Boston scientists reveal how Ebola infects cells

By Carolyn Y. Johnson

August 24, 2011

3 minutes to read

Two teams of local scientists revealed new insights today into how Ebola, the deadly virus that riveted readers in “The Hot Zone,’’ infects cells — and how to potentially stop the virus altogether.

Using different techniques, one group led by scientists from the Whitehead Institute for Biomedical Research in Cambridge and another led by Brigham and Women’s Hospital researchers found that a protein that ordinarily is involved in the transport of cholesterol is essential for infection to occur. Researchers took cells from patients with a rare, genetic disease called Niemann-Pick type C1, who have a defective form of that protein, and found that the virus could not infect those cells in a laboratory dish.

The findings, published in back-to-back papers in the journal Nature, describe more fully how the deadly virus gains access to cells and points the way to possible strategies to intervene. Both teams also identified compounds that could inhibit Ebola infection, at least in laboratory tests. But the researchers who did the work and an outside scientist cautioned this work was a long way from a therapy.

“It’s neat. Scientifically, it’s very exciting. … It’s a long way from taking something like this and saying this is a strategy that you would end up using for a drug,’’ said Thomas Geisbert, a professor of microbiology and immunology at the University of Texas Medical Branch at Galveston. “I’m just a little cautious. I literally have a whole shelf full of compounds that can completely protect mice or guinea pigs against Ebola or Marburg.’’

What the new research adds is a more complete picture of how Ebola, a virulent pathogen that causes hemhorragic fever and was only discovered in 1976, gains access to cells. The virus is known to approach the outside of a cell, which then engulfs the virus by forming a balloon-like enclosure, called an endosome, around it. But for the virus to get into the engine of the cell, it needs to break out of the bubble and enter the cell. Previous work had shown that an enzyme produced by the cell, called cathepsin B, cleaved off the cap of a mushroom-shaped Ebola protein. Now, the new work suggests that the stalk of the protein needs the host’s Niemann-Pick protein to exit the endosome.

“We think that by knowing these host factors, you would also have an idea of cellular targets that you could inhbit in order to prevent the virus from entering,’’ said Thijn Brummelkamp, the senior author of one of the papers and a former fellow at the Whitehead Institute who is now a group leader at the Netherlands Cancer Institute.

The team of Brigham and Women’s researchers screened thousands of compounds to identify a new compound that inhibited Ebola virus infection, which led them to understand that the Niemann-Pick protein was necessary for infection.

In order to do the work, Boston and Cambridge researchers had to use altered forms of the virus. Work on the real virus was conducted at the US Army Research Institute of Infectious Diseases at Fort Detrick, in Maryland.

Sean Whelan, an associate professor of microbiology and immunobiology at Harvard Medical School who worked with Brummelkamp, said that the team took a livestock pathogen that does not infect humans and replaced the surface protein on that virus with the mushroom-shaped one found on Ebola. That gave them a safe way to study virus infection.

“I think this study may have some important consequences for how one thinks about therapy against Ebola infection,’’ Whelan said. “Here’s a target we should go after now therapeutically — and we know this is something we should be able to exploit.’’