Fighting Malaria by Manipulating Mosquitoes' Sense of Smell

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Malaria

Imagine a small village in Sub-Saharan Africa in 2015. Few of the children exhibit the violent bouts of chills and fever or the persistent anemia and listlessness that characterize acute malaria and chronic long-term infection, respectively. The picture was much different just 10 years earlier. If you walked into a classroom in the village's primary school, you would have seen handfuls of empty desks. While most children who contract malaria at this age recover enough to return to class, equally as tragic were the large number of children who never got to sit behind one of the desks because they died of this dread disease before they reached their first birthday.

The reason for the improvement in the village children's health is a dramatic drop in the numbers of malaria-infected mosquitoes in the area. The cause of the insect's decline is the addition of a new mosquito control system that supplements traditional methods. The new system consists of unobtrusive traps that contain powerful attractants mixed with insecticide that lure the mosquitoes to their death. At the same time, villagers can purchase affordable and highly effective repellents from small kiosks that also sell cooking oil, sodas and bednets.

This vision or something quite similar could become reality with the success of an ambitious research project that has been selected for funding as part of the Grand Challenges to Global Health Initiative. The initiative, which was launched by the Bill and Melinda Gates Foundation, has just announced the selection of 43 "groundbreaking" research projects to improve health in developing countries that will receive a total of $436 million in support. As part of this effort, mosquito researchers from Vanderbilt University, Yale University, the Wageningen University in the Netherlands, the Ifakara Health Research and Development Centre in Tanzania and the Medical Research Council Laboratories in the Gambia will be developing to "a chemical strategy to deplete or incapacitate a disease-transmitting insect population."

Malaria is considered to be the most prevalent life-threatening disease in the world, with estimates of the number of new cases that range from 300 million to 660 millions cases per year. The Anopheles gambiae mosquito is its primary vector in Africa. Current efforts to control this disease, which combine the use of insecticides with improved access to effective diagnosis and treatment, have great potential to save lives but face enormous challenges and cannot eradicate malaria without the development of complementary control technologies.

Recent advances in the genetics, biology, immunology and behavior of mosquitoes open up new and unexplored avenues for controlling malaria and other mosquito-borne diseases. The goal of the Vanderbilt-led research team is to pursue one of the most promising of these new avenues: developing chemical compounds that disrupt the sense of smell that Anopheles females use to identify the human hosts for the blood meals that they need to reproduce.

The effectiveness of the olfactory strategy has been demonstrated by a program with the African tsetse fly that has replaced the practice of treating large tracts of land with persistent insecticides with the use of scented baits. It is widely considered to be an environmental and technological success. Unlike insecticides, the chemicals involved in insect olfaction tend to be relatively non-toxic. They also tend to be specific to closely related species, so widespread application is not likely to impact other beneficial insect populations.

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With the foundations' support, the researchers will set up a pipeline for identifying and testing non-toxic chemical odorants that attract, repel or simply confuse the mosquito's olfactory system.

The pipeline begins with the high-tech genetic engineering and molecular biology laboratories at Vanderbilt and Yale, which will identify chemical compounds that interact strongly with receptors in the female mosquito's antennae and appear to be related to host selection.

The most promising of these mixtures will be shipped to Wageningen University where their effects on the behavior of live mosquitoes will be determined. Compounds that pass the behavioral tests will be forwarded to Ifakara, Tanzania, where they will be evaluated with laboratory-reared mosquitoes in a large biosphere that simulates the natural environment. Here the researchers will experiment with various mixtures of synthetic attractants and repellents to identify the most effective and long-lasting combinations.

Finally, odorants that have passed all these screens will be field tested in cooperating villages near Ifakara and in The Gambia under the supervision of IHDRC and MRC Laboratories' researchers. The two sites are at opposite geographic extremes in the enormous expanse of tropical Africa infested with locally diverse populations of malaria mosquitoes, so compounds that work in both locations are likely to work everywhere in between.

"By combining laboratory-based and field-based studies we expect to establish an effective strategy for developing extremely powerful attractants and repellents for Anopheles mosquitoes and identifying effective methods for using them to reduce the spread of malaria," says Laurence J. Zwiebel, associate professor of biological sciences at Vanderbilt, who is the principal investigator on the project.

The mixtures developed in the project could be useful against other disease-carrying mosquitoes, such as Aedes aegypti that spreads dengue fever and Culex pipiens that carries the West Nile virus. In addition the project will demonstrate a basic approach that can be directed against a number of other insect species, including agricultural pests and those that carry other human and animal diseases.

In addition to chemical compounds that are effective and non-toxic, the researchers will give priority to those that are available from local plants and animals based on the assumption that such an olfactory-based system will have maximum impact if the major ingredients can be made locally so costs can be kept as low as possible.

The Grand Challenges initiative was launched by the Bill & Melinda Gates Foundation in 2003, in partnership with the National Institutes of Health, with a $200 million grant to the FNIH and is a major international effort to achieve scientific breakthroughs against diseases that kill millions of people each year in the world's poorest countries. It is funded with a $450 million commitment from Gates Foundation, $27.1 from the Wellcome Trust, and $4.5 million from the Canadian Institutes of Health Research (CIHR). The initiative is managed by global health experts at the Foundation for NIH, the Gates Foundation, the Wellcome Trust, and CIHR.

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