NIH Scientists Unravel Clues to Ebola Hemorrhaging
Ebola virus is a rare but deadly microbe that kills up to 90 percent of the people it infects. Now, scientists from the National Institutes of Health (NIH) have identified a part of the virus that likely is responsible for the massive internal bleeding leading to most of those deaths. Their research, published in the August edition of Nature Medicine, identifies a viral protein that destroys endothelial cells -- the cells that line the blood vessel walls. By attacking this protein, new drugs and vaccines may be designed to reduce or prevent the disease.
Ebola virus is the most infamous of the hemorrhagic fever viruses, a group of microbes found only in humans and monkeys. Although these outbreaks are not common or widespread, they have received much publicity because of their lethal nature and horrifying symptoms, which include high fever and massive internal bleeding. To add to the mystery, Ebola virus strikes sporadically, often devastating an isolated town or village before disappearing back into the jungle, where scientists believe it may hide away in an as yet unknown host.
Ebola strains from Zaire, Sudan and the Ivory Coast are usually fatal to humans, while a monkey strain that infected laboratory workers in Reston, Virginia, in 1989 failed to cause overt disease. The reason for this difference was not clear, but because Ebola virus produces several different proteins, researchers believe one or more of these likely holds the key.
While studying these viral proteins, Zhi-Yong Yang and Gary Nabel, M.D., Ph.D., of the Dale and Betty Bumpers Vaccine Research Center (VRC), located on the NIH campus, led a research team investigating glycoprotein (GP), a sugar-containing molecule that sticks out from the surface of the Ebola virus. Along with other scientists from the VRC, the National Heart, Lung, and Blood Institute, and the Centers for Disease Control and Prevention, Yang and Dr. Nabel discovered that a specific portion of the protein caused it to destroy human and monkey endothelial cells in the test tube. The protein also caused isolated blood vessels to leak, which may explain the internal bleeding seen in infected individuals. GP isolated from the Reston strain, however, destroyed only monkey blood vessels, possibly explaining why this Ebola strain did not cause disease in humans.
As the scientists focused on GP, they found that a part of the protein that becomes modified with sugars had a toxic effect on the virally infected cells. When the researchers made forms of GP that lacked this region, the protein no longer destroyed the blood vessels but was otherwise active. The protein therefore serves two functions: it targets Ebola to the endothelium, and once sufficient GP has been manufactured by the infected cells, it kills those cells leading to the toxic effects of the disease.
By discovering the part of the protein that appears to be responsible for Ebola-induced hemorrhaging, the researchers have made important strides toward finding better ways to attack the virus. "We have been able to define the major Ebola virus gene that kills cells, and have provided a molecular target for potential new antiviral drugs and vaccines," states Dr. Nabel. This study also begins to reveal the basic mechanisms of how Ebola virus attaches to and enters cells, and future studies will continue to investigate how different regions of the virus surface perform different tasks for the invading microbe.
The Vaccine Research Center is a unique venture within the NIH intramural research program that receives joint funding from the National Institute of Allergy and Infectious Diseases (NIAID) and the National Cancer Institute (NCI), and is spearheaded by NIAID, NCI and the NIH Office of AIDS Research.
Reference: Yang Z-Y et al. Identification of the Ebola virus glycoprotein as the main viral determinant of vascular cell cytotoxicity and injury. Nature Medicine 6:886-89 (2000).
NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.
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