New clues found to common respiratory virus
Washington University School of Medicine in St. Louis News Jul 20, 2017
By age 2, most children have been infected with respiratory syncytial virus (RSV), which usually causes only mild cold symptoms. But people with weakened immune systems, such as infants and the elderly, can face serious complications, including pneumonia.
Now, scientists studying the virus, led by researchers at Washington University School of Medicine in St. Louis, have found clues to how RSV causes disease. They mapped the molecular structure of an RSV protein that interferes with the bodyÂs ability to fight off the virus. Knowing the structure of the protein will help them understand how the virus impedes the immune response, potentially leading to a vaccine or treatment for this common infection.
ÂWe solved the structure of a protein that has eluded the field for quite some time, said Daisy Leung, an assistant professor of pathology and immunology, and of biochemistry and molecular biophysics at Washington University School of Medicine in St. Louis, and the studyÂs co–senior author. ÂNow that we have the structure, weÂre 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.Â
The study was published June 30 in the journal Nature Microbiology.
Scientists have long known that a non–structural RSV protein is key to the virusÂs 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.
ÂItÂs an enigmatic protein. Everybody thinks it does many different things, but weÂve never had a framework to study how and why the protein does what it does, said co–senior author Gaya Amarasinghe, an associate professor of pathology and immunology.
Leung, Amarasinghe and colleagues used X–ray crystallography  a technique that involves crystallizing the protein, bouncing X–rays off it, and analyzing the resulting patterns  to determine the 3–D 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.
To test their hypothesis, the researchers created different versions of the NS1 protein, some with the alpha 3 helix region intact, and some with it mutated. In collaboration with others  Rohit Pappu, the Edwin H. Murty Professor of Biomedical Engineering, Michael Holtzman, MD, the Selma and Herman Seldin Professor of Medicine, Maxim Artyomov, an assistant professor of pathology and immunology, and Christopher Basler of Georgia State University  they 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.
They found that the viruses with the mutated helix region did not suppress the immune response while the ones with the intact helix region did.
ÂOne 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, said 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 bodyÂs 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. 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, the researchers said.
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Now, scientists studying the virus, led by researchers at Washington University School of Medicine in St. Louis, have found clues to how RSV causes disease. They mapped the molecular structure of an RSV protein that interferes with the bodyÂs ability to fight off the virus. Knowing the structure of the protein will help them understand how the virus impedes the immune response, potentially leading to a vaccine or treatment for this common infection.
ÂWe solved the structure of a protein that has eluded the field for quite some time, said Daisy Leung, an assistant professor of pathology and immunology, and of biochemistry and molecular biophysics at Washington University School of Medicine in St. Louis, and the studyÂs co–senior author. ÂNow that we have the structure, weÂre 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.Â
The study was published June 30 in the journal Nature Microbiology.
Scientists have long known that a non–structural RSV protein is key to the virusÂs 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.
ÂItÂs an enigmatic protein. Everybody thinks it does many different things, but weÂve never had a framework to study how and why the protein does what it does, said co–senior author Gaya Amarasinghe, an associate professor of pathology and immunology.
Leung, Amarasinghe and colleagues used X–ray crystallography  a technique that involves crystallizing the protein, bouncing X–rays off it, and analyzing the resulting patterns  to determine the 3–D 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.
To test their hypothesis, the researchers created different versions of the NS1 protein, some with the alpha 3 helix region intact, and some with it mutated. In collaboration with others  Rohit Pappu, the Edwin H. Murty Professor of Biomedical Engineering, Michael Holtzman, MD, the Selma and Herman Seldin Professor of Medicine, Maxim Artyomov, an assistant professor of pathology and immunology, and Christopher Basler of Georgia State University  they 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.
They found that the viruses with the mutated helix region did not suppress the immune response while the ones with the intact helix region did.
ÂOne 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, said 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 bodyÂs 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. 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, the researchers said.
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