A shapeshifting protein explains rabies’ deadly power

• Viruses are masters of efficiency, able to take over our cells and control vital processes using only a handful of genes.
• For years, scientists have wondered how something so small could do so much.
• Researchers have now uncovered the answer -- a discovery that could reshape our understanding of how viruses work and lead to new ways to fight them.

Breakthrough Reveals How Viruses Outsmart Human Cells

A team of Australian scientists has uncovered how certain viruses manage to seize control of human cells, a finding that could lead to the next generation of antivirals and vaccines.

The research, led by Monash University and the University of Melbourne and published in Nature Communications, explains how the rabies virus can manipulate a wide range of cellular activities despite producing only a few proteins.

Scientists believe this same mechanism could also be at work in other deadly pathogens, including Nipah and Ebola viruses. If so, the discovery could pave the way for new treatments that block these viral strategies.

How Viruses Do So Much With So Little

Co-senior author Associate Professor Greg Moseley, head of the Monash Biomedicine Discovery Institute's (BDI) Viral Pathogenesis Laboratory, described the remarkable efficiency of viruses.

"Viruses such as rabies can be incredibly lethal because they take control of many aspects of life inside the cells they infect," Associate Professor Moseley said. "They hijack the machinery that makes proteins, disrupt the 'postal service' that sends messages between different parts of the cell, and disable the defenses that normally protect us from infection."

He explained that scientists have long puzzled over how viruses with such limited genetic material could be so powerful. "Rabies virus, for example, has the genetic material to make only five proteins, compared with about 20,000 in a human cell," he said.

The Key: A Shape-Shifting Viral Protein

Co-first author Dr. Stephen Rawlinson, a research fellow in the Moseley Lab, said the team's work offers a long-sought answer.

"Our study provides an answer," he said. "We discovered that one of rabies virus's key proteins, called P protein, gains a remarkable range of functions through its ability to change shape and to bind to RNA."

"RNA is the same molecule used in new-generation RNA vaccines, but it plays essential roles inside our cells, carrying genetic messages, coordinating immune responses, and helping make the building blocks of life."

Taking Over the Cell's Inner World

Co-senior author Professor Paul Gooley, who leads the University of Melbourne's Gooley Laboratory, said the viral P protein's ability to interact with RNA allows it to shift between different physical 'phases' within a cell.

"This allows it to infiltrate many of the cell's liquid-like compartments, take control of vital processes, and turn the cell into a highly efficient virus factory," Professor Gooley said.

Although this research focused on rabies, he noted that similar tactics may be used by other deadly viruses, including Nipah and Ebola. "Understanding this new mechanism opens exciting possibilities for developing antivirals or vaccines that block this remarkable adaptability," he added.

Rethinking How Viral Proteins Work

Dr. Rawlinson said the findings challenge how scientists have traditionally viewed multifunctional viral proteins. "Until now, these proteins were often viewed like trains made up of several carriages, with each carriage (or module) responsible for a specific task," he said.

"According to this view, shorter versions of a protein should simply lose functions as carriages are removed. However, this simple model could not explain why some shorter viral proteins actually gain new abilities. We found that multifunctionality can also arise from the way the 'carriages' interact and fold together to create different overall shapes, as well as forming new abilities such as binding to RNA."

A New Perspective on Viral Adaptability

Associate Professor Moseley said that the ability of the P protein to bind RNA allows it to move between different physical 'phases' inside the cell.

"In doing so, it can access and manipulate many of the cell's own liquid-like compartments that control key processes, such as immune defense and protein production," he said. "By revealing this new mechanism, our study provides a fresh way of thinking about how viruses use their limited genetic material to create proteins that are flexible, adaptable, and able to take control of complex cellular systems."

This study involved Monash University, the University of Melbourne, the Australian Nuclear Science and Technology Organisation (Australian Synchrotron), Peter Doherty Institute for Infection and Immunity, Commonwealth Scientific and Industrial Research Organisation (CSIRO), the Australian Centre for Disease Preparedness (ACDP), and Deakin University.