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How this common virus evades the immune system

Scientists now know how respiratory syncytial virus evades the immune system, a discovery that could potentially lead to a vaccine or treatment.

By age two, most children have been infected with respiratory syncytial virus (RSV), which usually causes only mild cold symptoms. But people with weakened immune systems, including infants and the elderly, can face serious complications, including pneumonia and—in some cases—death.

“We solved the structure of a protein that has eluded the field for quite some time,” says Daisy Leung, assistant professor of pathology and immunology, and of biochemistry and molecular biophysics at Washington University School of Medicine in St. Louis, co-senior author of the study in Nature Microbiology.

“Now that we have the structure, we’re able to see what the protein looks like, which will help us define what it does and how it does it. And that could lead, down the road, to new targets for vaccine or drug development.”

Each year in the United States, more than 57,000 children younger under 5 stay in the hospital due to RSV infection, and about 14,000 adults older than 65 die from it.

There is no approved vaccine for RSV and treatment is limited—the antiviral drug ribavirin is used only in the most severe cases because it is expensive and not very effective—so most people with RSV receive supportive care to make them more comfortable while their bodies fight off the virus.

New clues to why RSV sends babies to the hospital

For people with weakened immune systems, though, fighting RSV can be tough because the virus can fight back. Scientists have long known that a non-structural RSV protein is key to the virus’s ability to evade the immune response. However, the structure of that protein, known as NS1, was unknown. Without seeing what the protein looked like, scientists were unable to determine exactly how NS1 interfered with the immune system.

“It’s an enigmatic protein. Everybody thinks it does many different things, but we’ve never had a framework to study how and why the protein does what it does,” says co-senior author Gaya Amarasinghe, an associate professor of pathology and immunology.

The researchers used X-ray crystallography—a technique that involves crystallizing the protein, bouncing X-rays off it, and analyzing the resulting patterns—to determine the 3D structure of NS1. Then, in a detailed analysis of the structure, they identified a piece of the protein, known as the alpha 3 helix, which might be critical for suppressing the immune response.

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To test their hypothesis, they created different versions of the NS1 protein, some with the alpha 3 helix region intact, and some with it mutated and then tested the functional impact of helix 3 and created a set of viruses containing the original or the mutant NS1 genes, and measured the effect on the immune response when they infected cells with these viruses.

The viruses with the mutated helix region did not suppress the immune response while the ones with the intact helix region did.

“One of the surprising things we found was that this protein does not target just one set of genes related to the immune response, but it globally modulates the immune response,” says Amarasinghe, also an associate professor of molecular microbiology, and of biochemistry and molecular biophysics.

The findings show that the alpha 3 helix region is necessary for the virus to dial the body’s immune response down. By suppressing the immune response, the virus gives itself a better chance of surviving and multiplying, or in other words, of causing disease.

RSV usually can only cause disease in people whose immune systems are already weak, so a vaccine or treatment that targets the alpha 3 helix to prevent immune suppression may be just what people need to be able to successfully fight off the virus.

Other researchers from Washington University in St. Louis and Georgia State University are coauthors of the study.

Support for the work came from the National Institutes of Health; the Defense Threat Reduction Agency of the Department of Defense; the National Science Foundation; the Children’s Discovery Institute; and the American Heart Association.

Source: Washington University in St. Louis

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