April 27, 2009

New Insights Into Dengue Virus

Close-up photo of a mosquito Aedes aegypti, a domestic, day-biting mosquito that carries dengue virus. Image by David Gregory & Debbie Marshall. Wellcome Images.

Doctors currently have no specific drugs to treat dengue fever, a painful and sometimes fatal illness spread by mosquitoes. In a finding that could lead to the development of anti-dengue therapies, scientists identified several cellular components in both mosquitoes and humans that the dengue virus uses to multiply after infection.

The dengue virus sickens 50 million to 100 million people worldwide each year. The only treatments doctors can recommend are fluids, rest and non-aspirin pain and fever reducers. The development of better treatments will depend on a better understanding of the virus.

All viruses co-opt parts of the cells they invade, but dengue virus has very little of its own genetic material, and so researchers believe it requires many factors from its hosts. Yet only a handful of mosquito or human dengue virus host factors have been identified because of the difficulty researchers have identifying the functions of mosquito genes.

To overcome this barrier, a team of researchers led by Dr. Mariano Garcia-Blanco of Duke University Medical Center turned to a familiar lab animal: the fruit fly (Drosophila melanogaster). Mosquitoes and fruit flies are fairly closely related. NIH's National Institute of Allergy and Infectious Diseases (NIAID) funded the new study, which appeared in the April 23, 2009, issue of the journal Nature.

The Duke researchers screened test-tube-grown fruit fly cells to find fly gene components used by dengue virus. They employed a technique called RNA interference (RNAi) to selectively turn off, or silence, fruit fly gene segments and identify those that dengue virus requires for growth. The screen turned up 116 host factors, of which 111 had not previously been identified.

The scientists also used RNAi and live mosquitoes to test whether silencing select host factors impaired the ability of dengue virus to infect the gut tissue of insects. They found that silencing a specific mosquito gene greatly impaired the capacity of the virus to multiply in the mosquito.

This finding, though preliminary, raises the possibility of selectively inhibiting dengue virus growth in mosquitoes, says Dr. Garcia-Blanco. For example, a spray with inhibitory chemicals could be developed to make mosquitoes a less-effective carrier of dengue virus. Because these chemicals wouldn't target the virus directly, the virus would have less opportunity to develop drug resistance.

The 116 host factors included 42 that appear to have counterparts in humans. Like the mosquito host factors, the human versions might also serve as targets for new kinds of RNAi-based drugs.

“In this important study, Dr. Garcia-Blanco and his collaborators have greatly expanded the list of candidate targets for dengue drug development,” says Dr. Anthony S. Fauci, director of NIAID. “Their discovery should spur a better understanding of how dengue virus causes illness and open new avenues for developing specific treatments for a disease that exacts a huge global burden.”

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