LJI research details measles virus neutralization

What happens when the measles virus meets a human cell? The viral machinery unfolds in just the right way to expose the key parts for fusing with the host cell membrane.

Once the fusion process is complete, the host cell disappears and becomes the virus's.

Scientists at the La Jolla Institute for Immunology (LJI) Vaccine Innovation Center are working to develop new measles vaccines and treatments that stop this fusion process. Using an imaging technique called cryo-electron microscopy, the researchers recently showed in unprecedented detail how powerful antibodies neutralize the virus before it can complete the fusion process.

“What's exciting about this work is that it captures a snapshot of the nuclear fusion process,” explained Dr. Erica Ollman Safire, professor, president and CEO of LJI, who co-led the research. Science “The series of images is like a flip book, where you can see snapshots of the fusion protein as it unfolds, and then you can see how the antibody fixes it before it completes the final step of the fusion process. We think the same thing happens with other antibodies against other viruses, but it's never been imaged like this before,” said Dr. Matteo Polotto, professor of viral molecular pathology (pediatrics) at Columbia University.

In fact, this research may prove important for more than just measles: The measles virus is just one member of the larger Paramyxoviridae family, which also includes the deadly Nipah virus, which is less contagious than measles but known to have a much higher mortality rate.

“What we learn about the fusion process may have medical implications for Nipah virus, parainfluenza virus and Hendra virus, all of which are viruses with pandemic potential.”

Dawid Zaila, lead author of the study and a postdoctoral researcher at the La Jolla Institute for Immunology

Urgent need for measles treatment

Measles is a highly contagious, airborne disease that tends to hit children hardest. Despite significant vaccination efforts, the virus remains a major health threat. According to the World Health Organization and the US Centers for Disease Control and Prevention, measles killed approximately 136,000 people worldwide in 2022, with recent outbreaks in more than a dozen US states. Most of the victims were unvaccinated or undervaccinated children under the age of five.

“Measles causes more childhood deaths than any other vaccine-preventable disease and is one of the most contagious viruses,” Safire said.

It's not just young children who are at risk, Zaira explains: “The current vaccines are highly effective, but they cannot be given to pregnant women or people with weakened immune systems.”

There is no specific treatment for measles, so researchers are searching for antibodies that could be used as an emergency treatment to prevent severe illness.

To better understand how the measles virus fuses with cells, the LJI team turned to an antibody called mAb 77. The researchers found that mAb 77 targets measles virus fusion. GlycoproteinsThe measles virus uses a specialized process called fusion to enter human cells.

Could mAb 77 act as a therapeutic antibody against measles? To find out, LJI scientists took a closer look at how antibodies fight the virus.

Membrane fusion, interruption

The LJI team needed to refine the measles fusion glycoprotein (a harmless fragment of the measles virus) into a version stable enough to be imaged with a cryo-electron microscope, and to do this, Zaila worked closely with scientists in the Pollot lab at Columbia University.

Pollot's group found a strange mutation in the measles variant that attacks people's central nervous system. This variant had some weaknesses in its fusion glycoprotein structure. To compensate, the virus evolved special stabilizing mutations. “The virus needs to mutate to get into the brain, and it needs these stabilizing mutations to compensate,” Pollot says.

Thanks to these discoveries at Columbia, Zaira now has a convenient blueprint for engineering fusion glycoproteins with the same stabilizing mutations that could be mass-produced in cell culture and were robust enough for structural investigations.

“The glycoprotein yields were very good, which also enabled structural biology, biochemistry and biophysics studies,” Zaila says.

The researchers then began taking images with the help of the LJI Cryo-Electron Microscopy Core, and the new images showed the fusion glycoprotein in “complex” with mAb 77.

The researchers found that mAb 77 blocks the virus midway through the fusion process, when the fusion glycoprotein is in the process of “folding” into the correct structure to complete membrane fusion. Finally, the researchers were able to see exactly how mAb 77 immobilizes fragments of the fusion glycoprotein and prevents viral infection.

“It was shocking to see what this intermediate stage of the fusion process actually looks like,” Zaira says.

Next steps to stop measles

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

In follow-up experiments, the researchers showed that mAb 77 provided significant protection against measles in a cotton rat model 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.

Going forward, Safire and Zailah are interested in studying different antibodies against measles, “trying to stop fusion at different points in the process and explore other potential treatments,” Zailah says.

Zaila also plans to continue working closely with measles researchers at Columbia University. “Combining LJI’s structural biology expertise with Columbia’s cell biology and virology expertise was key to moving this project forward,” Zaila says.