Mosquito-borne diseases kill about 700,000 people every year. Lives can be spared by applying insect repellents, including a chrysanthemum flower extract called pyrethrum that humans have used for thousands of years. A new study in Nature Communications finally shows how pyrethrum works, with two components acting synergistically to deter the pesky bloodsuckers.

Mosquitoes tend to develop resistance to a specific repellent over time, notes the study’s senior author Ke Dong, a Duke University neurotoxicologist. So “new, alternative ones need to be continuously developed to eventually replace current ones,” she says. Understanding repellent mechanisms could help. “We’re very excited because we are finally beginning to understand how a popular natural insect repellent, used worldwide, keeps mosquitoes from biting people.”

To observe pyrethrum’s effects, Dong and her colleagues attached tiny electrodes to hairs on mosquitoes’ antennae. This let them measure the insects’ responses to repellents at the level of individual odorant receptors in nerve cells. Many disease-carrying mosquito species have more than 100 such receptors, but the researchers found pyrethrum activates one in particular called Or31—and they confirmed that mosquitoes would not flinch from the substance if they were genetically modified to lack that receptor.

Unlike many other odorant receptors, Dong says, Or31 just happens to appear in all known disease-carrying mosquito species. Plus, many other natural repellents—unlike pyrethrum—work by activating multiple odorant receptors, and researchers still know very little about how those other receptors work. Considering these factors, the scientists suggest, Or31 could serve as a clear, universal target for developing better repellents.

The team also used chemical analysis to determine how two of pyrethrum’s molecular components—EBF and pyrethrin—elicit the repellent response. Mosquito experiments showed the chemicals work best when combined: EBF activates Or31, and pyrethrins enhance repellency by intensifying nerve signaling.

Dong and her colleagues next plan to investigate the neural circuits behind the repellency induced by pyrethrum and similar natural substances. They will also continue testing other potential repellent molecules, including the main component in citronella oil, which they found also activates Or31.

Johns Hopkins University neuroscientist Christopher Potter, who specializes in insect olfaction and was not involved in the research, says the findings could eventually help create “super mosquito repellents.” In particular, Potter says, untangling exactly which neurons determine mosquitoes’ responses to certain odors could reveal novel ways to manipulate their behavior. “Perhaps one day,” he observes, “we could identify how to turn this dial up even further or how to trick mosquitoes into becoming repelled by other odors—such as those that normally attract them to humans.”