Biologists at Purdue University have taken a "snapshot" of a Velcro-like protein on a cell's surface just after it attached to the dengue virus, a linkup thought to initiate the early stages of infection.
The virus, which is spread by mosquitoes, infects more than 50 million people annually, killing about 24,000 each year, primarily in tropical regions.
During the earliest stages of infection, the dengue virus attaches to the "carbohydrate recognition domain," or CRD, of a key binding protein called DC-SIGN, located on a host cell's surface.
Using a powerful imaging tool called cryo-electron microscopy, the biologists took a picture of the virus attached to the CRD shortly after the two joined together. It is the first time scientists have visualized the virus and CRD binding.
"We formed the virus-CRD complex, took a snapshot and determined its structure," said Michael Rossmann, the Hanley Distinguished Professor of Biological Sciences in Purdue's College of Science. "Ultimately, researchers might want to find ways to treat or prevent viral infections, but in order to do that we first have to learn how viruses work and how they initiate infection."
The findings are detailed in a research paper to appear on Feb. 10 in the journal Cell. The research was carried out by Elena Pokidysheva and Ying Zhang, post-doctoral research associates working with Rossmann and Richard J. Kuhn, a professor and head of Purdue's Department of Biological Sciences.
Researchers from the Howard Hughes Medical Institute at Columbia University provided a cloned gene that enabled the Purdue scientists to produce the CRD.
The CRD is part of a protein receptor molecule called DC-SIGN - or dendritic cell-specific ICAM3 grabbing non-integrin. ICAM stands for intercellular adhesion molecule, a family of cell proteins that viruses bind to, and the number 3 defines a specific protein.
"The binding occurs on dendritic cells, which are usually one of the first lines of defense in the immune system," Kuhn said. "The first step in a virus infecting a cell is usually the attachment of the virus to the receptor. That's essentially what we are looking at, except in this case, instead of having the receptor, which is normally bound or attached to the cell, we have just a portion of the receptor, the CRD, which we produced separately."
Dengue belongs to a family of viruses known as flaviviruses, which includes a number of dangerous insect-borne diseases such as West Nile, yellow fever and St. Louis encephalitis. These diseases, however, use different biological mechanisms than dengue to infect host cells. Dengue is prevalent in Southeast Asia, Central America and South America. Mosquitoes transmit the virus to people, setting in motion the infection process.
"We and others think that this CRD acts sort of like Velcro to get the virus to stick to the surface of the cell, although this has not been proven," Kuhn said. "Once the virus and protein receptor are linked, perhaps the virus then moves across the cell surface to find a second protein, attaching to that receptor and entering the cell.