The rabies virus kills 59,000 people each year, many of them children. Some victims, especially children, do not realize they have been exposed until it is too late. For others, intensive rabies treatment is out of the question: treatment is not widely available, and an average expense of $3,800 is an unimaginable economic burden for most people around the world.
Rabies vaccines, rather than treatments, are more affordable and easier to administer. But these vaccines also have a significant downside:
“Vaccines against rabies do not provide lifelong protection. Your pets should be vaccinated every one to three years,” says LGI professor Erica Ullmann Sapphire, Ph.D. Currently, rabies vaccines for humans and pets are made from dead viruses. But this inactivation process can distort the molecules – so these vaccines don’t show the correct shape of the immune system. If we made a better vaccine that was better trained and regulated, would immunity last longer? »
Safire and his team, along with a team led by Hervé Borhey, PhD, at the Pasteur Institute may have discovered the path to a better vaccine design. In a new study published in Scientists’ progressResearchers share one of the first high-resolution looks at the glycoprotein of the rabies virus in its compromised “triple” form.
“Rabies glycoprotein is the only protein that rabies expresses on its surface, which means that it would be the primary target for neutralizing antibodies during infection,” says Heather Calloway, PhD, a postdoctoral fellow at LJI, who is a researcher on the study. First author.
“Rabies is the most dangerous virus that we know. It is part of our history — we’ve been living with its spectrum for hundreds of years,” adds Saffir, who is also LJI’s president and CEO. However, scientists have never observed the organization of its surface molecule. Understanding this structure is important for making more effective vaccines and treatments — and understanding how rabies and other similar viruses get into cells. »
Scientists aren’t quite sure why rabies vaccines don’t provide long-term protection, but they do know that proteins that change their shape are a problem.
Like the Swiss Army Knife, rabies glycoprotein contains sequences that unfold and flip up when needed. The glycoprotein can switch back and forth between pre-fusion (before fusion with a host cell) and post-fusion forms. It can also collapse from a ternary structure (where three copies come together in a bundle) into a monomer (one copy alone).
This change of form gives Rage a kind of invisibility cloak. Human antibodies are built to recognize a unique site on a protein. They cannot track when the protein turns to mask or displace these sites.
The new study gave scientists a crucial picture of the correct form of a glycoprotein to target antibody protection.
Finally pick up the glycoprotein
For three years, Callaway has worked to stabilize and freeze rabies glycoprotein in its triplet form. This ‘pre-integration’ form is the form that the glycoprotein takes before infecting human cells.
Callaway paired the glycoprotein with a human antibody, which helped her locate a site where the viral structure is vulnerable to antibody attack. Next, the researchers captured a 3D image of the glycoprotein using LJI’s state-of-the-art cryo-electron microscopy equipment.
The new 3D architecture highlights several key features that researchers have not seen before. Importantly, the structure shows two essential structural components of the virus, called fusion peptides, as seen in real life. These two sequences attach the bottom portion of the glycoprotein to the viral membrane, but they protrude into the target cell upon infection. It is very difficult to get a stable picture of these sequences. In fact, other rabies researchers had to cut it out to try to image the glycoprotein.
Callaway solved this problem by capturing rabies glycoprotein in detergent particles. “This allowed us to see how the fusion sequences were related before they were elevated during injury,” Safire says.
Now that scientists have a clear view of this viral structure, they can better design vaccines that tell the body how to make antibodies to target the virus.
“Instead of being exposed to more than four different forms of protein, your immune system should really only see one — which is the good,” Calloway says. “It could lead to a better vaccine.”
Prevent a family of viruses
Sapphire hopes that stronger and broader immunity will help people who regularly come into contact with animals, such as veterinarians and wildlife workers, as well as the billions of people who might accidentally come into contact with a rabid animal. Rabies is endemic to every continent except Antarctica and affects many species including dogs, raccoons, bats, and skunks.
This new work could also open the door to a vaccine to protect against the entire Lyssa virus genus, which includes rabies and similar viruses that can spread between humans and other mammals.
The next step in this work is to capture more images of the rabies virus and its relatives with neutralizing antibodies. Callaway says scientists are working to solve many of these structures, which could reveal which antibody targets the lyssaviruses have in common.
“Because there were no rabies virus structures in this identical case before, it was difficult to design a broad-spectrum vaccine,” Calloway says.
Other authors of the study, “Structure of a rabies virus glycoprotein bound to a specific pre-integration antibody,” include David Zilla, Florence Larros, Gilherme Dias de Mello, Catherine M. Hastie, Ruben Diaz-Avalos, Alyssa Agarwal and David Corti.
This study was supported by the National Institutes of Health (Grants 5T32AI07244-36 and 5F32AI147531-03) and a Postdoctoral Fellowship in Early Mobility from the Swiss National Fund (P2EZP3_195680). Some of this research was supported by NIH grant U24GM129547 and was conducted at OHSU’s PNCC 742 and accessed through EMSL (network 436923.9), a DOE Office of Science user facility sponsored by the Bureau of Biological and Environmental Research. Confocal microscopy on a Zeiss LSM 880 was supported by NIH Equipment Grant 745 S10OD021831.
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