October 25, 2010

How Dengue Virus Infects Cells

Photo of a mosquito James Gathany, CDC.

Researchers have discovered a key step in how the dengue virus infects a cell. The finding will allow researchers to study the process in the laboratory and provide a valuable tool for testing new drugs to prevent or treat infection.

The virus that causes dengue is transmitted by mosquitoes. Dengue fever usually starts with a fever, joint pain, rash and nausea. Without treatment, the virus can cause damage to blood and lymph vessels and lead to dengue hemorrhagic fever, which is marked by difficulty breathing, bruising and bleeding from the nose, gums or under the skin. Each year, the virus infects up to 100 million people and kills about 22,000, most of them children.

To infect a cell, the dengue virus initially binds to the cell surface. It gains entry into the cell when it becomes enveloped by the cell membrane during the creation of a pouch-like structure known as an endosome. The virus waits inside the endosome until it has traveled deep within the cell; then, it fuses its membrane with the endosomal membrane and forms a pore through which it releases its genetic material. Once inside the fluid interior of the cell, the virus begins to reproduce itself.

Researchers have studied viral fusion in the laboratory at the cell surface or by using artificial cell membranes. However, attempts to fuse dengue virus under either of these conditions have been unsuccessful. The reason for the lack of fusion has puzzled researchers for years. A research team led by Dr. Leonid V. Chernomordik at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) set out to investigate how the dengue virus fuses with its target membranes.

The researchers tagged dengue virus and cell membranes with fluorescent probes that glow when the virus and membranes fuse. Viral samples were also exposed to artificial membranes to identify factors that allow fusion to occur. The study was funded by NICHD and NIH’s National Institute of Allergy and Infectious Diseases (NIAID).

The results appeared in the October 7, 2010, issue of PLoS Pathogens. The researchers discovered that 2 conditions are essential for dengue virus fusion. The first is an acidic environment—a fundamental characteristic of endosomes. The second is the presence of negatively charged lipids in the endosome membrane, which are present only after an endosome has been taken deep within the cell.

"The confluence of acidity and a negative charge deep in the cell's interior ensures that the virus is safe within the endosome early in its journey, when it is most vulnerable, but can release its genome when it reaches its destination," Chernomordik explains.

"We spent several years trying to understand how the dengue virus fuses with its target membrane," Chernomordik says. "The findings will now enable us to test new ways to disrupt the fusion process and prevent infection."

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