Sylvester Comprehensive Cancer Center

Sylvester Researcher Discovers Key Molecule That Triggers Immune Response

08.23.2008

Study Published in Nature Could Lead to Treatment of Viral Cancers

Scientists have long been working to uncover the mystery of what sparks the body’s immune system. Researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine have discovered a key component in that puzzle: a new molecule that recognizes a virus infection and initiates the signal to generate an immune system response. Glen N. Barber, Ph.D., professor of medicine and Eugenia J. Dodson Chair in Cancer Research, and Hiroki Ishikawa, Ph.D., a post-doctoral fellow, have published their findings in the September issue of the prestigious journal Nature.

Barber and Ishikawa have identified a molecule, STING (STimulator of INterferon Genes), which activates the body’s innate immune system by triggering the production of interferon. In turn, interferon generates antiviral genes, producing an immune response that kills the virus. “STING plays a very fundamentally important role in the recognition of virus infection,” explains Barber, who was the principal investigator of the two-year study.

Interferon lies dormant in a cell until it recognizes a virus infection. At that time, it sends a signal to all other cells alerting that there is a virus infection, initiating the immune response to create hundreds of antiviral genes which attack and kill the virus. “Following a virus infection,” says Barber, “we respond by making interferon. If you don’t have interferon, you have no antiviral defense.”

Scientists have known that interferon helped stimulate the adaptive immune response, involving T and B cells, but it wasn’t clear how interferon was made. This research from Barber and Ishikawa – funded by the National Institutes of Health — identifies the key molecule that initiates the sequence of events necessary to fight an infection. STING, which lies in the endoplasmic reticulum, activates interferon when it senses a virus.

This discovery turns out to have dual implications for scientists. There are two types of viruses — DNA viruses and RNA viruses. The scientists not only found that the STING molecule recognizes DNA viruses, but they also discovered it was critical in shutting down certain RNA viruses, known as negative strand viruses. “This makes it twice as important,” says Barber. “This molecule facilitates the production of interferon and innate immune response in reaction to DNA viruses and certain RNA viruses.”

Four years ago, Barber led another study that was published in Nature which identified a pathway that is activated in response to a viral infection at the very earliest stage. When a virus infects a cell, it begins a process that generates large amounts of double-stranded RNA. Those RNA structures produced by viruses require molecules called FADD and RIP to turn on the interferon process.

Barber and Ishikawa are now exploring how this latest discovery will help fight cancer. With very few exceptions, DNA viruses are the major causes of viral-associated cancers such as many forms of lymphoma, cervical cancer, and the Epstein-Barr virus which creates interferon-resistant tumors. Scientists believe there are many more cancerous tumors that could be viral. Barber is now examining whether viruses associated with cancer work to suppress the STING molecule as a way of evading the immune system. Based on what he has seen so far, “it makes sense.” From there, scientists must examine what factor in the cancer virus is working to suppress STING.

William J. Harrington Jr., M.D., professor of medicine and co-leader of the Viral Oncology Research Program at Sylvester, calls Barber’s work “a major discovery that provides important information about the mechanisms whereby DNA cancer viruses such as HPV and EBV evade the immune system.”

Barber sees other applications as well. STING was also activated when it encountered bacteria, indicating that line of attack could be effective in fighting bacterial infections. “There’s all sorts of very, very exciting things going on,” says Barber.

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