After uncovering the structure of a protein that allows respiratory syncytial virus (RSV) to skirt the immune response in a 2017 study, a team of researchers at Washington University in St. Louis went back to the lab to uncover more details about that protein, called NS1.
The WashU team discovered that NS1 slips into the cell's nucleus and undermines the body's ability to fight off the disease. It accomplishes that feat by binding to spots on the genome responsible for regulating gene expression, the researchers reported in the journal Cell Reports. The new research lays the groundwork for potential new treatments and could even be the starting point for a vaccine, the team said.
While RSV typically leads to a mild cold, the common respiratory virus carries the risk of pneumonia or bronchiolitis in young children infected for the first time or older adults with lower immunity. Those lung infections lead to about 58,000 hospitalizations a year in children under 5 years old.
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Part of the WashU team behind this research described of a key piece of the NS1 protein, the alpha 3 helix, in a 2017 Nature Microbiology report. For this study, co-first author Jingjing Pei, Ph.D., infected cells taken from the respiratory tract of an RSV patient and used an antibody to track where the protein traveled inside the cells. The virus' genome and many proteins stayed outside the nucleus and made more copies of the virus, but NS1 darted to the nucleus.
The findings could provide hints as to why RSV and asthma are linked, said co-senior author Jacqueline Payton, M.D., Ph.D., an assistant professor of pathology and immunology, in a statement. Children who survive a serious case of RSV are up to 40% more likely than the general population to experience recurrent wheezing or asthma.
“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."
The hunt for an RSV vaccine and treatments to rival Synagis from AstraZeneca's MedImmune has been tough, but recent trials might change the tide. AstraZeneca and Sanofi's drug candidate nirsevimab performed similarly to Synagis in a phase 2/3 trial, the companies said in late June and is on track for regulatory approval filings in the first half of 2022.
Meanwhile, Johnson & Johnson's Janssen has an RSV vaccine that was as much as 80% effective in preventing severe infections in people 65 and older in a mid-stage trial, the Big Pharma said earlier this month. That shot will move into a phase 3 trial and comes a month after Pfizer advanced its own vaccine candidate into a late-stage study. Moderna and GlaxoSmithKline are also investigating RSV vaccine candidates.