In research published online in the journal EBioMedicine, NIEHS scientists report that a mutation in the gene of a white blood cell protein contributes to the severity of respiratory syncytial virus (RSV) infection. RSV contributes to bronchiolitis, pneumonia, asthma, and respiratory failure, and is the leading cause of respiratory illness in infants, immunocompromised adults, and the elderly worldwide.
The findings may help identify individuals at risk for severe RSV infection and provide therapeutic strategies to prevent disease. This is particularly important because there is no vaccine for RSV.
Novel gene associated with RSV
Members of the NIEHS Environmental Genetics Group, led by Steven Kleeberger, Ph.D., and collaborators, were the first to use genome-wide association studies in mice to identify several candidate genes involved in RSV severity. The most promising gene, macrophage receptor with collagenous structure (MARCO), produces a protein that allows a particular type of white blood cell to fight infection. Kleeberger said MARCO had not been associated with RSV before, so the finding was surprising.
When team members deleted the MARCO gene in mice exposed to RSV, the animals experienced more severe symptoms compared to wild-type mice exposed to RSV. "MARCO is an immune system gene that helps clear inflammation," Kleeberger said. "If the gene is mutated, it can’t resolve the inflammation, so cells and mucus remain in the lung, blocking the airway."
He explained that critically ill children with RSV have lower blood oxygen, which leads to hospital stays with a ventilator breathing for them. In countries that do not have access to that kind of health care, these children may die.
Finding ways to save lives
When the team turned its attention to human versions of MARCO, the results were strikingly similar. In two independent populations of children, infants born with a mutated MARCO gene exhibited more severe RSV symptoms than those with the wild-type gene.
The research also determined that mice could inherit different forms of the MARCO gene, each one differing slightly from the fully functioning version. Kleeberger said the finding may explain why in some children, RSV infection is like a cold, whereas others experience acute respiratory distress. According to the U.S. Centers for Disease Control and Prevention, RSV is the most common cause of lung infection in babies younger than one year old, and almost all children by the age of two years will have had RSV.
Some of the health effects of the virus are irreversible, according to Kleeberger, so if even a small number of RSV-induced asthma or pneumonia cases could be prevented, it would have a huge impact.
Using information learned from mouse and human studies, Kleeberger’s group is working toward developing a diagnostic tool that will identify which infants could get severe RSV disease before they get sick.
"RSV antibody therapy can treat these kids, but it’s expensive, which means some patients aren’t treated with it," said co-author Kirsten Verhein, Ph.D., an NIEHS Intramural Research Training Award fellow in Kleeberger’s group. "We are working to identify the populations of kids at risk of having severe RSV, so they can get the life-saving treatment," she said.
Combining animal and human data
The Kleeberger group has been studying the genetics of other lung diseases since the 1990s, but switched its focus to RSV in the mid-2000s, partnering with a like-minded clinical researcher — Fernando Polack, M.D., from Vanderbilt University School of Medicine in Nashville, Tennessee.
"Steve and I conducted a series of translational studies during the last decade trying to understand the pathogenesis of RSV bronchiolitis in infants," Polack said. "Now, these findings suggest an important role for keeping the small airways open."
Polack also heads the Infant Foundation in Buenos Aires, Argentina, an organization that examines the causes of respiratory disease in children. He and Kleeberger believe their translational research will eventually bring relief to the millions of children with severe RSV disease.
Citation: High M, Cho H-Y, Marzec J, Wiltshire T, Verhein KC, Caballero MT, Acosta PL, Ciencewicki J, McCaw ZR, Kobzik L, Miller-DeGraff L, Gladwell W, Peden DB, Elina Serra M, Shi M, Weinberg C, Suzuki O, Wang X, Bell DA, Polack FP, Kleeberger SR. 2016. Determinants of host susceptibility to murine respiratory syncytial virus (RSV) disease identify a role for the innate immunity scavenger receptor MARCO gene in human infants. EBioMedicine; doi:10.1016/j.ebiom.2016.08.011 [Online 6 August 2016].