Research details how a virus hijacks cell signals to cause infection

A common virus that causes meningitis and heart inflammation takes a "back door" approach to evade natural barriers, then exploits biological signals to infect human cells. Broadening knowledge of how viruses cause infection, a new study describes elaborate methods that the virus has evolved to bypass the body's defenses.

"This study helps to explain how group B coxsackieviruses infect cells," said Jeffrey M. Bergelson, M.D., a pediatric infectious diseases specialist at The Children's Hospital of Philadelphia. "We found new steps in the virus life cycle."

Dr. Bergelson's study, co-authored with Carolyn B. Coyne, Ph.D., also of Children's Hospital, appears in the Jan. 13 issue of the journal Cell.

Group B coxsackieviruses (CVBs) are common in people, but usually are defeated by the immune system after causing minor infections. However, CVBs may sometimes cause myocarditis, a potentially severe inflammation of the heart in children and adults, as well as viral meningitis, which inflames the lining of the brain. Rarely, the virus may lead to fatal, overwhelming infection in newborns.

CVBs typically reach people in contaminated food or water, with the virus entering cells that line the intestine, called epithelial cells. Just how the virus enters those cells has been puzzling to scientists. Dr. Bergelson previously discovered a cell receptor called the coxsackievirus and adenovirus receptor (CAR) to which the virus attaches itself. However, the CAR remains below the surface of epithelial cells, in a seemingly inaccessible location called the tight junction.

In the new study, Drs. Bergelson and Coyne found that CVBs have evolved an indirect route of attack. The virus first attaches itself to more accessible cell receptors called DAF receptors that lie exposed on the upper surface of epithelial cells.

After attaching itself to a DAF receptor, the virus triggers two signals that open the door to infection. One signal causes the virus to move into the tight junction, where it can reach the CAR. A second signal leads the virus to move deeper into cells where it can release its nucleic acid payload and complete the process of infection.

"We showed for the first time that this virus is dependent on signaling pathways to drive invasion," said Dr. Bergelson. Specifically, the coxsackievirus activates kinases, enzymes that are instrumental in moving structures within cells.

"These particular kinases were previously known to be active in cancers, where their signaling functions go out of control," he added. "However, kinases have a normal function, in enabling cells to respond to hormones or growth factors. We showed in this study that viruses can co-opt kinase signaling processes to advance an infection."

In describing how the coxsackievirus takes advantage of signaling pathways, added Dr. Bergelson, his investigations revealed steps in a virus's life cycle that were previously unknown. "Eventually this understanding may yield clinical benefits, by contributing to future therapies to block viral infections. For now, we have learned more about cell functions, and how viruses may evolve unexpected methods to force themselves into cells."

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About The Children's Hospital of Philadelphia
The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking second in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 430-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.


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