BLACKSBURG, Va., Oct. 30, 1998 -- Malaria, a parasitic disease transmitted by mosquitoes to humans and animals, has made such a dramatic re-emergence in many areas of the world that the last five years has seen the growth of global interest in finding novel strategies to control the disease. Somewhere in the workings of the genes of mosquitoes may be a key to disrupting the insect's complex relationship with the parasites, a key that could break the cycle of transmission.
Shirley Luckhart, an assistant professor of biochemistry at Virginia Tech, is searching for that key. She's studying the two-week period when the malaria parasite develops inside a mosquito.
Only about 70 of the hundreds of mosquito species are capable of transmitting malaria. The disease-causing parasites must negotiate a torturous life cycle that alternates between the mosquito and an animal host. Parasites are ingested by a susceptible mosquito as it sucks blood from an infected host.
The parasite must then mature and reproduce during a two-week period in the mosquito, creating a new generation of parasites which are injected into another host when the mosquito feeds again.
Luckhart said that resistant parasites have emerged for each of the eight drugs that are commercially available to treat malaria. The species of mosquitoes that carry malaria are also becoming resistant to a number of control methods.
Countries witnessing a rising incidence of the disease are often experiencing dissolving social structures, which leads to increasingly ineffective control measures.
"The approach we're taking, if it's successful, is to develop transgenic mosquitoes that are incapable of transmitting the parasite," she said. "We're really at the beginning of a three-step process. First we need to identify candidate genes that affect the life cycle of the parasite. Then we need to develop strategies to manipulate the gene and to introduce the modified gene into a population of mosquitoes."
Luckhart is looking at biological and biochemical events occurring in the mosquito and in the parasite during the two-week incubation period.
"What we want to do is identify points in that process where the mosquito's immune system keeps the parasite's development in check," Luckhart said. "We've discovered recently that the immune response of mosquitoes involves the production of nitric oxide; humans also produce nitric oxide in response to malaria infection."
The toxic nitric oxide kills some of the parasites in the mosquito, but by the time it is produced the parasite has multiplied sufficiently to ensure that some individuals will survive.
"There's a limit to the amount of nitric oxide that can be produced," Luckhart said. "It's an incredibly toxic substance. Uncontrolled, it's a suicide response because it's so toxic that it would kill the mosquito.
"We may be able to enhance the production of mosquito nitric oxide, or we may be able to change it's timing," she said. "If we can trigger the release of nitric oxide sooner in the process, we may be able to eliminate the parasite before it has established itself."
The gene for the enzyme responsible for nitric oxide production in mosquitoes is very similar to the same gene in humans. Luckhart is looking at what drives nitric oxide production, such as the signaling that turns on the gene in mosquitoes.
"We've completed characterizing the gene," Luckhart said. "We're just starting to characterize it's regulatory aspects. There's a great deal of work yet to come."
There is also the possibility that by understanding the biochemical processes occurring in the mosquito, scientists may be able manipulate other responses to the parasite or they may be able to interfere with other pathogens, like viruses, that mosquitoes transmit.
Luckhart developed the project at the Walter Reed Army Institute of Research during a three-year fellowship before she came to Virginia Tech in July. She will continue to collaborate with the Army, which has a variety of research programs concerning mosquitoes because of the potential for soldiers to find themselves in areas where malaria is prevalent.
Her work is also supported by grants from the National Institutesof Health and from the World Health Organization. Luckhart earned her bachelor's degree from the University of Florida, her master's from Auburn University, and her doctorate from Rutgers University.
With her program, Virginia Tech adds a new dimension to the transgenic capabilities of the university's biotechnology effort. Other Virginia Tech researchers have gained international attention for pioneering work in developing transgenic plants and animals for the production of pharmaceuticals.
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