What Mosquitoes Want -
Secrets Of Host Attraction

By Martin Enserink
Science Magazine

Why do mosquitoes feast on some people and leave others alone? Researchers are trying to find out, hoping it will help them design the perfect mosquito trap.
Life isn't fair. Whereas some people never seem to get bitten by mosquitoes--and often don't even seem to notice the critters-- others spend their evenings frantically swatting them, usually to no avail. If you're in the latter category, you've probably wondered: Why me? Is it thin skin? My gorgeous body odor? Sumptuous blood vessels begging to be punctured? Or is it all between the ears, as some people say, and you simply fuss and fret more about mosquito bites?
Rest assured, it's not your imagination: Several studies have shown that to mosquitoes, all people really aren't created equal. Besides factors such as heat and carbon dioxide, mosquitoes use odors to find their victims, and humans appear to exude different amounts of the volatile compounds the insects love.
By studying mosquito behavior, entomologists are trying to tease out these favorite smells. It's a complex story, they say. Millions of years of evolution have resulted in sophisticated odor-based navigation systems that differ greatly from one mosquito species to the next, depending on where it lives and which host it prefers. Even so, chemical and behavioral studies--often using human volunteers as bait--have helped identify some of the smells that tempt several mosquito species. And recently, molecular researchers have begun identifying the receptors that pick up these odors and translate them into neural signals.
Researchers hope to use odor cues to lure mosquitoes into the perfect trap or otherwise outwit them--say, by designing repellents that foul their sense of smell. Garden parties and golf getaways might be the first beneficiaries; indeed, one U.S. company is already marketing the $500 to $1200 Mosquito Magnet, which purportedly attracts mosquitoes by emitting a compound called 1-octen-3-ol, as well as heat, CO2, and water vapor.
But the ultimate goal is a far cry from such pricey gadgets, says Willem Takken of Wageningen Agricultural University in the Netherlands, a pioneer in the field. He'd like a simple, $1 or $2 trap that people in developing countries could affix to their doorposts to keep out the mosquitoes that spread deadly diseases. Key targets are Anopheles gambiae, the species that transmits malaria, and Aedes aegypti, which spreads dengue and yellow fever.
-------------------------------------------------------------------------------- Footwork. Anopheles gambiae (left) bites mainly on the feet and ankles; An. atroparvus prefers the face.
Blood, sweat, and cheese For almost a century, researchers have been trying to divert mosquitoes from their pursuit of human blood. The field blossomed in the 1950s, when dozens of entomologists in several countries set out to discover what attracts females--the only mosquitoes that bite--to their hosts. Anthony Brown of the University of Western Ontario in London, Canada, for instance, built human-shaped steel tanks, which he called robots, dressed them up, and then counted the number of mosquitoes that landed on them in a forest. He found, among other things, that the robots became more attractive if their skin was 37ºC (the temperature of the human body) than at lower temperatures, if they exhaled CO2, or if they wore a wet jerkin--or, better still, one soaked in human sweat.
By the mid-1960s, most research on host attraction had stopped, in part because DDT made mosquito extermination so easy. Lately, however, emerging resistance and second thoughts about insecticide use have sparked a renewed interest in alternative control methods.
Scouting for potentially attractive compounds, researchers are taking a closer look at the more than 300 chemicals present on human skin. Martin Geier of the University of Regensburg, Germany, for instance, takes skin rubbings and then chemically removes a certain group of compounds--say, the ketones or the fatty acids. If one group attracts mosquitoes, it can be further separated into its individual components, he says.
To test how compelling single compounds or mixtures are, researchers use a specialized instrument called an olfactometer, whose central part is a Y-shaped wind tunnel. Two different odors are blown into the short legs of the Y; when mosquitoes are set loose at the other end, they fly upwind and, like quiz show contestants choosing between two doors, decide whether to go left or right. Researchers can also fixate mosquitoes, apply miniature electrodes to their nerves, and test whether exposing them to a whiff of some compound elicits an electrical signal.
Recent studies have confirmed what Brown and others discovered half a century ago: that for most mosquito species, CO2, heat, and moisture are key attractants. But these lead a mosquito to any warm-blooded animal--bird, cow, or human. That might be fine for species that aren't too picky, such as Culex pipiens, a West Nile vector in the United States. But those that dine almost exclusively on humans, such as An. gambiae and Ae. aegypti, need much more specific attractants.
Hunting for cues, Bart Knols, a researcher in Takken's group, noticed in 1995 that An. gambiae had a predilection for biting its victims on the feet and ankles--even when their entire bodies were exposed. (This clearly set it apart from related species, such as An. atroparvus, a mosquito from Holland that goes mainly for the face.) A native of the Dutch province of Limburg, Knols also realized that foot odor bears a remarkable resemblance to the pungent cheese from that region. And sure enough, An. gambiae turned out to be heavily attracted to the smell of Limburger cheese.
The finding, after making snickering headlines around the globe, led researchers to tempt different mosquitoes. "It became sort of a madhouse," Knols recalls. "People started taking Limburger cheese all over the world." But the stinky dairy product turned out to be an acquired taste, he says; just those few mosquitoes that feed primarily on humans were strongly attracted.
Knols says the common denominator between feet and cheese is obvious: a bacterium used in cheese production, called Brevibacterium linens, which is a close relative of Brevibacterium epidermis, a bug known to reside in the warm, humid clefts between human toes. Both turn glycerides into a specific set of breakdown products, such as fatty acids. Takken's group is now trying to find out exactly which products provide the draw.
Over the years, researchers have found that individual species have their own idiosyncratic tastes for various attractants. Ae. aegypti find lactic acid--which humans produce on their skin but other mammals don't--sublime; to An. gambiae, it's only so-so. With ammonia, it's the other way around. And even in Aedes, Geier explains, lactic acid alone isn't all that attractive; rather, it boosts the appeal of several other compounds.
Complicating matters, explains Ring Cardé of the University of California, Riverside, an effective trap depends not just on the right attractants but also on the physical properties of the odor plume. Cardé has spent most of his career studying how male moths home in on females by navigating pheromone plumes--which, from the insect's viewpoint, consist of a series of small odor filaments swirling through the air. More recent work in mosquitoes, carried out by Cardé's colleague Teunis Dekker, suggests that they, too, use the fine structure of an odor plume to navigate, and Cardé believes that the shape and structure of a plume will determine any trap's efficacy.
Takken and others hope that molecular researchers, who joined the field just 2 years ago, will help make sense of it all. They are making some headway: In a study published on page 176, a team led by Laurence Zwiebel at Vanderbilt University in Nashville, Tennessee, has scoured the newly sequenced An. gambiae genome for so-called G protein-coupled receptors, which include odor receptors.
The team, working with researchers at the University of Notre Dame in Indiana, the University of Illinois, Urbana-Champaign, and Celera Genomics in Rockville, Maryland, found 79 odor-receptor candidates, only five of which had been known before. Of these, 64 were expressed solely in the mosquitoes' olfactory tissues--evidence that they're probably involved in odor recognition. And at least one of the candidate receptors is produced only in mature females--an important clue that it might be involved in host seeking. So far, the group hasn't been able to link any of the odors known to attract An. gambiae to any of the receptors. Still, the study is a "nice breakthrough," says Takken, that might speed the discovery of other, more powerful attractants. Building the perfect trap.
Whether chemical lures can be fashioned into an irresistible mosquito trap, much less one that would be cheap and effective in developing countries, isn't clear. But there is a precedent. In many East African countries, simple traps have helped virtually eradicate tsetse flies, the carriers of sleeping sickness and a livestock disease called nagana. (One trap consists of a simple black-and-blue cloth, baited with acetone and octenol--or, alternatively, buffalo urine--and sprayed with insecticide.)
Mosquitoes, however, could pose a more daunting challenge. One tsetse fly produces only a handful of offspring over her lifetime, making the population vulnerable to even a slight increase in mortality. By contrast, mosquito mothers can produce hundreds of young. It might also be "very difficult," says Geier, to produce a trap that can compete with the real thing: living, breathing humans who emit not just smell but also heat and moisture. (A trap could do that too, of course, but it would quickly get too complicated and costly.) But even if they only reduced the number of mosquitoes, "traps could have a fantastic impact," says Takken. "We all agree that no single measure will ever solve the malaria problem completely."
Short of that ambitious goal, traps might also be effective in monitoring the risk of epidemics and focusing control efforts. Some countries already use a relatively unsophisticated trap developed by the U.S. Centers for Disease Control and Prevention (CDC) to keep track of pathogens. But this trap, which relies on just CO2, light, or a combination, catches a motley array of insects--often not those most relevant to human health. To catch An. gambiae, says Takken, a human needs to be nearby, and because the attractiveness of people varies, so does the nightly catch. Spiking such a trap with a specific odor blend could lead to a much better and more reproducible haul, he says.
Other mosquito-thwarting strategies on the drawing board are clever new repellents. If, for instance, researchers could find compounds that overstimulate crucial odor receptors, they might be able to disorient the insects, dooming them to a life of aimless buzzing, Zwiebel says. It might even be possible, he says, to tinker with the receptors that help mosquitoes find nectar or places to lay their eggs.
In the meantime, attraction studies with human volunteers suggest another, more down-to-earth approach to keeping mosquitoes at bay. Among his human subjects, chemist Ulrich Bernier of the U.S. Department of Agriculture in Gainesville, Florida, has found some people who are almost never bitten. His team has isolated compounds from their skin--he declines to discuss which ones--that he believes might be a clue to the protection. Someday, he speculates, they could serve as a natural, less toxic alternative to DEET.
Splashing yourself or your house with somebody else's body odor might not sound all that enticing. But at the levels needed to keep bugs away, Bernier assures, humans won't smell a thing.


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