure to measles virus showed no or reduced signs of infection in lung tissue.

Looking ahead, researchers interested in studying different antibodies against measles. “We would like to stop the synthesis at different stages of the process and explore other therapeutic options,” says Zayla. In addition, his team plans to continue to work closely with measles researchers at Columbia University. “The combination of LJI’s expertise in structural biology and Columbia University’s expertise in cell biology and virology was key to moving this project forward,” concludes Zayla.