Now, scientists from the Florida campus of The Scripps Research Institute (TSRI) have been awarded $2.3 million to study a category of viruses that cause dengue fever, West Nile, yellow fever and other diseases spread by mosquitoes and ticks. These diseases can result in flulike symptoms, extreme pain (dengue has been called "bone-break fever") and, in some cases, encephalitis.
This family of viruses, called "flavivirus," affect some 2.5 billion people worldwide and cause hundreds of thousands of deaths each year. There are no antiviral treatments and a just handful of vaccines that provide protection against only a few of these diseases.
The principal investigator for the new five-year study is TSRI Associate Professor Hyeryun Choe, who will lead the effort to understand the virus's mode of infection and how new therapies might interrupt it.
"Flavivirus uses a very clever method of infection," Choe said. "It's like using a side door to enter a house when the front door is locked."
The viruses take advantage of the process that normally occurs during programmed cell death. During programmed cell death ("apoptosis"), a lipid usually found on the inner side of the cell membranes, specifically phosphatidylserine (PS), shifts to the surface, making itself readily available to any passing cellular stranger. This is where the trouble begins.
When cells are dying from a flavivirus infection, their freshly exposed PS is grabbed by the exiting virus, and phagocytes—cells that devour invading pathogens and dead and dying cells—engulf the virus as if it were a dying cell. Once engulfed by the phagocyte, the virus quickly turns the cell's own biology on its head, forcing it to produce copies of the virus.
While some viruses (influenza A for example) do not use PS in their life cycle, the flavivirus exploits this opportunity to the hilt. Infection of cells by dengue or West Nile viruses is markedly enhanced when phagocytes express receptors that recognize and bind PS.
It appears, however, that flaviviruses use only a subset of these receptors. The high selectivity, and the potency with which some of these receptors promote flavivirus infection, suggest only a small number of receptors might be effectively targeted to treat these diseases.
"We want to understand which PS receptors contribute the most to flavivirus infections and how we might block them," Choe said. "Our studies are designed to offer insights useful in the development of new therapies."
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