How does DEET fend off malaria mosquitoes?

The mosquito that transmits malaria is one of the most ruthless killers of people, contributing to 435,000 deaths in 2017. For decades, people have used repellents like DEET to try to ward them off. And DEET has worked for the most part, but researchers haven’t really understood how.

Until now. A group of scientists reports that DEET seems to keep mosquitoes from smelling humans by preventing compounds on our skin from vaporizing and finding their way to the mosquitoes’ antennae. The lead researcher, Christopher Potter of the Johns Hopkins University School of Medicine, says understanding how mosquitoes’ olfactory systems interact with repellents could lead to a next generation of mosquito-fighters that are less toxic than DEET, but equally effective (Curr. Biol. 2019. DOI: 10.1016/j.cub.2019.09.007.)

“What’s been done traditionally is to screen thousands and thousands of chemicals and hope you find something that repels mosquitoes,” he says. “Now that we have a better understanding of how the mosquito responds to DEET and other chemicals, we can maybe take a shortcut. We can identify things that would be better repellants without having to screen through thousands and thousands of chemicals.”

To study how mosquitoes sense repellents, Potter’s team developed a test that makes neurons in the mosquitoes’ antennae fluoresce when the odor receptors embedded in the cells turn on. Mosquito antennae work similarly to human noses, Potter says: When an odorant binds to an odor receptor, it launches a calcium-based response inside the neuron that leads to electrical activity in the brain.

Potter’s group first tested a swath of sweat chemicals, such as 1-octen-3-ol and benzaldehyde, that waft off our skin and are known to attract mosquitoes. They immobilized mosquitoes, puffed some of the attracting compound into the space near the insects, and looked for fluorescence in their antennae neurons.

After showing that the system responded to human odorants, the scientists tested several repellents, including three synthetic ones (DEET, picaridin, and IR3535) and two natural products (lemongrass oil and eugenol). The synthetic repellents had no effect on the mosquitoes’ olfactory system. The natural products did. Potter says these results suggest that the natural repellents likely work through a different mechanism than the synthetic repellents.

Then the team mixed human odorants with repellents and repeated the puffs. Pairing DEET and the other synthetic repellents with the human compounds quashed the sensory signal in the mosquitoes’ antennae. Something about the repellents was preventing the human odorants from binding to the odor receptors.

Using a photoionization detector, the researchers observed that smaller amounts of the human odorants were becoming volatile in the presence of DEET compared with the odorants alone. The chemistry behind how DEET does this masking still needs to be solved, Potter says.

Jeff Riffell, a mosquito researcher at the University of Washington, notes that other researchers, most notably Leslie Vosshall at the Rockefeller University, have found that different species of mosquitoes respond to DEET via a different mechanism.

Potter agrees with that caution. About 100 of the thousands of species of mosquitoes actually feed on humans, and only 10 or so of those transmit disease, including some of the ones in our backyards. “Other mosquitoes might be able to smell DEET and perhaps it’s a repellent odor to them,” he says, noting that different species have differences in their olfactory systems. “They’ve diverged 100 million years ago. They’re very, very different.”