It’s one of summer’s recurring questions: Why is it almost impossible to escape the pursuit of a mosquito? Another reason why they itch me more? Scientists and repellent manufacturers have long known that exhaled carbon dioxide (CO₂), or octanol, a volatile compound in sweat, creates airways for mosquitoes to reach a victim. What they didn’t know and just discovered is that mosquitoes have more than one receptor for smells and tastes in each of their thousands of olfactory neurons. And that makes them unique in the animal kingdom.
In 2004, researchers Richard Axel and Linda Buck received the Nobel Prize in Medicine for their discoveries about the sense of smell. A decade earlier, they had found that about 1,000 genes are involved in smelling and that they give rise to a similar number of olfactory receptors. His work also found that each olfactory neuron expressed just one of these receptors, the information from which was perceived from the outside was sent as an electrical signal to the olfactory bulb, the part of the mammalian brain that processes and interprets the world of aromas. The head of the Laboratory of Neurogenetics and Behavior at Rockefeller University (USA), Leslie Vosshall, who was a student of Richard Axel, now says that “mosquitoes threw up all the rules of Axel and Buck”.
Vosshall is leading research that began years ago and focused on what the olfactory system of mosquitoes looks like. In their case, they have focused on the species Aedes aegypti, commonly known as the dengue mosquito as it is the vector of the virus that causes this disease. But the pathogens of yellow fever, chikungunya, Zika fever or the Mayaro virus can also be infected with their picks. Blocking the Egyptians’ perception of the smells of the females, the only ones who sting, would also be worthy of a Nobel Prize. But this lockdown won’t be easy.
Detail of an antenna of an ‘Aedes aegypti’ mosquito seen under an electron microscope. Fluorescent green corresponds to olfactory neurons stained with the CRISPR technique.Margo Herre
The latest research by Vosshall and his colleagues, published in the scientific journal Cell, shows that mosquitoes, like other animals, have a single receptor on some of their neurons. But at least those of this species can have up to two other receptors on most neurons. “If you’re human and you lose a single olfactory receptor, all of the neurons that express that receptor lose the ability to perceive that odor,” the researcher explains. “It takes something more to kill mosquitoes because eliminating a single receptor has no effect,” he adds. “Any future attempt to fight mosquitoes with repellents or anything else must take into account how unrelenting their attraction to us is.”
After sequencing the mosquito genome and identifying the genes that express the odorant receptors, the researchers used various techniques to track them down and localize them in neurons. For example, using the modern gene-editing technique CRISPR, they managed to introduce fluorescent proteins of different colors for different receptors. So they could see that in many neurons more than one was activated. They found that the neurons stimulated by the octenol in human smell were also activated by other chemical compounds derived from ammonia, the amines that also attract insects.
“The mosquitoes have a plan B for their plan B for their plan B. For me, the system is unbreakable.”
Leslie Vosshall, Head of the Laboratory of Neurogenetics and Behavior at Rockefeller University (USA)
The researcher from the University of Boston (USA) and co-author of the study Meg Younger explains the finding: “Surprisingly, neurons that recognize humans through 1-octen-3-ol [octenol] and the amine receptors were not separate populations.” In an email, her Rockefeller University colleague Margo Herre adds: “Mosquitoes also use decanal and undecanal aldehydes [dos compuestos químicos volátiles] and more research is needed to know the precise composition of human odor and which of the odors mosquitoes perceive.”
The image these discoveries describe is that the Egyptians have a double or triple redundancy system in which if they cannot perceive one aroma they perceive another or a third. And when they all recognize, the signal is amplified. As Vosshall puts it in a note, “Mosquitoes have a plan B for their plan B for their plan B. To me, the system is unbreakable.”
The finding could have far-reaching consequences. On the one hand, it would explain the repeated failure to control these mosquitoes as carriers of various pathogens. As Younger recalls, females are hematophagous “because they need the proteins present in the blood for their eggs to mature.” There are millions of years of evolution supporting their desire for snacking.
The females of the mosquito “Aedes aegypti” can transmit dengue, but also yellow fever, chikungunya or Zika fever viruses. In the picture, a researcher at the Butantan Institute in São Paulo, who is developing a dengue vaccine, shows his mosquito-infested hand. Diego HerculanoGetty
So far, various attempts to block its olfactory receptors through genetic modification have failed, perhaps because they were based on the accepted idea of specificity, that a given gene only expresses a particular receptor for each type of neuron. The same approach would explain the relative effectiveness of DEET, the repellent discovered by the US military in 1946 and found in the composition of the vast majority of chemical repellants. Although its mechanism is not yet clear, it is believed that N,N-diethyl-meta-toluamide (DEET) inhibits CO₂ or lactic acid receptors, but there would still be others present in the same neuron when we stop breathing or sweating try to go unnoticed. The good part of the bad news from this research is that they now know to focus their efforts on multiple recipients at once, not just one.
It also remains to be seen whether it is also the case with other species of mosquitoes, such as the Aedes albopictus, the various Anopheles species that transmit malaria, or the Culex, such as the common mosquito or the tiger mosquito, which in rare cases only cause itching. Christopher Potter, a neuroscientist at Johns Hopkins University School of Medicine, fears so. In 2019, they demonstrated in their laboratory that the fruit fly (Drosophila melanogaster, used in laboratories) also had this double or triple expression of receptors in a neuron. And earlier this year, they published that they had found the same thing in a species of Anopheles mosquito.
Potter, unrelated to the current research, believes “this redundancy may be common in insects.” And he highlights his colleague’s work that “the dogma before it was that an olfactory neuron would only express one type of olfactory receptor; that was the norm as far as we knew.” But she concludes, “Dr. Vosshall now suggests that a mosquito’s olfactory neurons could be much more adaptable, particularly to key scents like humans, which they need to “locate their hosts” needed for host search.
you can follow MATTER on Facebook, Twitter and Instagram, or sign up here to receive our weekly newsletter.