New images of RSV could reveal stubborn viruses

FROMLINE: Renata Solan

The complex form of respiratory syncytial virus poses a hurdle that limits the development of treatments for an infection that leads to hospitalizations or worse for hundreds of thousands of people in the United States each year, according to the Centers for Disease Control and Prevention. New images of the virus from researchers at the University of Wisconsin-Madison may hold the key to preventing or slowing RSV infections.

RSV is of greatest concern in young children, the elderly, and adults at high risk for respiratory complications. But unlike the flu and other common communicable respiratory diseases that hit schools every year, there are few ways to combat RSV. In the US, prophylactic treatments are available for young children and existing vaccines are only approved for pregnant women and the elderly.

The structure of the virus – which consists of tiny, bending filaments – has escaped researchers. This has made it difficult to identify key drug targets, including viral components that are conserved among related viruses.

“There are a number of viruses related to RSV that are also important human pathogens, including measles,” says Elizabeth Wright, a professor of biochemistry at UW-Madison. “What we know about related viruses gives us clues about the structures of RSV proteins, but to identify drug targets we need to take a closer look at the RSV proteins that are tightly linked to host cell membranes.”

Using an imaging technique called cryo-electron tomography, Wright and her team have now revealed details of molecules and structures essential to the form and function of RSV. They recently published their results in Nature.

Cryo-ET freezes virus particles or other molecules at ultra-cold temperatures, stopping biological processes. This allows researchers to study the structures of organisms, cells and organelles, as well as viruses, and to capture small-scale images of structures frozen in time. Freeze lots of RSV particles at lightning speed, and cryo-ET imaging captures (almost) all possible configurations of the virus from many different angles. These 2D images are combined to create a high-resolution representation of the virus's 3D structures – even at the level of individual atoms.

Wright's recent study provided high-resolution images that detail the structure of two RSV proteins, RSV M protein and RSV F protein, which are critical to the interaction between the virus and the host cell membrane. Both proteins are also found in related viruses.

The RSV M protein interacts with host cell membranes, holding the virus's filamentous structure together and coordinating viral components and other proteins – including RSV F proteins. RSV F proteins sit on the virus surface, ready to contact host cell receptors and regulate virus fusion and entry into the host cell. The scientists' images show that in RSV, two F proteins combine to form a more stable unit. Wright says this compound could prevent the F proteins from prematurely infecting the host cell.

“Our primary results reveal structural details that allow us to better understand not only how the protein regulates the assembly of viral particles, but also the coordination of proteins that enable the virus to be infectious,” says Wright.

The scientists believe that F protein pairs could be a key to destabilizing the virus before it is ready to infect its next host, which could make pairs of F proteins a possible target for future drug development. They will continue to research how RSV proteins interact with each other and cause infection.