In this edition:
Research from the Wright Lab in the Department of Biochemistry reveals new insights into the structure of respiratory syncytial virus (RSV) that could inform new treatments for this infectious pathogen. Here’s the run down on their latest research, published recently in the journal Nature Communications:
- Respiratory syncytial virus (RSV) can cause serious respiratory illness in children, the elderly, and adults at risk for respiratory complications. The virus’s structure has been difficult to characterize, limiting the development of therapeutics.
- Cryo-electron tomography (cryo-ET), a specialized imaging technique that allows researchers to examine small molecules such as viruses in 3D, is a key tool for scientists looking to uncover RSV’s structure.
- New cryo-ET images from the Wright Lab reveal structural components in RSV and interactions among viral proteins that may serve as targets for antiviral development.
What background information do you need to know?
Among the litany of viruses that plague families each year is respiratory syncytial virus (RSV). In young children, the elderly, and adults at high risk for respiratory complications, the virus can cause significant respiratory illness. In the aftermath of severe RSV infection, previously healthy individuals are at higher risk for developing asthma and contracting pneumonia.
Yet unlike other common, communicable respiratory illnesses such as the flu, there are few options for treating or preventing RSV. In the U.S., prophylactic treatments are available for young children, and existing vaccines are approved only for pregnant women and the elderly.
One reason it’s been difficult to develop vaccines and antivirals for RSV is because researchers have limited information about the structure of the virus and its proteins. RSV particles are tiny, long, bending filaments. More detailed structural information, including which viral components are conserved across related viruses, is key in identifying drug targets and developing therapeutics.
Why is it difficult to identify a mutation’s functional impacts?
Cryo-electron tomography is an imaging technique that allows researchers to examine three-dimensional structures of organisms, cells and organelles, and viruses. By freezing viral particles — or other molecules — at ultracold temperatures, biological processes are stopped in action. This allows researchers to capture images of structures frozen in time at very small scale (smaller than the size of a single molecule of water).
Flash-freeze many RSV particles, and cryo-ET imaging will capture (nearly) all the virus’s possible configurations from many different angles. These 2D images are combined to produce a representation of the virus’s 3D structures at high resolutions (even at the level of individual atoms!).
How have scientists made progress?
Researchers in the Wright Lab used cryo-ET to reveal detailed images of proteins, RNA and lipids, essential to RSV’s form and function. Their recent study focused on the RSV matrix protein (M) and a surface protein called RSV fusion glycoprotein (F), which are both conserved across related viruses.
The RSV M protein interacts with host cell membranes, regulating the assembly of viral components. It’s responsible for holding together the virus’s filamentous structure and coordinating other proteins and complexes. In viruses related to RSV, researchers previously identified matrix proteins organized in checkerboard-like structures. The Wright Lab’s new images confirm a similar structural arrangement to RSV M proteins, with the checkerboard twisting helically — much like the spiraling ridges in licorice — as the viral filaments elongate.
The helical checkerboard of RSV M proteins coordinate the arrangement of RSV F proteins, which sit on the viral surface and click into the RSV M protein lattice, ready to engage with host cell receptors and regulate the virus’s fusion and entry into the host cell. F proteins are comprised of three identical subunits arranged in a triangle (called a trimer, by scientists). The scientists’ images reveal that in infectious viral particles, two F proteins come together to form a more stable unit. Associating with each other may prevent the F proteins from engaging with host cell receptors until the virus is ready to trigger infection.
The Wright Lab believes that F protein pairs may be a key to destabilizing the virus before it is ready to infect its next host, making pairs of F proteins a possible target for future drug development. They will continue to explore how RSV proteins interact with each other to cause infection.
Written by Renata Solan.
In Research In Brief: The What, Why, and How, we explore new research from the UW–Madison Department of Biochemistry to learn more about the world around us — and inside us.
This edition of Research in Brief: The What, Why, and How is based on the following publication:
Sibert, Kim, Yang, Ke, Stobart, Moore, and Wright. Assembly of respiratory syncytial virus matrix protein lattice and its coordination with fusion glycoprotein trimers. Nature Communications, 2024, 15:5923.
This research was funded in part by grants from the National Institutes of Health (NIH) R01 GM114561 and U24 GM139168, the University of Wisconsin–Madison Department of Biochemistry, and a University of Wisconsin–Madison Vilas Associates Award.