When most people in the developed world think of measles, what comes to mind is only a dim memory of a vaccination at a pediatrician's office. But while childhood vaccination has virtually eliminated measles from North America and much of Europe, researchers remain interested in the virus.
This fascination persists partly because improving the measles vaccine could help eliminate the more than 10 million measles infections and 150,000 measles-caused deaths that still occur worldwide. But it also has another source: Scientists believe that modified measles viruses can be "re-targeted" to attack only tumor cells, and thus transformed into a powerful new therapy for cancer.
Now, a new discovery about the process by which measles invades cells has brought the dream of transforming the virus into a weapon against cancer one step closer to reality. A research team including scientists from the University of Texas Medical Branch at Galveston and the Mayo Clinic in Rochester, Minn. have produced a detailed picture of the intricate molecular mechanism that measles virus uses to attach to and enter the cells it infects.
The key players are two proteins that form the spherical envelope surrounding the genetic material of the measles virus. One is an attachment protein that binds to receptor molecules on the outer membrane of a host cell, and the other is a fusion protein that merges the viral envelope with the cell membrane, enabling the virus to infect the cell. The study, published in the recent issue of Nature Structural Biology & Molecular Biology demonstrated that the intrinsic flexibility of the attachment protein is a necessary condition to initiate the cell fusion process.
"The overall goal of our Mayo Clinic collaborator, Roberto Cattaneo, is to redirect the measles virus to attack specific cancer cells, and to accomplish that he and his group need to know as much as they can about the mechanisms of measles infection," said UTMB professor Werner Braun, an author of the study. "We have a long-standing collaboration with his group, using our theoretical predictions and computational methods to help them better target their experimental work."
UTMB Health research scientist Numan Oezguen used computer-based molecular modeling to predict interaction sites and suggested specific mutations that would alter the interaction and mobility of the attachment protein heads. Results of these experiments performed by the Mayo Clinic team -- led by Cattaneo -- showed that cell entry of the measles virus depends on a twisting motion of the attachment protein's heads.
To produce an accurate portrait of the dynamic mechanism the Mayo Clinic group created measles viruses with mutations affecting the mobility of their attachment protein heads, and then tested the mutated viruses to determine each type's ability to infect cells. "What Dr. Cattaneo's experiments showed was that the motion of these two parts of the attachment protein has a dramatic effect on infectivity," Braun said. "In a simplified sense, we think this works like a lever -- if the cell receptors pull on the attachment protein properly, they generate this type of motion, and this triggers the fusion protein and leads to infectivity."
Other authors of the paper include Cattaneo, Chanakha Navaratnarajah, Levi Rupp, Leah Kay and Vincent Leonard of the Mayo Clinic. The National Institutes of Health and the Mayo Clinic Cancer Center supported this research.
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