We’re finally starting to understand how Ebola infects living organisms, which means we’re getting closer to finding a way to stop it. The virus enters and infects cells thanks to channels in the cell’s membrane, according to a study published in Science today — and a molecule found in an Asian herb appears to be able to stop that process in mice.
half of the mice survived a lethal dose of Ebola
About 23,600 people have been infected with Ebola since the beginning of the outbreak in West Africa, according to the World Health Organization. Of those, 9,500 have died. To curb the outbreak, researchers have been trying to come up with a vaccine — the most likely solution, given the number of Ebola vaccine trials currently underway. But some researchers have opted to take the road less traveled: they’re trying to understand how Ebola infects the cell, so they can protect people who have been exposed. Today's study provides the groundwork for that approach.
In the study, researchers stained cells with a dye to show their anatomy. Then they observed the Ebola virus enter cells using powerful microscopes. They found that a calcium channel called "two-pore channel 2" (TPC2) controls the final stages of Ebola virus entry into the cells. In short, the channel is involved in the release of the virus's genome into the cell — the final step before viral replication.
"We identified a new step in Ebola virus infection process," says Robert Davey, a virologist at the Texas Biomedical Research Institute and a co-author of the study. Blocking this step might therefore result in the virus being destroyed — a side effect that could be exploited to treat people infected with Ebola.
To test this idea, Davey and his team searched for molecules that could block TPC activity. They identified a few, but one drug stood out: tetrandrine, a drug derived from an Asian herb. People in China — the only country where it's approved — use tetrandrine to lower blood pressure in humans. When the drug was given to mice who had been given a lethal dose of Ebola the day before, half of the mice survived. "Tetrandrine was the most potent and caused the least side effects," Davey says.
Trapping the Ebola virus so the cell can destroy it
Figuring out that Ebola needs TPC2 to enter cells "is exciting," says Darryl Falzarano, a virologist at the University of Saskatchewan who didn’t participate in the study. "The data supporting the requirement for TPC2 is really solid," he says. And the mouse experiment shows that this technique could work; blocking TPC activity with tetrandrine appears to trap the Ebola virus in the membrane compartment it’s using to enter the cell. Because it can’t get out to replicate, it’s "destroyed by the cell," Davey says. "This stops infection."
Unfortunately, tetrandrine isn't an ideal drug candidate; it's banned for human use in most countries. Plus, treating a human with a dose equivalent to the one given to the mice could be toxic, according to Falzarano. Moreover, the effectiveness of the drug was reduced in mice when the treatment was delayed by a single day.
tetrandrine is banned for human use in most countries
Despite these issues, the findings relating to how Ebola enters cells are significant, Davey says. Other research groups have been able to increase survival in mice infected with Ebola using known drugs, but they weren’t able to explain the mechanism behind the survival effect. Understanding the mechanism is a crucial step if you want to make better drugs and gain FDA approval, he says.
These findings have been a long time coming. In 2008, Davey and his team published a study that showed that switching off calcium-sensing proteins stopped Ebola virus infection. "We thought it must be something to do with calcium channels, but we did not know which ones," Davey told The Verge. It wasn’t until 2012 that the researchers realized that TPC proteins were the root cause. And it took an additional two years to understand that TPC proteins were controlling the way the virus moves into cells.
Now that Davey and his team have figured out that tetrandrine can block Ebola infection in mice, the next step will be to test the drug on monkeys. "We are testing the treatment to make sure it is safe in animals and are also looking to see if related compounds have lower side effects." These tests will take quite some time to complete.
"This does not mean we have a miracle treatment."
"This does not mean we have a miracle treatment," Falzarano says. Blocking TPC activity could form the basis of future drug interventions, but any drug that acts that way would have to be very efficient, he says — so much so "that I think it is unlikely to be successful on its own." Moreover, tetrandrine isn’t an approved drug, so the finding "will have no effect of the ongoing outbreak," he says. We may one day have a drug that can be used to block infection in people who have been exposed to the virus, but that probably won’t happen soon. "I still think that implementing one of the vaccine platforms will have the most significant public health impact," Falzarano says.