Cholesterol helps Ebola virus enter human cells

March 2, 2021
The way Ebola responds to human RNA may lead to a way to defeat it. (CDC via AP/Frederick Murphy)

The way Ebola responds to human RNA may lead to a way to defeat it. (CDC via AP/Frederick Murphy)

Scientists removed cholesterol from the membranes of the most dangerous Ebola viruses and found that it heavily reduced their success in embedding in cells, directly demonstrating for the first time that the lipid is a crucial component to Ebola infection.

The findings, recorded in a paper published Jan. 18 in Nature Structural & Molecular Biology, pinpointed that cholesterol supports viral entry by binding to the Ebola virus’ “spike” protein, although the discovery may not lead directly to a new treatment. The Ebola virus is one of several that require cholesterol during entry, including HIV, influenza and herpes; cholesterol may also be an important compound for COVID-19 infections.

Ebola, a contagious hemorrhagic fever that can cause heavy bleeding and has a high mortality rate of roughly 50%, has killed tens of thousands of people during outbreaks mostly located in Africa since its emergence in 1976. Of the four viral strains that cause the virus, Zaire ebolavirus is the most fatal and is often called simply the “Ebola virus.”

Efforts to suppress the virus are still ongoing, with the U.S. Food and Drug Administration approving the first Ebola virus vaccine in December 2019 and the first treatment last October.

The only protein on the Ebola virus’ surface is its glycoprotein, also called the spike protein. After the virus is brought into the cell by endosomes, the glycoprotein reacts to lowered pH levels and fuses the virus with the endosome membrane and opens the door to replication. Cholesterol — a common membrane component that adds stiffness — was known to affect viral entry in other viruses, but its particular interaction with the Ebola glycoprotein and the virus’ own entry process had not been previously investigated.

“There had been very little research done on cholesterol and Ebola virus,” said Lukas Tamm, a professor of molecular physiology and biological physics at the University of Virginia and an author of the study. “There were some anecdotal evidences that people who had low-cholesterol diets were a little less susceptible to infection by Ebola, but nobody really knew whether this was actually true or good scientific evidence for it.”

Tamm and his UVA lab tested how the presence or absence of cholesterol affected the performance of virus-like particles, which had membranes similar to the Ebola virus but were not contagious because they did not contain genetic material. Compared with a control group, particles treated with cholesterol-reducing statins successfully entered human cells between about 10% and 25% as often, according to Tamm.

The team also located the domain on the glycoprotein where it binds with cholesterol, which subsequently alters the protein’s structure and possibly facilitates fusion with the endosome membrane. Virus-like particles with glycoproteins containing mutations at these sites saw even less entry success.

The researchers say that alongside previous results, their study suggests that statins should be considered for inclusion in multipart treatments for patients with Ebola. But Tamm warned that this approach of removing cholesterol from Ebola viruses is not a promising candidate for curing the disease. It does not eliminate the virus entirely, and removing too much cholesterol could interfere with the healthy function of human cells, he said.

“I don't know if one could find a statin-like analog that's much more specific to these Ebola virus particles,” Tamm said. “That would be great, but I mean, it's not going to be easy.”

Tamm’s lab is currently investigating other steps in Ebola virus entry, including compounds in cell vesicles that trigger its attachment. It could pose a better basis for a future therapeutic treatment that would be more targeted than the cholesterol approach, he said.

The article “Ebola virus glycoprotein interacts with cholesterol to enhance membrane fusion and cell entry” was published Jan. 18 in Nature Structural & Molecular Biology. The authors of the study were Jinwoo Lee, University of Virginia and University of Maryland, College Park; and Alex Kreutzberger, Laura Odongo, Elizabeth Nelson, David Nyenhuis, Volker Kiessling, Binyong Liang, David Cafiso, Judith White and Lukas Tamm, University of Virginia. The lead author was Jinwoo Lee.

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