Local study pinpoints how viruses invade cells

Local scientists have discovered how a family of dangerous viruses invades healthy cells, a finding that promises new treatments for dengue fever, West Nile, and other diseases that infect more than 50 million people every year.

The dengue virus, which sparks severe fevers and can cause internal bleeding, and the West Nile virus, which has been carried across the United States by birds, are both emerging diseases in the Americas, but scientists had not known how they infect cells once they are in the body.

Now, using advanced imaging equipment, researchers at Children's Hospital in Boston have found the microscopic machinery the viruses use to rip through the cell's protective wall.

The discovery, described in today's edition of the journal Nature, gives scientists a blueprint to design drugs to block the viruses -- a strategy that has already been successful at combating the virus that causes AIDS.

"This is a very significant breakthrough," said Richard J. Kuhn, a virus specialist who is a professor of biological sciences at Purdue University.

In a field dominated by the quest to understand genetics, this research marks a success for a very different approach: uncovering the raw mechanics of cells. It is part of a growing field of research that looks at biology's physical structures -- microscopic whips, protective walls, and spring-loaded hooks -- and how they clash in every cell's battle to survive.

This winter, Harvard University launched a new Center for Molecular and Cellular Dynamics to pursue this work and the benefits it might bring to medicine.

"If you want to intervene, we have to understand how all the parts work," said Stephen C. Harrison, a coauthor of the paper being published today and director of the new center, which is a part of Harvard Medical School. "We are generating masses of genomics data now, but the two approaches can't live without each other."

The work announced yesterday was done on the virus that causes dengue fever, but scientists said that it could lead to treatments for a variety of similar viruses, including West Nile, yellow fever, and hepatitis C. All of those viruses have very similar structures, so it is likely that they use the same machinery to invade.

A virus's entry into the cell is a crucial, and potentially vulnerable, point in its life cycle. Viruses work by entering and then hijacking healthy cells, releasing instructions to the cell to build more of the virus.

The principle has led to at least one drug currently in use: Fuzeon, approved by the Food and Drug Administration last year, which combats AIDS by interfering with HIV's ability to fuse with cell membranes and pass through.

In the new research, Harvard postdoctoral fellow Yorgo Modis isolated the protein used by the dengue virus when it invades and took images of it, before and after it is deployed, using X-ray crystallography. This gave him detailed three-dimensional snapshots of the protein's structure.

Then, by combining these images with elaborate biochemical sleuthing, the team uncovered a story in which the dengue virus behaves like a pirate ship, pulling alongside an unsuspecting cell and then forcing itself aboard.

When a healthy cell first encounters the virus, it surrounds it with a membrane and then draws it into the cell, leaving the virus trapped in a kind of bubble. Inside this bubble, called an "endosome," the environment then becomes more acidic as the cell attempts to break down whatever is inside.

This, the paper reports, is when the virus moves into action. Long proteins reach out from the virus and hook themselves into the cell membrane. When these are locked into place, they snap back, slamming the virus through the membrane and freeing it to do its damage.

To treat dengue fever, a drug could be created that would interfere with these long protein hooks. The team has filed patents on this approach through Children's Hospital, and begun to look at some chemicals that could have that effect, Modis said.

Dengue fever infects about 50 million people every year, and kills about 20,000, according to the World Health Organization. There is no cure for dengue, or West Nile, but doctors can treat the symptoms while the patient's immune system fights back.

While the dengue research used long-established techniques, the new Harvard center hopes to employ more recently developed ones -- such as the ability to track tiny structures in a living cell -- to create detailed "movies" of how viruses attack and how the cells respond. Harrison, who is also a member of the Howard Hughes Medical Institute, said that he has been working intensively on another virus that causes havoc in the Third World: the rotavirus.

Rotavirus is a major child killer, he said, yet a better understanding of its structure and how it moves might point the way to a cure, he said. "We are on the verge of being able to work that out." Gareth Cook can be reached at cook@globe.com.