Mosquitoes are notorious for their bite, and more importantly, for their role in spreading human disease. The species Anopheles gambiae is especially pernicious, as it is the most important vector of malaria in Sub-Saharan Africa. A. gambiae finds humans primarily through olfaction, but the underlying molecular mechanism remains largely unknown.
In a recent study published in Nature, Yale researchers report their characterization of A. gambiae odorant receptors, in which they identify over two-dozen receptors that could be used as targets for mosquito control. Their research could lead to more effective control of the transmission of malaria.
“In this country, people don’t think much about malaria,” said Dr. John Carlson, Eugene Higgins Professor of Molecular, Cellular, and Developmental Biology and senior author of the paper, “but in the real world it’s an enormous problem, afflicting two to five hundred million people and killing one million children every year, mostly in Africa. Tropical diseases may seem far away from Yale, but there’s a lot of concern that with climate change these diseases will spread.”
The Carlson lab studied 72 A. gambiae odorant receptors among a family of 79 receptors recently identified through bioinformatics. To study these receptors, they used an in vivo “empty neuron” system in the fruit fly Drosophila melanogaster. Each odorant receptor under study was expressed in a mutant fly olfactory neuron that does not express natural D. melanogaster receptors.
The researchers then exposed the engineered flies to 110 chemically diverse scent compounds. Using an electrode inserted into the fruit fly antenna, they monitored the resulting firing rate of the neuron expressing the A. gambiae odorant receptor. In conducting these tests, Allison Carey, an MD-PhD student in the Carlson lab, collected a total of 27,000 physiological recordings.
For each scent compound and odorant receptor pair, researchers in the Carlson lab compared the measured firing rate to the engineered neuron’s firing rate in the absence of any odor. They identified many receptors that responded to human odors, including as indole, the most abundant component of human sweat.
For the next step, the Carlson lab, in collaboration with several other labs across the globe, is searching for additional compounds that interact with the A. gambiae odorant receptors. These compounds might eventually be used to create more effective mosquito repellants or attractants, and they could have major benefits in fighting the spread of malaria.
The researchers have already found a number of inhibitors for A. gambiae odorant receptors. These inhibitors are being tested in Holland for their effect on mosquitoes in the lab, and in Africa for their effectiveness in the field. The Carlson lab is also looking forward to using a new tool—computational biology. “We have a big database of odors that we know have an effect on different receptors,” said Carlson. “Sophisticated computational algorithms can use that database to predict what other compounds might work.”
As his lab searches for compounds affecting mosquito odorant receptors, Carlson keeps the practical issues in mind. “Any control method for malaria needs to be inexpensive and environmentally friendly,” he noted.
Carlson nevertheless looks forward to the potential benefits of his work for malaria control. He admits, “We don’t know how well this is going to work, but with a disease affecting 500 million people a year, even if it decreases incidence by only 0.1%, it would then help many—500 thousand—people every year. And it could be very helpful if used in conjunction with other control methods.”
Carlson does not purport that his research will cure the malaria pandemic in Africa and other parts of the world. His work has already, however, proven itself to be an important step toward understanding mosquito olfaction at the molecular level.
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