New findings reveal a key step in how the deadly virus infects cells
Little by little, new research is stripping away the mystery surrounding the Ebola virus. Two studies released online August 24 in Nature pinpoint a protein found throughout the body that is complicit in the virus’s entry into cells. One of these also identifies compounds that seem to prevent the viral infection.
Ebola has been slow to give up its secrets. Scientists have yet to fully understand what makes the virus so virulent, typically killing up to 90 percent of those it infects. And researchers are still debating exactly which cell-surface proteins serve as Ebola’s entry point into a cell, the first step for a viral infection. But the new findings shed light on a subsequent step by identifying one of the virus’s key co-conspirators inside cells. The research offers hope that new compounds will someday disrupt that link.
“It’s early, but nevertheless this is a real possibility,” says Kartik Chandran, a virologist at the Albert Einstein College of Medicine in New York City who worked on both studies. “All this is a cause for cautious optimism.”
In one of the papers, Chandran and his colleagues exposed human cells in lab dishes to an innocuous virus toting an Ebola protein. The cells carried a variety of genetic mutations. The screen revealed that cells with a genetic mutation causing them to underproduce NPC1, the Niemann-Pick C1 protein, fended off infection by the virus.
Further tests in mice that were exposed to Ebola or its cousin, the Marburg virus, showed that the viruses’ ability to infect a cell was greatly diminished in animals genetically engineered to lack a full supply of the NPC1 protein. Nearly all such mice survived, while most mice making a full allotment of NPC1 died within 10 days.
In the other study, hematologist James Cunningham of Harvard Medical School and his colleagues tested tens of thousands of compounds. The researchers used a robotic device to scan lab plates containing cells exposed to Ebola while various compounds were added. One called benzylpiperazine adamantane diamide 3.0 seemed to protect against the virus. The researchers made roughly 100 variations on the 3.0 compound, Cunningham says, and came up with several that inhibited the virus’s infectivity.
These compounds, the researchers found, interfere with NPC1.
“These are important new findings,” says virologist Judith White of the University of Virginia School of Medicine. “What’s really powerful is that these two very different approaches converged on the same molecule. That makes it very convincing.”
NPC1 now becomes the second human protein implicated in Ebola virus infection. Chandran, Cunningham and others reported in 2005 that an enzyme called cathepsin B shears off part of Ebola’s protein coat as part of the infection process. The new studies indicate this scissor work enables the virus, while trapped in a cell compartment, to bind to NPC1. How the virus goes from that point to getting loose inside a cell and infecting it remains unknown.
Chandran says the next step will be to test the NPC1-neutralizing compounds against Ebola in other animals, preferably monkeys.
J. E. Carette et al. Ebola virus entry requires the cholesterol transporter Niemann–Pick C1. Nature. doi: 10.1038/nature10348
M. Cote et al. Small molecule inhibitors reveal Niemann–Pick C1 is essential for Ebola virus infection. Nature. doi: 10.1038/nature10380
K. Chandran et al. Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science, Vol. 308, June 10, 2005, p. 1643.
K. Schornberg et al. Role of endosomal cathepsins in entry mediated by the Ebola virus glycoprotein. Journal of Virology, Vol. 80, April 2006, p. 4174.