Unraveling the Mystery: How Mosquitoes Smell Humans

For a variety of mosquito-borne diseases, most notably malaria, nearly one million deaths each year are attributed to simple mosquito bites. Therefore, curbing the deadly attraction between mosquitoes and humans is an important public health priority. Unfortunately, attempts to do this by interfering with the way mosquitoes pick up our scent have so far proved unsuccessful.

Now, a revealing new scientific study explains why the mosquito’s sense of smell is so difficult to disrupt. The research recently published in the journal cellreveals an extremely complex olfactory system that gives power Aedes aegypti Mosquitoes specialize in hunting humans and spreading viruses such as dengue, zika, chikungunya, and yellow fever. Longstanding assumptions about how mosquitoes perceive and interpret odors are turned on their head by the data presented in the publication.

“At first glance, the smell of mosquitoes makes no sense. The way the mosquito organizes its sense of smell is totally unexpected,” said Leslie Vosshall, Robin Chemers Neustein Professor at Rockefeller University and chief scientific officer of the Howard Hughes Medical Institute. “But for the mosquito, it makes perfect sense. Every neuron that interprets smells is so redundant that the olfactory system is essentially indestructible. That could explain why we haven’t found a way to break the mosquito’s attraction to humans.”

Violation of the laws of smell

From insects to mammals, scientists generally assume that the brain processes smell through a 1:1:1 system. Each olfactory neuron expresses an olfactory receptor that communicates with a cluster of nerve endings known as the glomerulus. Evidence for the one-neuron-one-receptor-one-glomerulus model in insects includes the observation that many species have almost exactly the same number of olfactory receptors as glomeruli. Fruit flies have about 60 receptors and 55 glomeruli; honey bees, 180:160; Tobacco Moth, 60:70.

Studies suggest that the same clean 1:1:1 ratio exists even in evolutionarily distant organisms like flies, mice, and even humans. And although mosquitoes have twice as many receptors as glomeruli, previous work from the Vosshall lab suggested they, too, would abide by the same basic laws of smell. “It was reasonable to assume that every organism would function this way,” says co-first author Margaret Herre.

In contrast to the sense of taste – in which a cell responsible for recognizing bitter flavors can express many bitter receptors to ensure that bitter foods taste uniformly bitter – the 1:1:1 model for smell seemed as necessary as it was universal to be. “It would allow animals to live in a rich olfactory space and to recognize and discriminate a wide range of odors,” says Herre.

But while studying, like Aedes aegypti Mosquitoes smell the unique bouquet of body odor and carbon dioxide emitted by humans, Meg Younger, a former postdoc in Vosshall’s lab and now an assistant professor at Boston University, made a surprising discovery. Although the 1:1:1 rule dictated that mosquitoes should have one neuron, one receptor, and one glomerulus for smelling body odors, and a separate schema for carbon dioxide, Younger, working with Herre, found evidence for single olfactory neurons with multiple different receptors.

Further investigation yielded more confusing results. “It was a mush, a train wreck,” says Vosshall. “Almost every cell expressed everything. The supposedly lagging olfactory system was completely muddled with mosquitoes.” Single core

” data-gt-translate-attributes=”[{” attribute=””>RNA sequencing carried out by co-first author Olivia Goldman, a Ph.D. student in Vosshall’s lab, confirmed that the Aedes olfactory system differed from the conventional model; in vivo electrophysiology directly measured mosquitoes’ brain cell activity, demonstrating that these cells were actually detecting multiple odor molecules—all in blatant violation of olfactory dogma.

The team suspects that, unlike mice and other generalist species that find food in many different places, mosquitoes evolved a unique smell system to help them track a blood meal at all costs. For Aedes aegypti, which cannot reproduce without drinking blood, odor sensing that is laser-focused on sniffing out humans may be more important than the ability to detect a cornucopia of odors.

Meanwhile, the redundancy and resilience of the system may explain why prior attempts to knock out genes central to olfaction haven’t stopped mosquitoes from homing in on humans. “Understanding how mosquitoes locate humans is essential to our ability to manipulate this system and make people less vulnerable to mosquito-borne diseases,” Goldman says. “Studying this system will help us better understand why mosquito olfaction is so unbreakable.”

Growing beyond dogma

Around the same time that Vosshall was puzzling over her findings, a team of scientists led by Christopher Potter at Johns Hopkins observed similarly jumbled odor-sensing patterns in fruit flies. What was once dogma in insect olfaction began unraveling quickly. But Vosshall, whose prior studies were instrumental in establishing the conventional model of insect olfaction, is unfazed.

“I find it exciting,” she says. “It means my early work missed this complexity, and it shows that the progress of science bends toward truth.”

Vosshall notes that another study recorded evidence of unconventional odor coding in fruit flies even earlier, but the authors dismissed their findings as random noise and improbably concluded that their data supported, rather than overturned, the conventional model.

“Dogma is useful, but problematic,” Vosshall says. “It can be difficult to speak up when you find something unusual, because your first instinct is to assume that your experiment didn’t work and it’s just noise. Our findings should inspire people to, if they see something, say something.”

For now, “the bad news is that it may turn out to be impossible to break mosquito attraction to humans,” Vosshall says, citing the sheer resilience of their olfactory systems. The good news, however, is that the results provide an opening for scientists to reach beyond mice and fruit flies to re-examine how other, less celebrated organisms perceive smell.

“There’s more out there than the species that everyone studies,” Vosshall says. “We want to know: do ticks have conventional olfaction? What about honeybees? It’s exciting to study systems in non-model organisms and discover that our favorite principles do not always apply.”

Reference: “Non-canonical odor coding in the mosquito” by Margaret Herre, Olivia V. Goldman, Tzu-Chiao Lu, Gabriela Caballero-Vidal, Yanyan Qi, Zachary N. Gilbert, Zhongyan Gong, Takeshi Morita, Saher Rahiel, Majid Ghaninia, Rickard Ignell, Benjamin J. Matthews, Hongjie Li, Leslie B. Vosshall and Meg A.Younger, 18 August 2022, Cell.
DOI: 10.1016/j.cell.2022.07.024