Findings aid antiviral drug discovery
Many viral infections, such as the common cold, cause mild illnesses that the body’s immune system eventually defeats. But when viruses cause severe disease, doctors have few options for effective treatment.
Studying mice with a variety of viral infections, scientists at Washington University School of Medicine in St. Louis have demonstrated a way to dial up the body’s innate immune defenses while simultaneously attacking a protein that many viruses rely on to replicate.
The findings, published Oct. 19 in Nature Immunology, reveal previously unknown weapons in the body’s antiviral immune arsenal and provide guidelines for designing drugs that could be effective against a broad range of viruses. The strategy involves enhancing the body’s interferon signaling system, long understood to be a vital part of antiviral defenses.
“We’ve discovered a new component of the interferon system,” said senior author Michael J. Holtzman, MD, the Selma and Herman Seldin Professor of Medicine. “It does something that other components don’t do, and it works on both sides of the fence: It dials up the body’s internal genes that fight viruses, and it attacks viral proteins directly.”
Holtzman and lead author Yong Zhang, PhD, an instructor in pulmonary medicine, suspect that the researchers’ one-two punch against the virus may explain the large difference in survival rates between control mice and mice genetically engineered to have increased signaling in their interferon systems.
When infected with encephalomyocarditis virus, which causes severe damage to vital organs including the brain, heart and pancreas, 97 percent of the genetically engineered mice survived, compared with none of the control mice. Even when the concentration of the injected virus was increased 100-fold, 82 percent of the genetically altered mice survived. And at 100-fold lower concentrations, all genetically engineered mice survived the infection, compared with only 25-28 percent of the control mice.
Holtzman pointed out that past research by other groups has shown that increasing the amount of interferon directly results in some improvements in fighting viruses, but not to the same extent as the current work. In addition, more modest improvements shown by other investigators usually are accompanied by autoimmune problems resulting from the chronically activated immune response. Despite the strong antiviral immune response seen in the new study, Holtzman and his colleagues reported no evidence of autoimmune disease in these mice.