|New Understanding of Dengue Virus Points Way to Possible
Therapies for Dengue Fever
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
“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
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
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
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. News releases, fact sheets and other
NIAID-related materials are available on the NIAID Web site at
Additional information about NIAID research efforts on dengue
fever is available at http://www3.niaid.nih.gov/topics/DengueFever/default.htm.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
It is the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates
the causes, treatments, and cures for both common and rare diseases.
For more information about NIH and its programs, visit www.nih.gov.
Reference: OM Sessions et al. Discovery of insect
and human dengue virus host factors. Nature DOI: 10.1038/nature07969