Researchers Take Major Step Toward Cracking Ebola Code

February 16, 1998

ANN ARBOR---Ebola is an extremely lethal virus that has frustrated the medical world's attempts to learn how it works. Now, researchers are gaining valuable insight into how Ebola wreaks its deadly havoc.

Investigators from the University of Michigan Medical School, the Howard Hughes Medical Institute and the Centers for Disease Control and Prevention found that Ebola works by waging a war on two fronts. Their results are published in the Feb. 13 issue of the journal Science.

Ebola virus causes a rapidly progressing, often fatal, infection that can lead to vomiting, diarrhea, rash, high fever, hemorrhaging and shock. Often, liver and kidney functions are impaired.

The research team, led by Gary Nabel, M.D., Ph.D., professor of internal medicine and biological chemistry at the U-M Health System and an investigator at the Howard Hughes Medical Institute, reports that the virus employs a glycoprotein (a protein with sugar attached) in two different ways to disable the immune response and attack certain cells.

Study results show the glycoprotein, secreted by the virus, appears to interfere with the inflammatory response that is used at a cellular level to fight off the virus. Another form of this glycoprotein stays bound to the Ebola virus and attaches itself to endothelial cells which line blood vessels, likely causing the hemorrhaging characteristic of Ebola.

This particular glycoprotein was found in Ebola virus by investigators at the CDC nearly 20 years ago, but its role in Ebola's cellular invasion remained a mystery.

Nabel and his team, tracked the glycoprotein in two ways. The secreted glycoprotein was detected by its ability to bind to cells, using an antibody to this viral gene product. The binding characteristic of the transmembrane (or virus-bound) form of the protein was detected by using a technique of molecular genetics to insert this protein on the surface of another virus---a mouse retrovirus---which carried a reporter gene (a gene that encodes a protein whose activity can be readily measured in the laboratory) to identify infected cells.

Researchers had hypothesized that the secreted form of glycoprotein (sGP) might act as a decoy to steer inflammatory cells away from the transmembrane form of glycoprotein (GP). However, Nabel says it now appears sGP actually binds to neutrophils and hinders an early inflammatory response that might stop the virus from replicating.

The second part of the glycoprotein 1-2 punch comes from the transmembrane version of GP. This version attaches to endothelial cells, possibly clearing the way for the Ebola virus to enter into the cell where it begins its destructive process.

"These study results provide insight into the strategies that Ebola virus uses to evade detection and cause disease in infected individuals and point to potential antiviral targets," Nabel says.

Research is now under way on how the glycoprotein causes disease in animals. Nabel says investigators can look for potential treatment strategies that would activate the inflammatory defense system (to counteract the secreted glycoprotein) or protect endothelium cells---which line small blood vessels---to prevent bleeding and circulatory collapse.

The new findings may have far-reaching benefits for fighting other illnesses. The Ebola virus glycoprotein might also be used for therapeutic purposes, for example, by incorporating it into gene therapy vectors derived from different, safer viruses in order to deliver therapeutic genes into endothelial cells in cancer or cardiovascular disease.

"The virus has developed an insidious means to target different cells in the body to promote its growth at the expense of its host," Nabel says. "These studies provide greater understanding of its molecular control and approaches which might protect against infection."

University of Michigan

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