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06.06.03

Shape of virus may hold key to deadly disease
 

ith one quick bite, a tiny mosquito bred in the lingering rainwater in a discarded tire or crushed beer can, can infect a human with the potentially fatal dengue virus. The virus’ potentially lethal complication, dengue hemorrhagic fever, infects as many as 100 million people annually, and the Centers for Disease Control and Prevention calls dengue the most important mosquito-borne viral disease affecting humans today. And although the disease is largely tropical, the United States is far from immune: dengue outbreaks have been reported in Texas, Hawaii and the southeastern United States.

But recently, Children’s researchers discovered a method that can potentially block the protein that helps the virus develop into the shape that allows it to infect cells. This discovery may shorten the race to find a dengue cure, and scientists are confident it will help them better understand the lethal implications of the virus. The findings were reported in the Procedings of the National Academy of Sciences in May. Stephen Harrison, PhD, Howard Hughes investigator, was senior author of the study.

The dengue virus is so threatening because of its ability to bypass the human body’s first layer of defense, the cell membrane. The dangerous E protein, which forms the harmful shape of the virus, folds itself into a fist-like shape and punches a hole through the protective membrane of a cell, allowing the virus to enter, replicate itself and spread to other cells. The E protein achieves its virulent effects by stretching, bending and ultimately dumping its viral genes into a cell. The researchers discovered a pocket in the protein that could prevent the formation of that dangerous shape. If the pocket can be filled with a drug to prop the protein open, the virus may not be able to fuse or infect healthy cells.

“Inhibiting fusion is a sensible way of inhibiting viral replication,” says Harrison “This may turn out to be a false lead, but it suggests an interesting avenue to screen for compounds to inhibit dengue fusion.” The study’s implications go beyond dengue and may yield advances in treating yellow fever, tick-borne encephalitis, Japanese encephalitis and other types of viruses. The study is part of a new initiative at Harvard Medical School, known as the Center for Molecular and Cellular Dynamics, in which Harrison and other researchers are looking for meaningful ways to integrate their growing understanding of genes, proteins, and molecular structures into a better overall understanding of human health and disease.—ZB