The first study was led by four senior scientists: Sean Whelan, associate professor of microbiology and immunobiology at Harvard Medical School; Kartik Chandran, assistant professor at Albert Einstein College of Medicine; John Dye at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) and Thijn Brummelkamp, originally at the Whitehead Institute for Biomedical Research and now at the Netherlands Cancer Institute. The second study was led by James Cunningham, a Harvard Medical School associate professor of medicine at Brigham and Women's Hospital, and also co-authored by Chandran.
"This research identifies a critical cellular protein that the Ebola virus needs to cause infection and disease," explained Whelan, who is also co-director of the HMS Program in Virology. "The discovery also improves chances that drugs can be developed that directly combat Ebola infections."
Both papers are published in the August 24 online issue of Nature.
The African Ebola virus—and its cousin, Marburg virus—are known as the filoviruses. Widely considered one of the most dangerous infections known, Ebola was first identified in 1976 in Africa near the Ebola River, an area in Sudan and the Democratic Republic of the Congo. Infections cause severe hemorrhage, multiple organ failure and death. No one quite knows how the virus is spread, and there are no available vaccines or anti-viral drugs that can fight the infections.
Through conducting a genome-wide genetic screen in human cells aimed at identifying molecules essential for Ebola's virulence, Whelan and his colleagues homed in on Niemann-Pick C1 (NPC1).
NPC1 has been well known in the biomedical literature. Primarily associated with cholesterol metabolism, this protein, when mutated, causes a rare genetic disorder in children, Niemann-Pick disease.
Using cells derived from these patients, the group found that this mutant form of NPC1 also completely blocks infection by the Ebola virus. They also demonstrated that mice carrying a mutation in the NPC1 gene resisted Ebola infection. Similar resistance was found in cultured cells in which the normal molecular structure of the Niemann-Pick protein has been altered.
In other words, targeting NPC1 has real therapeutic potential. While such a treatment may also block the cholesterol transport pathway, short-term treatment would likely be tolerated.
Indeed in the accompanying paper, Cunningham's group describes such a potential inhibitor.
Cunningham and his group at Brigham and Women's Hospital investigated Ebola by using a robotic method developed by their colleagues at the National Small Molecule Screening Laboratory at Harvard Medical School to screen tens of thousands of compounds. The team identified a novel small molecule that inhibits Ebola virus entry into cells by more than 99 percent.
The team then used the inhibitor as a probe to investigate the Ebola infection pathway and found that the inhibitor targeted NPC1.
For Cunningham and Chandran, this finding builds on a 2005 paper of theirs for which Whelan was also a collaborator. In that study, he and his group discovered how Ebola exploits a protein called cathepsin B. This new study completes the puzzle. It now seems that cathepsin B interacts with Ebola in a way that preps it to subsequently bind with NPC1.
"It is interesting that NPC1 is critical for the uptake of cholesterol into cells, which is an indication of how the virus exploits normal cell processes to grow and spread," said Cunningham. "Small molecules that target NPC1 and inhibit Ebola virus infection have the potential to be developed into anti-viral drugs."
INFORMATION:
The paper coauthored by Whelan was funded by the U.S. National Institute of Allergy and Infectious Diseases and the National Human Genome Research Institute, the U.S. Army, and the Burroughs Wellcome Fund. Cunningham's work was funded by the New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases at Harvard Medical School.
Written by Robert Cooke and Lori Shanks
Additional media contact:
Lori J. Shanks
Brigham and Women's Hospital
ljshanks@partners.org
617-534-1604
Full citation:
Nature, August 24, 2011, early online publication
"Ebola virus entry requires the cholesterol transporter Niemann-Pick C1," Carette et al.
"Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection," Cote et al.
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