Scientists solve 3-D structure of a protein used by deadly poxviruses to disarm humans’ immune system

Finding could aid biodefense against smallpox, development of rheumatoid arthritis therapy

SAN ANTONIO (Dec. 19, 2008) — Smallpox and the emerging human monkeypox are caused by poxviruses, which are among the most feared bioterrorism agents. Although the human body’s immune system can successfully fend off many disease-causing agents, it is often ineffective against poxviruses, because these viruses employ an arsenal of proteins to disarm many infection-fighting proteins in the human immune system.

A rare snapshot of a poxvirus protein caught in the middle of its act against a human immune molecule called IL-18 (short for interleukin-18) is revealed by a 3-D crystal structure solved by a team of scientists from The University of Texas Health Science Center at San Antonio and Oklahoma State University. The study is described in the Dec. 15-19 early online edition of the Proceedings of the National Academy of Sciences of the United States of America.

IL-18 serves as a trigger to alert the immune system to battle infection, but poxvirus has a protein that binds IL-18 so it cannot do its job. “In essence, the poxvirus protein ties up and gags this sentry so no alarm is sent,” said study senior co-author Yan Xiang, Ph.D., assistant professor of microbiology and immunology at the UT Health Science Center. The new crystal structure reveals more about how the poxvirus protein is able to do this.

“Determining the crystal structure is an important step toward designing an inhibitor for this poxvirus protein as a treatment for disease caused by a poxvirus,” Dr. Xiang said. “Drugs against poxviruses are greatly needed as there is currently no effective therapy against poxviruses and the current vaccine has many side effects.”

The structure can also help the development of effective inhibitors against IL-18 to treat autoimmune diseases in which IL-18 is too active, Dr. Xiang added. Inhibitors against proteins similar to IL-18 are being used in clinics to treat rheumatoid arthritis.

Dr. Xiang and Junpeng Deng, Ph.D., a structural biologist at Oklahoma State University, are the co-corresponding authors of the paper. “A lot of credit goes to Dr. Deng and his group,” Dr. Xiang said. “Xiangzhi Meng, Ph.D., a talented research scientist in my lab, also contributed significantly and deserves praise for her hard work and dedication.”

Dr. Xiang joined the UT Health Science Center in 2002 after a postdoctoral fellowship at the National Institutes of Health (NIH), where he discovered the poxvirus proteins that bind IL-18. Dr. Xiang recently was awarded a four-year, $1.3 million NIH grant to study the same poxvirus proteins with the goal of developing better vaccines and therapeutics for poxviruses.

 

 

The University of Texas Health Science Center at San Antonio is the leading research institution in South Texas and one of the major health sciences universities in the world. With an operating budget of $668 million, the Health Science Center is the chief catalyst for the $15.3 billion biosciences and health care sector in San Antonio’s economy. The Health Science Center has had an estimated $35 billion impact on the region since inception and has expanded to six campuses in San Antonio, Laredo, Harlingen and Edinburg. More than 23,000 graduates (physicians, dentists, nurses, scientists and other health professionals) serve in their fields, including many in Texas. Health Science Center faculty are international leaders in cancer, cardiovascular disease, diabetes, aging, stroke prevention, kidney disease, orthopaedics, research imaging, transplant surgery, psychiatry and clinical neurosciences, pain management, genetics, nursing, dentistry and many other fields. For more information, visit www.uthscsa.edu.



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