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It weighs less than a ten thousandth of an ounce and its maximum speed is less than two miles at the hour. Nevertheless, the female mosquito is one of the most dangerous animals on the planet. Because, while flying from person to person, this tiny creature transmits microbes that can make sick and kill millions of people each year.
Recently, however, scientists at Rockefeller University have shown that it's possible to persuade female mosquitoes not to bite at all.
Their work, which appears in the newspaper Cell, illuminates the biology that underlies host-seeking and blood-feeding behaviors that make these insects such a threat – and could lead to new ways to stop these behaviors.
The researchers conducted their experiments on Aedes aegypti mosquitoes, species responsible for the spread of dengue, Zika, chikungunya and yellow fever.
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Female Aedes are fiercely attracted to humans, whose blood contains the protein they need to produce their eggs. However, once fed, this attraction declines rapidly and the balloon-swollen mosquitoes show little interest in finding another blood meal for several days.
"It's like the ultimate Thanksgiving dinner," says Laura Duvall, a postdoctoral fellow who led the project.
Scientists can replicate this 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 combinations of neuropeptides and receptors is long and better tools were needed to develop compounds that could more effectively suppress a woman's eating behaviors without having other undesirable effects.
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Fortunately, similar receptors regulate the feeding behavior of many species, including ours. And this shared evolutionary legacy provided Duvall and his colleagues the clue they needed to solve the mystery of the mosquito's lack of appetite.
In humans, neuropeptide Y or NPY receptors regulate food intake and the pharmaceutical industry has developed anti-obesity drugs that activate and inhibit them.
Duvall and colleagues felt that the same drugs could also affect NPY-type mosquito receptors. And they were right.
When researchers fed female mosquitoes a saline solution doped with drugs activating human NPY receptors, the attraction of insects to a human host – measured by their willingness to fly to a piece of stockings Nylon that Duvall had worn long enough to absorb body odors screaming "meal time" at the mosquitoes – a fall like they had had a blood meal. Alternatively, when the researchers fed the blood of mosquitoes doped with a drug inhibiting the same receptors, they behaved as if they had eaten nothing at all.
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To identify the particular receptor on which the drugs for human use were acting, the team used its knowledge of the mosquito genome to clone all 49 possible neuropeptide receptors of the species and expose them to the same compounds. Only one NPY-type receptor, called NPYLR7, responded to all the human drugs that affected mosquitoes.
"We were impressed and amazed by the fact that drugs designed to affect human appetite worked perfectly to suppress the appetite of mosquitoes," said Vosshall, professor of Professor Robin Neustein's Chemistry.
Moreover, when the team feeds the blood of mutants Ae. aegypti Genetically engineered to not possess the proper NPYLR7 receptors, these mosquitoes remained as interested as ever at their next meal – confirming that NPYLR7 was indeed the receptor they were looking for.
At that time, the researchers knew that NPYLR7 could be what they had been looking for for a long time: a way to prevent mosquito bites. But the drugs used by humans to manipulate the receptor in the lab could not be used in nature, where they could affect both people and mosquitoes.
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Instead, they began looking for molecules that would selectively activate NPYLR7 without triggering human NPY receptors. From an initial list of more than 250,000 candidates, the team finally opted for "compound 18" – a molecule that suppressed Aedes"Host search behavior without untargeted effects.
To show that a drug will encourage female mosquitoes to put their nose in a piece of fragrant nylon is, however, one thing. Prove that it will prevent them from biting a living host who breathes when he is lying in front of them, like a Thanksgiving turkey is another.
So, for their last test, the researchers dropped mosquitoes on a live mouse. (While Aedes prefer humans, they will be content with other mammals if necessary.) To their great satisfaction, mosquitoes fed compound 18 were as indifferent to feeding on rodents as mosquitoes that had eaten blood.
The findings of the team have profound implications for both future research and vector control.
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Now that researchers know which receptor is responsible for extinguishing Ae. aegypti Mordant behaviors and in search of hosts, they can begin to identify where it is produced in the body of the insect and when it can be naturally activated by the chemicals that the mosquitoes produce themselves. (Although they still do not know exactly which natural neuropeptides activate NPYLR7, Duvall and his colleagues now have a list of nine possible candidates.) It will also help them trace the more important neural circuits that govern the nutritional behavior of NPYLR7. mosquito.
At the same time, their findings suggest a new strategy to reduce the transmission of mosquito-borne diseases – and possibly diseases also transmitted by other insects.
In addition, because these disease-carrying mosquitoes are invasive, changes in their populations would not affect surrounding ecosystems.
Hopefully, chemists could refine compound 18 to produce an even more potent molecule that could be transmitted to female mosquitoes in the wild by bait traps or sperm from male genetically modified mosquitoes to produce them -Same.
Muzzle Ae. aegypti would be a boon in itself. But other arthropods that feed on blood and transmit diseases, including mosquitoes that spread malaria and ticks that transmit Lyme disease, also have NPY-like receptors. It seems likely that a compound that suppresses Ae. aegypti eating behaviors would also suppress them. And that would significantly reduce the global burden of disease imposed by these perverse blood-suckers.
(Source: Rockefeller University)
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