In the October 4 issue of Science, the researchers report that they have discovered genes in naturally occurring populations of the mosquito, Anopheles gambiae, that enable the insects to resist infection by the malaria parasite, Plasmodium falciparum, which is deadly when transmitted to humans though an insect bite. The finding potentially opens new avenues to preventing malaria, one of the world's greatest scourges.
"The new genes we have found are the first ones that make the Anopheles mosquito highly resistant to real, natural populations of the most deadly of the human malaria parasites, as opposed to laboratory parasite strains, and there are several ways that this basic research finding could help prevent malaria transmission," says Kenneth Vernick, Ph.D., Associate Professor in the Department of Medical and Molecular Parasitology, who led the research.
Although it is too soon to know whether the research will result in new treatments or prevention strategies, Dr. Vernick says it may be possible to spread the parasite-blocking genes among mosquito populations, and thereby deny the parasite enough mosquitoes to sustain itself in nature. The genes might also produce a parasite-killing compound that could be developed into a drug for human use, he speculates.
Malaria is transmitted from person to person through the bite of female mosquitoes in the genus Anopheles, which carry malaria parasites. In order to sustain itself, the parasite must undergo a part of its lifecycle inside of the mosquito.
Dr. Vernick says that the genes that were found appear to have a large effect on the parasite's growth. In one case, mosquitoes with two copies of a parasite-blocking gene had an average of 0.2 parasites per mosquito, while insects with two copies of the alternate form of the gene, which makes insects susceptible to the parasite, had an average of 50 parasites per mosquito.
It isn't yet known how many parasite-blocking genes there are in the Anopheles mosquito, or how common these genes are in nature. Dr. Vernick estimates that at least half of the mosquitoes in natural populations may carry genes for resistance. Then why do they still transmit malaria? "It's likely that for many or most of the genes for resistance, the parasite develops its own 'counter-resistance' genes. There has been the general idea that the African malaria parasite and its mosquito vector were co-adapted, that is, they had arrived at a stable evolutionary relationship. Clearly, from our work, nothing could be farther from the truth.
"There is a high frequency of resistance genes in mosquitoes in nature, indicating that the parasite and the mosquito are in an intense evolutionary battle. The vector is trying to escape the parasite by developing a myriad of resistance mechanisms. The parasite, of course, doesn't want to go extinct, so it is permanently compelled to develop counter-measures to these mechanisms," says Dr. Vernick.
In addition to the genes that were found, the new study is novel because naturally occurring mosquitoes in a part of Africa where malaria is endemic were genetically screened by linkage analysis in the outbred population.
The study took place in Mali in West Africa. Dr. Vernick and NYU colleagues Oumou Niaré and Frederick Odoul collected some 5,000 mosquitoes that had bitten people infected with malaria, and counted the number of oocysts, one of the life stages of the malaria parasite, in the guts of the insects. They also extracted DNA from the insects in order to perform genetic screens. The mosquitoes that were analyzed were the offspring of wild mosquitoes from a village in Mali where malaria is endemic. Because female mosquitoes mate only once, the offspring analyzed in the study came from a single-pair mating that happened in nature. This approach insured that the results gave an accurate picture of the real mosquito genes that block the actual parasites currently infecting people in the endemic area.
The software used for the genetic analysis was designed by Kyriacos Markianos and Leonid Kruglyak from the Fred Hutchinson Cancer Research Center in Seattle, who are co-authors on the study. The software was designed to map the location on the mosquito's chromosomes of genes that influenced the number of parasitic oocysts.
Dr. Vernick's co-authors on the study are Oumou Niaré and Frederick Oduol from NYU School of Medicine; Kyriacos Markianos and Leonid Kruglyak from Fred Hutchinson Cancer Research Center; Jennifer Volz, Fotis Kafatos, Claudia Blass, and Rui Wang from the European Molecular Biology Laboratories in Heidelberg, Germany; and Abdoulaye Touré, Magaran Bagayoko, Djibril Sangaré, Sekou Traoré, Guimogo Dolo, Madama Bouaré, and Yeya Toure from the University of Mali School of Medicine in Bamako.
The study was supported by grants from NIAID/National Institutes of Health.