With the colder weather approaching, and more people interacting in person, cold season is starting. One of the most common causes of lower respiratory tract infections is human respiratory syncytial virus (RSV). In fact, nearly everyone gets repeated RSV infections over the course of a lifetime, starting in childhood. In many people, RSV causes nothing more than a mild cold. But for some, serious lung infections develop that can lead to hospitalization and death.
Now, a team of researchers has uncovered how the virus undermines the body’s defenses, a step toward understanding why the virus is capable of causing serious illness in vulnerable populations. The scientists discovered that the virus’s nonstructural protein 1, or NS1, slips inside the nucleus and alters the activity of immune genes, sabotaging the immune response. This work points toward new strategies to prevent or treat RSV infection, and may even provide clues to why severe cases of RSV put people at elevated risk of developing asthma.
This work is published in Cell Reports, in the paper, “Nuclear-localized human respiratory syncytial virus NS1 protein modulates host gene transcription.”
“RSV is a significant health burden. It leads to thousands of hospitalizations and a significant number of deaths in the United States every year, and there aren’t many effective therapies or any vaccines currently available for it,” said Daisy Leung, PhD, associate professor of medicine, biochemistry, & molecular biophysics, and pathology & immunology at Washington University School of Medicine (WUSTL). “NS1 is an important part of the reason RSV is capable of causing disease. Not only does the protein interfere with the immune response, it is also important for viral replication. I think the work that we describe in this paper provides a basis for targeting NS1 therapeutically or for vaccine development.”
Before this study, RSV researchers already had NS1 on their radars as one of the ways the virus counters the body’s defenses. In 2017, Leung published a paper in Nature Microbiology identifying the precise part of the protein involved in undermining the immune response. But it wasn’t clear how the protein was doing so.
Jingjing Pei, PhD, then a postdoctoral researcher in Leung’s lab, found that while the virus genome and other viral proteins stayed in the main part of the cell and produced more copies of the virus, NS1 went into the nucleus. There, NS1 sabotaged the cell’s antiviral efforts by altering the expression of its immune genes.
“NS1 wasn’t just floating around the nucleus, it was interacting with the proteins that regulate gene expression,” said Jacqueline E. Payton, MD, PhD, assistant professor of pathology & immunology at WUSTL. “The group of genes most affected were the immune-response genes whose expression gets turned on really high when a cell is infected by a virus. It was binding right at the spots on the genome that control expression—the same ones that you’d expect if it were trying to interfere with the immune response.”
The authors noted, “Nuclear NS1 coimmunoprecipitates with Mediator complex and is chromatin associated. Chromatin-immunoprecipitation demonstrates enrichment of NS1 that overlaps Mediator and transcription factor binding within the promoters and enhancers of differentially expressed genes during RSV infection.”
By illuminating the details of how NS1 manipulates gene expression, this study provides crucial data that could aid efforts to target the protein for drug or vaccine development. It may even provide a clue to the link between RSV and asthma. The key, Payton suggested, may lie in the epigenome, the pattern of chemical units attached to DNA that influence gene expression.
“Once a cell—any cell, not just an immune cell—encounters an infection, its epigenome changes and primes it to be able to respond more quickly the next time it encounters an infection,” Payton said. “My theory is that NS1 may alter the epigenome in susceptible patients such that the next time they encounter RSV or maybe even just dust or cat dander—they have an aberrant inflammatory response that is damaging rather than protective. That is an idea we are exploring now.”