New Dengue virus discovery could lead to development of anti-dengue drugs

Apr 22 2009

Doctors have no specific drugs to treat dengue fever, a viral illness spread by mosquitoes that sickens 50 million to 100 million people worldwide each year. Instead, the only treatments they can recommend for this painful and sometimes fatal illness (20,000 deaths globally each year) are fluids, rest and non-aspirin pain and fever reducers.

Now, researchers have identified cellular components in mosquitoes and in humans that dengue virus uses to multiply inside these hosts after infecting them. Their findings could lead to the development of anti-dengue drugs that would inhibit one or more of these host factors, thus curtailing infection and the development of disease.

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, funded the research, which was led by Mariano Garcia-Blanco, M.D., Ph.D., of Duke University Medical Center. The research appears in the current issue of the journal Nature.

"In this important study, Dr. Garcia-Blanco and his collaborators have greatly expanded the list of candidate targets for dengue drug development," says NIAID Director Anthony S. Fauci, M.D. "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."

All viruses co-opt parts of the cells they invade, but dengue virus is believed to require many such host factors because it has very little of its own genetic material, says Dr. Garcia-Blanco. Yet only a handful of mosquito or human dengue virus host factors (DVHF) have been identified to date, he adds, because researchers lack the tools for determining the functions of mosquito genes.

To overcome this barrier, the researchers turned to a familiar lab animal, the fruit fly. Mosquitoes and fruit flies (Drosophila melanogaster) are closely related, and researchers have multiple tools for determining Drosophila gene functions, notes Dr. Garcia-Blanco.

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

The scientists also used RNAi and live mosquitoes to test whether silencing select DVHFs impaired the ability of dengue virus to infect the gut tissue of the 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 containing inhibitory chemicals might be developed that would be used not to kill the mosquitoes, he says, but to make them a less-effective carrier of dengue virus. Because these envisioned drugs would not target the virus directly, but rather at a host factor, the virus would have less opportunity to develop drug resistance, Dr. Garcia-Blanco adds.

The 116 DVHFs discovered through the Drosophila screen included 42 that the investigators found to have counterparts in humans. Like the mosquito DVHFs, these newly discovered human DVHFs may serve as targets for new kinds of RNAi-based drugs, says Dr. Garcia-Blanco.

"Our research is motivated in part by a desire to understand how these tiny viruses manage to live in two such unrelated organisms as mosquitoes and humans," says Dr. Garcia-Blanco. "But we should also keep in the front of our minds - not the back - the magnitude of suffering caused by dengue fever to millions around the world. Our study is a big leap in terms of the amount of information we have about dengue host factors and this information could, we hope, be applied in ways that will help people."

Dr. Garcia-Blanco's collaborators included NIAID grantee George Dimopoulos, Ph.D. and others from Johns Hopkins University's Bloomberg School of Public Health. NIAID grantee Priscilla Yang, Ph.D. and others from Harvard Medical School also contributed to the new research.

NIAID conducts and supports research - at NIH, throughout the United States, and worldwide - to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses.

http://www.niaid.nih.gov