What occurs when the measles virus encounters a human cell? The virus’s biological mechanisms unfold precisely to expose crucial components that enable it to merge with the host cell membrane.
What happens when measles virus meets a human cell? The viral machinery unfolds in just the right way to reveal key pieces that let it fuse itself into the host cell membrane.
Once the fusion process is finished, the host cell is taken over by the virus.
Scientists at the La Jolla Institute for Immunology (LJI) Center for Vaccine Innovation are focusing on creating new measles vaccines and treatments to impede this fusion process. Recently, they used an imaging method known as cryo-electron microscopy to illustrate in unprecedented detail how a potent antibody can thwart the virus before it finalizes the fusion process.
“This study is notable because we’ve captured images of the fusion process happening in real-time,” explained LJI Professor, President, and CEO Erica Ollmann Saphire, Ph.D., who collaborated on the Science study with Matteo Porotto, Ph.D., Professor of Viral Molecular Pathogenesis (in Pediatrics) at Columbia University. “The sequence of images is akin to a flipbook where we witness snapshots of the fusion protein unfolding, followed by the antibody binding it together before it can finish the last stage of the fusion process. We believe that other antibodies against different viruses might act similarly but have not been visualized like this before.”
This research could have implications beyond just combating measles. Measles virus is just one member of the paramyxovirus family, which also includes the lethal Nipah virus. The Nipah virus is known to be less transmissible but has a significantly higher mortality rate than measles.
“The insights we gain about the fusion process could have medical relevance for Nipah, parainfluenza viruses, and Hendra virus,” stated Dawid Zyla, Ph.D., the lead author of the study and a Postdoctoral Researcher at LJI. “These viruses all have the potential for pandemics.”
The critical need for measles treatments
Measles is a highly contagious airborne disease that particularly impacts children. Despite extensive vaccination campaigns, the virus continues to pose a significant health risk. In 2022, measles led to approximately 136,000 deaths globally, with recent outbreaks in more than a dozen U.S. states, according to the World Health Organization and the U.S. Centers for Disease Control. The majority of the victims were young children under the age of five who were either unvaccinated or partially vaccinated.
“Measles causes more deaths in children than any other preventable disease through vaccination, and it is also one of the most contagious known viruses,” Saphire noted.
It’s not just young children who are vulnerable, as Zyla explained, “The current vaccine is effective, but it is not suitable for pregnant individuals or those with compromised immune systems.”
Since there is no specific treatment for measles, scientists are exploring the use of antibodies as an emergency treatment to prevent severe illness.
To gain a better understanding of how the measles virus merges with cells, the LJI team investigated an antibody called mAb 77. Studies have shown that mAb 77 targets the measles fusion glycoprotein, the viral component that measles uses to enter human cells through a specialized fusion process.
Could mAb 77 be utilized as a therapeutic antibody against measles? To find out, LJI researchers studied how the antibody fights against the virus.
Blocking membrane fusion
The LJI team needed to create a version of the measles fusion glycoprotein—a harmless portion of the virus—that was stable enough to be imaged using a cryo-electron microscope. For this purpose, Zyla collaborated closely with scientists in Porotto’s laboratory at Columbia University.
Porotto’s team had identified some unusual mutations in a measles strain that targeted individuals’ central nervous systems. This mutated strain had vulnerabilities in its fusion glycoprotein structure. To compensate, the virus had developed specific stabilizing mutations. “The virus undergoes mutations to access the brain, but then it requires these stabilization mutations to counteract that,” Porotto explained.
With these findings from Columbia, Zyla had a blueprint for constructing a fusion glycoprotein with these same stabilizing mutations. This new fusion glycoprotein could be manufactured in large quantities in cell culture and was robust enough for structural analysis.
“We obtained very high yields for the glycoprotein, which allowed us to conduct structural biology, biochemical, and biophysical analyses,” Zyla stated.
Subsequently, the researchers started capturing images with the assistance of the LJI Cryoelectron Microscopy Core. The new images displayed the fusion glycoprotein bound “in complex” with mAb 77.
The researchers discovered that mAb 77 halts the virus midway through the fusion process—when the fusion glycoprotein is already partially folded into the proper conformation for completing membrane fusion. Finally, the researchers were able to observe precisely how mAb 77 connects the fusion glycoprotein fragments to prevent viral infection.
“It was remarkable to see the appearance of this intermediate step in the fusion process,” Zyla commented.
Future endeavors to combat measles
Now that they have uncovered how mAb 77 operates, the researchers believe that the antibody could be incorporated into a treatment regimen to shield individuals from measles or treat those actively infected with measles.
In a subsequent investigation, the researchers demonstrated that mAb 77 offered substantial protection against measles in cotton rat models infected with the measles virus. Cotton rats that received mAb 77 before exposure to the measles virus either showed no infection or displayed reduced signs of infection in their lung tissue.
Moving forward, Saphire and Zyla aim to explore other antibodies against measles. “We want to obstruct fusion at different stages in the process and explore other therapeutic possibilities,” said Zyla.
Zyla also intends to continue collaborating with measles researchers at Columbia University. “The collaborative efforts between LJI’s expertise in structural biology and Columbia’s expertise in cell biology and virology were instrumental in advancing this project,” Zyla concluded.
This research received support from the National Institutes of Health (NS105699, NS091263, and AI176833), Swiss National Science Foundation Postdoc Mobility fellowships (P2EZP3_195680 and P500PB_210992), the Measles Virus Biobank, the Dutch Research Council NWO Gravitation 2013 BOO, Institute for Chemical Immunology (ICI 024.002.009), and institutional funds of La Jolla Institute for Immunology (EOS)
