A prominent researcher at the Sylvester Comprehensive Cancer Center at the Miller School has taken another major step in understanding the mechanisms of the immune system. For the second year in a row, Glen N. Barber, Ph.D., professor of medicine and the Eugenia J. Dodson Chair in Cancer Research, and Hiroki Ishikawa, Ph.D., a post-doctoral fellow, have published their findings in the prestigious journal Nature (online edition September, print October).
In their previous study, Barber and Ishikawa identified a molecule, STING (STimulator of INterferon Genes), which activates the body's innate immune system by triggering the production of interferon. That study focused on fibroblast cells, the most common cells, in vitro. When a virus invades a cell, interferon production is triggered, which then alerts other cells that there is a virus infection. This activates the immune response by creating hundreds of antiviral genes which protect uninfected cells from infection. Without interferon, the body has no early antiviral defense.
In this latest research, Barber and his team expanded their work to examine more specific cell types, including macrophages and dendritic cells which are responsible for activating anti-pathogen B and T cell responses. They also evaluated the importance of STING in an animal model. They found that STING is a "vital element," said Barber.
This NIH-funded study by Barber and Ishikawa further solidifies the importance of STING's role in activating the pathway to begin production of interferon.
STING, as Barber and Ishikawa discovered, initiates a sequence of events that unleashes interferon against viruses. What scientists did not know is how the innate immune system is propelled to react to DNA-based microbes. Armed with the knowledge that STING triggers interferon in basic cells, Barber and Ishikawa took a closer look at STING's role in attacking DNA pathogens such as herpes simplex virus, and the bacteria Listeria, among others. Mice lacking STING were found to be extremely sensitive to virus infection. "What we found," said Barber, "is that STING is absolutely essential to the body's defense against a variety of different DNA pathogen types."
This becomes an especially critical finding in gauging the immune system's reaction to plasmid DNA-based vaccines, such as those being used to develop new types of flu vaccines. Working with animal models, the scientists found that STING was a critical factor in facilitating DNA-mediated immune responses. Vaccines are meant to trigger the body to make antiviral or anti-bacterial antibodies and T cells.
"We think the human innate immune system reacts the same way," says Barber. The theory is that without STING, a DNA-based vaccine wouldn't be effective because the body would not create interferon and other cytokines which are essential for stimulating adaptive immune responses.
W. Jarrard Goodwin, M.D., director of Sylvester, describes the discovery of STING "of fundamental importance to our understanding of innate immunity." Goodwin says Barber's continued work in this area "is likely to be of direct benefit to patients dealing with the 20 percent of human malignancies that are known to be caused by viruses. I am very proud that Sylvester has supported this work along with the National Institutes of Health and other funding agencies."
The finding in this study is leading Barber to the next step in this critical research path. After the initial discovery of STING and its role in triggering the production of interferon in response to DNA and RNA viruses, the team will turn to other DNA-based pathogens. Barber and Ishikawa intend to examine STING's effect on parasites, such as malaria, and fungi. They'll also further evaluate the importance of this molecule in regulating T-cell response to DNA-based vaccines. Better understanding of that relationship, explains Barber, "could lead to improved and safer vaccines to combat cancer and other serious illnesses."
