ABOVE: Close-up of a mosquito antenna with fluorescently labeled glomeruli (green) Margo Herre

The constant buzz of a mosquito is not just annoying—in many cases, it is the soundtrack of deadly disease. Aedes aegypti, a species that transmits the pathogens that cause yellow fever, dengue, and chikungunya, has a particularly voracious appetite for humans. Now, researchers have uncovered that Ae. aegypti females’ ability to detect nearby humans is more complicated than previously assumed. The study, published today (August 18) in the journal Cell, reports that mosquitoes can express multiple chemoreceptors in each of their neurons, which likely ensures they can sniff us out no matter what.

For decades, scientists have assumed that individual olfactory neurons can only express a single chemoreceptor. That’s how it seems to work in humans and mice, after all—interactions between chromosomes ensure just one odorant receptor gene is expressed per neuron. However, the paper finds this “one receptor-one neuron” principle doesn’t apply to Ae. aegypti.

This study tells us that mosquitoes have . . . a very robust and redundant system, probably for detecting humans.

Laura Duvall, Columbia University

The “very comprehensive” and “very exciting” paper “shows us that the mosquito nervous system is not following the rules that we expect it to,” says Columbia University mosquito behavior researcher Laura Duvall, who was not involved in the study but who worked as a postdoc in the Rockefeller University lab of study coauthor Leslie Vosshall, a neurobiologist.

“The olfactory system is a lot more adaptable, a lot more variable than we thought,” says Christopher Potter, a neuroscientist at Johns Hopkins University who was not involved in the research. “It’s an amazing paper because . . . it’s changing the dogma of what we thought we knew about how insect olfaction actually worked.”

Mosquitoes possess three kinds of receptors that aid in sniffing out humans: odorant receptors (ORs), which detect alcohols and aldehydes; ionotropic receptors (IRs), which respond to acids and amines; and as gustatory receptors, which detect the CO2 in our breath. These are expressed by neurons in the animals’ antennae and maxillary palps (small appendages near their mouths). Early research had suggested that each neuron expresses just one type of receptor, and that all the neurons expressing a particular receptor link to a dedicated olfactory nerve cluster (called a glomerulus) in the antennal lobe of the mosquito’s brain.

See “Researchers Discover What Attracts Mosquitoes to Humans

However, there had been inklings that mosquito olfaction could be more complex, says Rockefeller University's Margaret Herre, a coauthor on the paper who was previously a graduate student in Vosshall’s lab. Vosshall’s group had already found that whenever researchers removed odorant or ionotropic receptors “that we thought would be important for them to smell people, they were still able to smell people. . . . This was really confusing for us, and frustrating.”

Because of those findings, the researchers sought to understand how exactly Ae. aegypti so exquisitely senses and tracks humans. They used a suite of experiments to look at olfactory neurons, including RNA in situ hybridization and single-nucleus RNA sequencing to elucidate gene expression, antibody staining to evaluate protein presence, and electrophysiological recording from individual antennal sensory structures (sensilla) to study neuronal function. And they found that, contrary to prior assumptions and their own expectations, OR and IR receptors are frequently coexpressed in the same neurons. Not just that, some groupings of particular receptors were frequently found together, though Herre says they don’t yet know why that is. “There may be some logic in this really different olfactory system,” she says.

The complexity continues to the brain, the team found. “In mosquitoes, we saw a lot of overlap in the brain,” says Herre, with individual antennal lobe glomeruli receiving olfactory information from multiple types of receptors. This overlap in the glomeruli, as well as the coexpression of receptors, may be why mosquitoes in previous experiments were able to keep smelling humans, even when one receptor type was missing or non-functional.

An illustrated comparison of the canonical 'one receptor-one neuron' model for olfaction and the new complex model proposed by Herre et al.
In the canonical model (top), neurons express a single receptor type (colored shapes), and all neurons with that receptor are linked to a dedicated glomerulus (colored circles). Now, researchers have found that mosquito neurons can express more than one receptor type and neurons with different receptors can be linked to the same glomerulus (bottom).
Adapted from Figs. 1D, 7J in Herre et al., CELL 185:1–20, 2022.

Duvall praises the study for being particularly comprehensive though she notes that “this is not the first paper that has put forward the idea that what you read in the textbooks may be too simple. . . . It is part of a new group of papers that are really challenging that [traditional] view.” Indeed, Potter’s team recently reported that fruit flies similarly coexpress olfactory receptors.

While mosquito olfaction appears to work differently than expected, “the rules for mosquito smell are still unwritten”, says Herre. “When we start to understand what these populations of neurons that express multiple receptors sense.”

A better understanding of the mosquito olfactory system could shed light on basic neuroscience questions, experts tell The Scientist. While for Herre, mosquito olfaction could be a model for understanding how multiple receptors function together in one neuron, Duvall wonders how these unexpectedly multipurpose olfactory neurons affect mosquito behavior.

Very likely, these rewritten neuronal rules won’t just apply to mosquito and fruit fly olfaction, adds Potter. “I think . . . we’ll find out [multireceptor nuruons are] being used in other olfactory systems . . . perhaps, to make the neuron more sensitive to complex odors or . . . to respond to a very important odor in the environment.”

As for the mosquitoes, Potter speculates that having multiple receptor types on each neuron may allow Ae. aegypti to maintain their deadly attraction to humans. “Mosquitoes perhaps are using . . . their ability to express more than one type of olfactory receptor at the same time to make sure that they can always find a host,” he says. The results “can help to explain why even knocking out big chunks of these sensory systems still didn’t effectively disrupt mosquitoes’ ability to detect hosts,” agrees Duvall.

“This study tells us that mosquitoes have . . . a very robust and redundant system, probably for detecting humans,” she adds. “So we may need to think about taking into account that redundancy when we think about ways to try and block mosquitoes from detecting us—that they have a plan A, and a plan B, and a plan C.”

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