New findings could make mosquitos more satisfied—and safer to be around

She weighs less than one ten-thousandth of an ounce and her top speed is less than two miles per hour. Nonetheless, the female mosquito is one of the most dangerous animals on the planet. For as she flies from person to person, biting us to draw the blood she needs to lay her eggs, this tiny creature transmits microbes that sicken and kill millions of people every year.

Recently, however, scientists in the lab of Leslie B. Vosshall have shown that female mosquitoes can be persuaded not to bite at all. Their work, which appears in the journal Cell, illuminates the biology underlying the host-seeking and blood-feeding behaviors that make these insects such a menace—and could lead to new ways of shutting those behaviors down.

A bloated mosquito is a safe mosquito

The researchers conducted their experiments on Aedes aegypti mosquitoes, the species responsible for spreading dengue, Zika, chikungunya, and yellow fever.

Female Aedes are fiercely attracted to human beings, whose blood contains the protein they need to produce their eggs. Yet once they have fed, that attraction declines precipitously, and the bloated mosquitoes show little interest in seeking another blood meal for several days.

“It’s like the ultimate Thanksgiving dinner,” says Laura Duvall, the postdoctoral fellow who led the project.

Scientists can reproduce that long-term postprandial effect by injecting female mosquitoes with large doses of small protein-like molecules called neuropeptides, which activate specialized receptors. But the list of possible neuropeptide-receptor combinations is long, and better tools were needed to develop compounds that could more efficiently suppress a female’s feeding behaviors without having other, unwanted effects.

Fortunately, similar receptors regulate feeding behavior in many species, including our own. And that shared evolutionary inheritance provided Duvall and her colleagues with the clue they needed to solve the mystery of the mosquito’s missing appetite.

Appetite suppressant

In humans, so-called Neuropeptide Y or NPY receptors regulate food intake, and the pharmaceutical industry has developed anti-obesity drugs that both activate and inhibit them.

Duvall and her colleagues reckoned the same drugs might affect the mosquitoes’ NPY-like receptors, as well. And they were right.

When the researchers fed female mosquitoes saline solution doped with drugs that activate human NPY receptors, the insects’ attraction to a human host—as measured by their willingness to fly towards a bit of nylon stocking that Duvall had worn long enough to absorb the bodily odors that scream “mealtime” to mosquitoes—plummeted just as if they had had a blood meal. Alternately, when the researchers fed the mosquitoes blood doped with a drug that inhibits the same receptors, they behaved as if they had not eaten at all.

To pinpoint the particular receptor that the human drugs were acting upon, the team used their knowledge of the mosquito genome to clone all 49 of the species’ possible neuropeptide receptors and exposed them to the same compounds. Only one, an NPY-like receptor known as NPYLR7, responded to all the human drugs that had affected the mosquitoes.

“We were impressed and amazed that drugs designed to affect human appetite worked perfectly to suppress mosquito appetite,” said Vosshall, Robin Chemers Neustein Professor.

What’s more, when the team fed blood to mutant Ae. Aegypti that had been genetically engineered to lack proper NPYLR7 receptors, those mosquitoes remained as interested as ever in their next meal—confirming that NPYLR7 was indeed the receptor they had been looking for.

Use only as directed

At that point, the researchers knew that NPYLR7 might be what they have long sought: a means of preventing mosquitoes from biting people. But the human drugs they used to manipulate the receptor in the lab wouldn’t be suitable for use in the wild, where they might affect people as well as mosquitoes.

Instead, they began searching for molecules that would selectively activate NPYLR7 without triggering human NPY receptors. Starting with an initial list of more than 250,000 candidates, the team ultimately settled on “compound 18”—a molecule that suppressed Aedes’ host-seeking behavior with no off-target effects.

Demonstrating that a drug will cause female mosquitoes to turn up their noses at a piece of tasty-smelling nylon is one thing, however. Proving that it will prevent them from biting a living, breathing host when it is laid out in front of them like a Thanksgiving turkey is another.

So for their final test, the researchers let the mosquitoes loose on a live mouse. (While Aedes prefer humans, they will make do with other mammals when necessary.) Much to their satisfaction, mosquitoes that were fed compound 18 were as disinterested in feeding on the rodent as mosquitoes that had enjoyed a full-blown blood meal.

A bite-free future?

The team’s findings have far-reaching implications, both for future research and for vector control.

Now that the researchers know which receptor is responsible for switching off Ae. Aegypti’s host-seeking and biting behaviors, they can begin to identify where it is produced in the insect’s body, and when it might be naturally activated by chemicals that the mosquitoes produce themselves. (Although they still do not know exactly which naturally occurring neuropeptides activate NPYLR7, Duvall and her colleagues now have a list of nine possible candidates.) That, in turn, will help them trace the larger neural circuits that govern the mosquito’s feeding behavior.

At the same time, their results suggest a new strategy for reducing the transmission of mosquito-borne diseases—and perhaps ailments spread by other insects, as well.

With a bit of luck, medicinal chemists could refine compound 18 to produce an even more potent molecule that could be delivered to female mosquitoes in the wild through baited traps, or through the semen of male mosquitoes that have been genetically modified to produce it themselves.

Muzzling Ae. Aegypti would be a boon in and of itself. But other blood-feeding, disease-carrying arthropods, including the mosquitoes that spread malaria and the ticks that transmit Lyme disease, also possess NPY-like receptors. It seems likely that a compound that suppresses Ae. Aegypti’s feeding behaviors would suppress theirs, too.

And that would take a significant bite out of the global disease burden imposed by these pernicious blood-suckers.

In related news:

Study: Mosquitoes can hear up to 10 meters away

Cornell and Binghamton University researchers report for the first time that mosquitoes can hear over distances much greater than anyone suspected.

The findings were published Feb. 7 in the journal Current Biology.

Until now, it was believed that organisms required eardrums for long-range hearing, and that the feathery antennae with fine hairs that mosquitoes and some insects use to hear only worked at close distances of several centimeters (a few inches).

A series of experiments has now provided neurophysiological and behavioral evidence that Aedes aegypti mosquitoes – which transmit such diseases as yellow fever, Dengue, Zika, West Nile and Chikungunya viruses – can hear specific frequencies as far away as 10 meters (32 feet) or more.
These frequencies overlapped well with the frequencies of female mosquitoes in flight as well as human speech.

“It’s been known for quite a long time that male mosquitoes are drawn to the sound of the female’s beating wings,” said Ron Hoy, the D & D Joslovitz Merksamer Professor of Neurobiology and Behavior and the paper’s senior author. Gil Menda, a postdoctoral researcher in Hoy’s lab, is the paper’s first author.

Hoy noted that since mosquitoes mate in mid-air, the sound of the female’s wings buzzing sets the males in motion. Previous experiments to prove that males are drawn to the sounds of females in flight were done at close range, which reinforced the idea that they only hear at close range – up to 30 centimeters (approximately 1 foot).

Past research by Menda and Hoy to prove hearing in jumping spiders gave them the methods and skills needed to tap the auditory nerves of mosquitoes, and record the electrical potential of the excited nerves.

Initial tests in the lab revealed the mosquitoes’ auditory nerves picked up sounds from across a room. To prove this principle, the researchers set up an experiment in Barton Hall, a field house with a 30 meter (100-foot) ceiling that would reduce echoes. Menda fitted mosquitoes with an electrode in their brains and made neurophysiological recordings of the auditory nerve being stimulated by pure-tones emitted from a loudspeaker 10 meters away.

“They’re hearing at distances that normally require ear drums, but these are hairs,” said Hoy. Ear drums work by picking up pressure from sound waves, while tiny hairs sense sound from air particles vibrating at certain frequencies.

They then moved the nerve physiology equipment to a super-quiet anechoic room run by collaborator Ron Miles, professor of mechanical engineering at Binghamton University. “It’s the quietest room in the Northeast and possibly in the country,” Hoy said.

“We found the sweet spot of frequency that the mosquitoes are sensitive to was between 150 to 500 hertz,” Menda said. Menda played back the tones of females’ wings beating, which occurs at a frequency of about 400 hertz. In behavioral experiments, when these 400-hertz tones were played from as far as 3 meters away – the length of the room – male mosquitoes in a mesh cage all instantly took to flight. The behavioral reaction was proved in individuals, to make sure they weren’t taking flight as part of a group response.

The mosquitoes’ frequency range for hearing also overlapped with human speech. “The most energetic frequencies of an average human vowel is in the range of 150 to 900 hertz,” Hoy said, so “they should be able to hear” people speaking.

Also, using the anechoic room, “we showed the sensitivity of the male mosquito was so low that when I played a tone, it was hard for me to hear it, but I can see the mosquito can hear it,” Menda said. They recorded excited auditory nerves at 30 decibels. Human speech is typically spoken at 45 to 70 decibels, also within the mosquito’s sweet spot.

While the study provides both neurophysiological and behavioral evidence that male mosquitoes hear sounds from far field, it offers no proof that they use it to home in on people. The insects are known to pick up sensory cues such as carbon dioxide, odors and warmth to locate people. But the results do show an intriguing correlation, Hoy said.

Though the study does not suggest viable new avenues for mosquito control, it does open the door for developing highly sensitive directional microphones and hearing aids that use fine hairs that sense the speed of air particles as they are jostled by passing soundwaves.

Laura Harrington, Cornell professor of entomology, and Paul Shamble Ph.D. ’15, a John Harvard Distinguished Science Fellow at Harvard University, are co-authors of the paper, which was funded by the National Institutes of Health and a Gates Challenges Explorations Grant.

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