Photo by Dr. Kenneth Vernick, NYU School of Medicine
Millions of tropical Africans who suffer from malaria - and a growing number of Americans infected with West Nile virus - don't view the lowly mosquito as a lawn-party pest. For them, the buzzy beast is a killer.
However, scientists are speculating that genetic ingenuity might restore a mosquito bite to the status of merely an itchy nuisance.
Researchers in the Human Biology Division and colleagues at New York University School of Medicine and in Heidelberg, Germany, and the West African nation of Mali have made a significant start. They are the first to identify genes in natural populations of the mosquito that enable it to resist infection from the most deadly malaria parasite.
The discovery, published last week in Science, may point to new ways to prevent malaria transmission. For instance, the parasite-resistance genes could be spread in mosquito populations, effectively interrupting part of the malaria life cycle.
That would be no small accomplishment, as malaria afflicts hundreds of millions of people each year and causes 3 million deaths annually, mostly in sub-Saharan Africa.
Dr. Kyriacos Markianos, research scientist, and Dr. Leonid Kruglyak, both of Human Biology, designed software used in the genetic analysis of the global effort, which was led by the laboratory of Dr. Kenneth Vernick at NYU.
Unique to the study, Kruglyak said, is that scientists applied genetic-mapping technology to a natural population of the malaria-hosting mosquito species, known as Anopheles gambiae.
"For most organisms other than humans, studies to map the location of genes on the chromosome are done with inbred laboratory strains," he said. "We analyzed mosquitoes from the actual population that causes disease in Mali. Our study was the first to examine genetic mechanisms for malaria resistance in a natural population."
The NYU-Kruglyak paper appears in a special edition of Science that contains the Anopheles genome sequence, an accomplishment that, along with recent completion of the human-genome sequence and that of Plasmodium, the malaria parasite, is expected to trigger better treatment and prevention of malaria.
Malaria is transmitted from person to person through the bite of female Anopheles mosquitoes that carry malaria parasites. To sustain itself, the parasite must undergo a part of its life cycle inside of the mosquito.
Previous research to identify malaria-resistance genes in mosquitoes has been conducted with laboratory strains of insects, which exhibit many biological differences from strains in the wild. In the current study, researchers took advantage of an unusual feature of mosquitoes' mating behavior to study a large population of insects derivedfrom a single mating in the field.
In Mali, where malaria is endemic, Vernick's group captured blood-fed female mosquitoes from village dwellings and reared their offspring in a local breeding site for insects.
Anopheles females mate only once, storing sperm to fertilize successive batches of eggs that mature after the insect feeds on human blood. Scientists used these progeny, as well as offspring produced by mass mating of the first generation, to obtain mosquitoes that were related genetically.
This extended "family" was fed blood infected with the Plasmodium parasite that causes malaria. Researchers then counted the number of oocysts - one of the life stages of the malaria parasite, in the guts of the mosquitoes - to identify insects in which the parasite could not propagate. Researchers also collected DNA from the insects to perform the genetic mapping.
Initial experiments revealed that genetic resistance is common among wild populations of mosquitoes, Markianos said.
"We compared resistance between mosquitoes that were derived from different wild-caught females and were fed on the same infected blood," he said. "We found significant differences for parasite count in most comparisons."
Because mosquitoes infected with the parasite have shorter life spans, produce fewer offspring and have impaired flight ability, scientists had speculated that resistance to infection by the parasite would be expected to evolve as a desirable trait that occurs at a high frequency in wild populations.
In the second stage of analysis, researchers used micro-satellite markers, genetic signposts whose physical positions along the chromosome are known.
The markers point to the positions of two genes that confer resistance to the malaria parasite.
Based on how often parasite resistance showed up in this natural population, researchers expect further studies to reveal more resistance genes.
Kruglyak said this work is just the first step toward developing prevention strategies or treatments.
One potential approach is to spread the parasite-blocking genes among mosquitoes and thereby deny the parasite enough mosquitoes to sustain itself in nature. The genes might also produce a parasite-killing compound that could become a drug for human use.
Another important outcome of the study, Kruglyak said, is the validation of this genetic approach for future studies to map genes in wild populations, which often differ considerably from those isolated in the lab.
"In principle, we should be able to apply a similar strategy to identify genes in other populations of organisms in the field," he said.