Apoptotic mechanism reveals broad-spectrum treatment for deadly viruses

Scientists have discovered a new phospholipid that takes advantage of “apoptotic mimicry” to promote deadly viruses such as dengue, Ebola, and West Nile. The scientists also found that the antibiotic duramycin can stop this process, and could be a broad-spectrum treatment for these and other pathogenic viruses, according to a study published online November 2, 2015 in Proceedings of the National Academy of Sciences.

“Most of these viruses use a specific molecule to enter cells. In the new study, we were able to show how a second molecule plays a major and previously unknown role in that process,” said lead investigator Hyeryun Choe, PhD, Associate Professor in the Department of Immunology and Microbial Science at The Scripps Research Institute (TSRI), in Jupiter, FL.

Dr. Choe added, “We also show an antibiotic called duramycin inhibits the actions of this molecule. This looks to be a promising broad-spectrum antiviral strategy and deepens our understanding of the entire infection process.”

The first molecule that Dr. Choe mentioned is the phospholipid phosphatidylserine (PS). Previous research has shown that many viruses use PS receptors to gain entry into target cells. Phagocytes also use these receptors to clear apoptotic cells. PS receptors mediate these activities by binding PS on the viruses or apoptotic cells.

When cells undergo apoptosis from a virus infection, the exiting virus grabs the cells’ freshly exposed PS that has risen to the cell surface. Phagocytes then engulf the virus. But once this occurs, the virus quickly turns a cell’s biology against itself, forcing it to produce copies of the virus.

In this investigation, Dr. Choe and her colleagues demonstrated that another molecule, phosphatidylethanolamine (PE), also binds to PS receptors. PE is exposed on the surface of apoptotic cells and promotes their uptake by phagocytes, the researchers explained.

PE is present in the virions of flaviviruses and filoviruses, the researchers found. Ebola, a filovirus, has an average fatality rate as high as 65%, although candidate vaccines are now in development. Dengue and West Nile are flaviviruses, and they cause tens of thousands of deaths each year.

“Despite the name, we found that PS receptors also detect PE, and viruses are able to take advantage of the abundance of PE on their surface,” said first author Audrey Stéphanie Richard, PhD, a research associate in the Choe lab at TSRI. “Through their PE, [viruses] latch onto the PS receptors on the host cell, taking control of the process and insuring entry and replication.”

The researchers found that duramycin, which is currently used as an imaging agent, blocks viral entry into an apoptotic cell by binding to the virus’s PE, preventing the virus from using PE to latch onto the PS receptors on the cell.

“Although duramycin itself…[is] expensive to synthesize and difficult to improve, its ability to control the replication of major pathogens such as [Ebola, dengue, and West Nile viruses] suggests that PE is a promising target for the design of broad-spectrum antiviral therapies,” the authors wrote.

“This new study goes a long way in helping us understand how so-called PS receptors contribute to flavivirus and filovirus infections and how we can block them through the PE-binding compounds,” Dr. Choe said.