Imma Perfetto
Cosmos science journalist
Rabies virus is one of the scariest viral infections on Earth. It’s nearly 100% lethal if left untreated and kills more than 50,000 people every year.
But while highly effective vaccines for rabies are available, and are much more affordable and easier to administer than treatment regimes, they don’t provide lifetime immunity.
Scientists think this might have something to do with the protein on the virus’ surface – rabies virus glycoprotein – which changes shape and could make it more difficult for the body’s antibodies to recognise the virus.
Now, researchers have shared one of the first high-resolution looks at the glycoprotein in its “trimeric” form in a new study published in Science Advances, which may assist in the development of better rabies vaccines in the future.
“Rabies is the most lethal virus we know,” says senior author Dr Erica Ollmann Saphire, President and Chief Executive Officer for La Jolla Institute for Immunology (LJI) in the US. “It is so much a part of our history – we’ve lived with its spectre for hundreds of years.
“Yet scientists have never observed the organisation of its surface molecule. It is important to understand that structure to make more effective vaccines and treatments, and to understand how rabies and other viruses like it enter cells.”
The rabies virus glycoprotein can change its shape
“The rabies glycoprotein is the only protein that rabies expresses on its surface, which means it is going to be the major target of neutralising antibodies during an infection,” says first author Dr Heather Callaway, a research fellow at LJI.
But, kind of like a Swiss Army knife, this protein can change its shape, with parts that unfold and flip upward when needed.
It can switch between four forms in total: the folded and unfolded conformations that occur before and after fusing with a host cell, and between a trimer structure (where three proteins come together in a bundle) and a monomeric structure (one by itself).
This is a problem because human antibodies recognise a single site on a protein and can’t follow along when it transforms to hide or move those sites.
The scientists set out to get a clearer picture of the trimeric form of the glycoprotein, which it takes before it infects human cells.
High-resolution images possible thanks to cryo-EM
Callaway did this by stabilising and freezing the protein in its trimeric form, and then pairing it with a human antibody to help her pinpoint one site where the viral structure is vulnerable to antibody attacks.
The researchers then captured a 3D image of the glycoprotein using cryogenic electron microscopy (cryo-EM), which highlighted several key features, including the part of the protein that flips up.
This is actually two sequences (called the fusion peptides) that link the bottom of the glycoprotein to the viral membrane, but then project into the target cell during infection.
Apparently, it’s very hard to get a stable image of these sequences.
“Better understanding of virus structures and how these are recognised by immune antibodies to neutralise the virus is always welcome, as this information may allow vaccines against that virus to be fine-tuned and improved,” says Dr Nikolai Petrovsky, professor of medicine at Flinders University and director of endocrinology at Flinders Medical Centre, Australia.
“Right now, rabies vaccines for humans and domestic animals are made from killed virus. But this inactivation process can cause the molecules to become misshapen, so these vaccines aren’t showing the right form to the immune system,” concludes Sapphire.
“If we made a better-shaped, better-structured vaccine, would immunity last longer?”