New research from University of Alberta microbiologists has shed new light on how the respiratory syncytial virus (RSV)—one of the most common viral infections—breaks into our cells to cause infection.
In a study published in the journal Nature, associate professor of medical microbiology and immunology David Marchant and an international team of researchers discovered that RSV tricks cells into letting it in by essentially ringing a doorbell that calls its receptor to the virus waiting at the door.
“RSV kills between 150,000 and 200,000 people—mainly children and infants—every year worldwide,” said Marchant, who is also the Canada Research Chair in Viral Pathogenesis and a member of the Li Ka Shing Institute of Virology and Alberta Respiratory Centre.
“This discovery identifies one of the first steps in RSV infection, and the hope is if we can block the interaction of the virus with the receptor, we may be able to stop the infection from happening.”
Currently, there is no vaccine or therapeutics to treat RSV, and nothing on the horizon, Marchant said. RSV most often affects infants and young children, infecting the lungs and airways. In fact, some experts estimate that almost all children have been infected with RSV by the time they reach the age of three. It’s the leading cause of infant hospitalization in the world and the second leading cause of infant mortality next to malaria.
RSV is unique because it lies on top of the surface of a cell for hours before gaining access and infecting it, unlike other viruses such as influenza, which can break into a cell within minutes by fusing with it.
In 2011, Marchant led a team that discovered that a receptor within the cell called nucleolin played a role in facilitating RSV’s entry into the cell—RSV bound itself to the receptor and piggybacked in. However, it was unknown how or why nucleolin “came to the door” in the first place.
In the new study, Marchant’s team found that RSV bound itself to a second receptor, called IGF1R, and a gene protein called PKC-zeta, using both to create a signal, or “doorbell,” to call nucleolin to the surface of the cell, where the virus awaits. Once nucleolin arrives at the surface, RSV binds itself to it to enter and infect the cell, like an imposing and uninvited guest.
“Essentially, RSV has evolved to exploit a normal, healthy function within the cell,” said Marchant. “It raises some interesting questions, like ‘Did the virus evolve to bind to IGF1R first or did it evolve to bind to the nucleolus first?’ I think we’ll be exploring this more over the next few years.”
Marchant said he hopes this discovery can lead to new treatments in the future, though he noted that developing a viable treatment for RSV is still years away.
“We have a number of different therapeutic candidates that we’re working on in the lab to try to help move these forward into the clinic, such as blocking other receptors that are downstream from nucleolin in the process,” he said. “But we don’t yet know if there are side-effects to inhibiting those other signals, so we’ve got to look into that.”
Marchant’s research was supported through grants from the Women and Children’s Health Research Institute, Li Ka Shing Institute of Virology, The Lung Association, the Canadian Lung Association and the Canadian Institutes of Health Research.