Learning to Treat RSV

After finding a switch that turns off some hyperactive genes, UTMB researchers may be poised to point the way to a more effective treatment for respiratory syncytial virus (RSV), the most common cause of lower respiratory tract infections in infants. In the United States alone, more than 120,000 infants are hospitalized every year due to severe RSV infections, which have been linked to chronic wheezing and even asthma. But the impact of the disease is much greater in developing countries.

When RSV attacks, a number of hormone-like mediators that attract immune system cells to particular sites in the body are produced. Called chemokines, these mediators summon too many cells to the lungs and cause the airways to become inflamed, says Roberto Garofalo, professor of pediatric infectious disease and immunology and senior author of a study on the subject published last March in the Journal of Virology. Rather than trying to target genes for each of these excitable chemokines, Garofalo’s group instead took aim at the chemical molecule that activates them.
This molecule, known as nuclear factor kappa B, or NF-kB, is the “master switch” that turns on the genes for chemokines downstream, Garofalo explains. When his group infected mice with RSV and then treated them with a substance called interleukin-10 (IL-10)—a natural immunosuppressive drug known to block NF-kB—the mice’s lungs were far less inflamed. IL-10 also can block the protein IKK, a molecule even farther upstream and one that influences NF-kB. When communication between IKK and NF-kB is blocked, the chemokine genes are not fully expressed and the immune response is damped down.

“It’s important that products of the chemokine gene attract some cells to the lung to fight the viral infection, but there has to be a balance,” Garofalo says. His group’s data show that the IL-10 or a specific inhibitor of IKK stopped the severe inflammation without shutting down the desired antiviral immune response.
There is still no vaccine to prevent RSV, so Garofalo and his colleagues are working to prevent the most severe manifestations of the disease. The infection is currently treated either with steroids to reduce inflammation or with antiviral medication. Neither therapy is very successful.

“My vision of the disease is that we probably need a combination of therapies—an anti-inflammatory therapy, similar to the approach we discussed in the Journal of Virology paper, and an antiviral agent,” Garofalo says. He posits that both therapies should be administered quite early—probably even before the infection moves from the upper respiratory tract to the lower.

To diagnose the infection this early, doctors will need very specific, sensitive tests. Finding the early signals of disease, known as biomarkers, is one of Garofalo’s latest research goals. “There are subsets of babies—such as those born prematurely, those born with congenital heart disease or affected by chronic lung diseases, as well as others for whom there are no obvious medical risk factors—who are prone to have this exaggerated response, and these are the ones we need to target early on with the aggressive combination of therapies,” he says.
—Judie L. Kinonen