Mutant Protein Is Key to Fighting Ebola Virus

The African Ebola filovirus is a master hijacker. Co-opting a host cell’s cargo-transport system, an Ebola virus passes undetected through a cell’s outer membrane and overtakes the host’s molecular machinery for its own proliferation.

The virus’ main targets are endothelial cells—which line the interior of blood vessels—as well as white and red blood cells. On a large scale, Ebola’s molecular “hijacking” manifests itself frighteningly in the human host, causing multiple organ failure and rapid hemorrhagic fever. Currently, no antiviral treatment is available for Ebola’s victims.

But two studies published in the Aug. 24 online issue of “Nature” have found unique features of Ebola’s viral entry that may at last lead to anti-filovirus treatment strategies.

The first study was led by Sean P. Whelan, associate professor of microbiology and immunobiology at Harvard Medical School, along with three colleagues from institutions across the world.

Using a genome-wide screen of mutations in human cells that could interfere with Ebola infection, Whelan and his colleagues identified a single gene, NPC1, that, when mutated, disrupts Ebola infection.

NPC1 is primarily involved in transporting cholesterol into the cell. Whelan’s team found that this cholesterol transporter is a critical protein that the Ebola virus needs in its uptake through the cell membrane and into the cell’s interior. When the NPC1 gene is mutated, the Ebola virus cannot enter the cell.

The team identified NPC1 from cells of patients with a rare genetic disorder called Niemann-Pick, type C1. The cells were resistant to infection by the Ebola virus.

Whelan said the NPC1 is “a truly essential protein in Ebola viral entry.” But he said that much remains to be learned of NPC1’s specific interaction with the Ebola virus.

The second study published last month was led by Harvard Medical School Professor James M. Cunningham.

Cunningham’s team at Brigham and Women’s Hospital took a therapeutic-focused approach to their research. After screening tens of thousands of chemical compounds that could potentially interrupt Ebola viral activity, the team found one small molecule that inhibits the Ebola virus’ entry into cells more than 99 percent of the time. Strikingly, this molecule interacts with the NPC1 protein, possibly interfering with the Ebola virus’ ability to co-opt the NPC1 protein for its own use.

Whelan said that the findings in Cunningham’s study are particularly promising because the small molecule inhibitors are similar in structure to a psychiatric drug that is already FDA-approved and thus may be safe for human use.

“Although many questions remain in how to adapt or re-design the drug, this is an exciting step,” he said.

Combining the findings of these studies, the possibility of an anti-viral drug that could inhibit Ebola’s interaction with NPC1—and the course of the viral infection—could become a reality.

— Staff writer Alyssa A. Botelho can be reached at abotelho@college.harvard.

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