In a twisted sense, the reason Ebola isn't even more of a threat is because it is so severe.

The virus, which causes hemorrhagic fever, has a quick onset, a 50 percent to 90 percent fatality rate and neither prevention nor cure. While all of that is bad news for those that contract it, it is probably also part of what has kept outbreaks localized.

Most of those outbreaks have occurred in Central Africa. But the Marburg virus, a cousin to Ebola, was named after the town in which the first outbreak occurred - a central German university village in which several researchers died in 1967 after handling an infected monkey. That monkey, though, came from Congo. But to date, none of the outbreaks, including the one in Angola that is currently making headlines, have turned into a wider epidemic.

Most outbreaks tend to be self-limiting because whether in Kinshasa, Luanda - or even Marburg - after infection with a hemorrhagic virus, "you're not going to get on a plane and fly to New York," James Cunningham, associate professor of medicine at Harvard Medical School, told BioWorld Today. "By the time you've been infected for four or five days, you are very sick."

Still, even if hemorrhagic viruses do not look like the most likely pandemic candidates, they are not going away either; thought to survive between outbreaks in an animal reservoir to whom they are presumably less devastating, Ebola and Marburg have flared up multiple times. And the current Marburg outbreak, believed to be the first to occur in Southwest Africa, suggests that the virus may slowly be expanding its geographic range.

In a paper published in the April 14, 2005, issue of Sciencexpress - the early online edition of Science - Kartik Chandran, from Harvard Medical School in Boston, and his colleagues from Harvard Medical School; the National Institute of Allergy and Infectious Diseases in Bethesda, Md.; and the Institute of Human Genetics, in Wuerzburg, Germany; reported on the mechanisms of Ebola infection.

The Ebola virus, like HIV and influenza, enters host cells by fusing its own membrane with that of the host, thus dumping its contents into the cytoplasm. The road into the cytoplasm goes via endosomes, organelles that the cell uses to internalize everything from nutrients to receptor-bound signaling molecules.

"If you look at the cell surface, it basically looks like bubbling oatmeal," said Cunningham, who is the paper's senior author. "Local patches are always curling up to pinch off and enter the cell. But if you think about it, inside that patch is still outside of the cell, because you haven't crossed the membrane yet."

Viruses have evolved a number of different strategies to make their getaway from those endosomes, and they are similar to a certain extent. All three involve an envelope protein, and "the overall global conformation of the envelope protein is similar," Williams said, "though they are not related in the sense of having evolved from the same ancestor."

All three viruses fuse their viral membrane with the membrane of the host endosome to enter the cell. But the mechanisms triggering fusion are different in each case.

In HIV, a two-step, receptor-mediated process is necessary to trigger fusion. In the case of influenza, fusion is triggered by acidic pH, which induces conformational changes in the protein, leading to insertion of a peptide into both viral and target membranes for fusion.

"What we have found, and what we are most excited about, is that in the case of Ebola, there is a third mechanism," Cunningham said. "A protease has to chew off part of the envelope protein, and that's the trigger."

For their experiments, the researchers used vesicular stomatitis virus containing the glycoprotein from the Ebola Zaire viral strain, which is a way of studying viral entry without having to work with Ebola itself.

Using that construct, the scientists showed that in cell culture, one end of the Ebola virus envelope protein is first cleaved by one of two proteases, cathepsin L or cathepsin B, found in the endosomes. A second round of cleavage is specifically done by cathepsin B and triggers membrane fusion. When the researchers pretreated host cells with cathepsin inhibitors before exposing them to Ebola, the pretreated cells had much lower viral titers than controls.

Though unique, the process bears similarities to several other viral strategies. The two-step process itself is somewhat analogous to HIV, including the fact that the first cleavage removes a part of viral protein that may hide the virus from the host immune system, but also prevent fusion.

Ebola virus also is not alone in its use of host cathepsins to trigger fusion. Reoviruses, including rotavirus, which causes infant diarrhea, are another viral family that is cleaved by cathepsin prior to entry into host cells.

Cunningham is cautious about the possible clinical implications of his work. "If there are a hundred steps necessary to bring this into the clinic, I'd say we are at step one. We have tested one dose level in a cell culture. We're not experts on cathepsin - if you gave that dose to a human it might be incredibly toxic, or it might become clear in very short order, for any number of reasons, that this will not work as a therapeutic strategy.

"Now, it stands to reason that if you find a new host factor [in viral infection], that could be a drug target. It obviously warrants looking at," he said. "But that's just common sense, not a scientific conclusion."