More than a decade ago, Leslie Vosshall, then an investigator at the Howard Hughes Medical Institute (HHMI), decided to switch from studying harmless fruit flies to much more dangerous creatures, namely mosquitoes.

Perhaps her extensive knowledge of how fruit flies sniff out their food could be applied to mosquitoes, she wondered, discovering new ways to reduce the insect’s unusual ability to find human prey. “I wanted to do something that audiences could get excited about,” she says.

This work it had indeed had a major impact, just not in the way she had anticipated. It was “a huge, mind-blowing surprise,” she says. Her research overturned the conventional model of the neural circuits that animals use to detect and distinguish between thousands of distinct odors in their olfactory systems. “It’s a big problem,” says neurologist Christopher Potter of the Johns Hopkins University School of Medicine. “It really changes the way we think the insect olfactory system works,” indicates Eurek Alert.

What’s more, the new result shows that it’s even harder than previously thought to confuse mosquitoes as they relentlessly seek out human blood. In the fight to reduce the enormous number of illnesses and deaths caused by mosquito-borne diseases, “this is not good news,” says Vosshall, now also vice president and chief scientific officer at HHMI.

The danger presented by mosquitoes

When Vosshall’s HHMI lab at Rockefeller turned their attention to the human-attracted mosquito, one of the initial tasks they successfully tackled was assembling the insect’s first complete genome. “No one had done genome editing before, in part because the genome was so fragmented,” explains Vosshall. Then, genome in hand, Meg Younger set out to try to answer a mind-boggling question. Mosquitoes are attracted to both the carbon dioxide that people exhale and the smell of the human body.

To try to find out, Younger thought he could identify which olfactory neurons responded to the presence of carbon dioxide and which to body odor, and then trace the signal pathways to the brain. So they used the gene-editing tool CRISPR to insert a fluorescent marker protein into neurons that had receptors for carbon dioxide and another marker into those that could detect body odor chemicals.

Each olfactory neuron has a single type of receptor, which detects a specific set of chemicals and then connects to a single structure (called a glomerulus) in the olfactory bulb. By this logic, there would be separate types of neurons that respond to the smell of strawberries, for example, some to peanut butter, some to gasoline, and so on.

Steps to better understand mosquitoes

By probing receptor genes with different fluorescent colors, Margaret Herre, a former PhD student, discovered that individual neurons were filled with many types of receptors, not just one. Research has confirmed that each neuron cell does indeed produce many types of receptors.

As Vosshall’s team’s findings and results spread through the community, they were met with a certain amount of skepticism. But not only was the evidence overwhelming, in fact, similar findings emerged from Potter’s lab at Johns Hopkins. Working with both fruit flies and a mosquito species, Potter’s team published a paper in eLife suggesting that “co-expression of chemosensory receptors is common in insect olfactory neurons.”

In the past, the conventional wisdom of one receptor per odorant and one receptor per neuron was so strong that there was no reason to probe multiple receptors, Potter says. “Now we know how to look.”

The complexity of the insect olfactory system

In retrospect, the added complexity of the insect olfactory system makes perfect evolutionary sense, especially for mosquitoes that need to find humans to survive. Having multiple types of receptors in each neuron amplifies the insect’s ability to detect exhaled carbon dioxide and the full mix of body odors. And when people try to repel biting insects by blocking some receptors, mosquitoes can still easily get into the blood using their other receptors.

“It’s a really good trick,” explains Vosshall. “Mosquitoes always have a Plan B.” Obviously, this is not good news for the effort to reduce the number of mosquito-borne diseases such as malaria, yellow fever and dengue by trying to block the receptors. But perhaps an alternative strategy could be to overwhelm the entire system with alternative smells, Potter adds. At least now “we have a more realistic view of what we’re up against,” he says.

Meanwhile, Vosshall aims to compare the olfactory neurons of blood-feeding mosquitoes with those of their purely vegetarian mosquito relatives to see if the more extreme complexity of the receptor is an adaptation unique to those species that hunt only humans. And as for the puzzle, Vosshall began researching how the combined detection of carbon dioxide and body odor greatly amplifies the message to the brain.

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