We know a lot about mosquito preferences up close, but how do mosquitoes find us from up to a hundred meters away? From repellants to app-based mosquito monitoring and a new malaria vaccine, researchers are making important breakthroughs in the fight against the biting insects.

Human body odor critical for mosquito host-seeking behavior over long distances, study finds

Using an ice-rink-sized outdoor testing arena in Zambia, researchers found that human body odor is critical for mosquito host-seeking behavior over long distances. The team also identified specific airborne body-odor components that might explain why some people are more attractive to mosquitoes than others. The work appears May 19 in the journal Current Biology.

Most studies of mosquito preference have been performed in confined laboratory settings that probably don't represent a mosquito's experience in the wild. To test how the African malaria mosquito Anopheles gambiae locates and chooses human hosts over a large and more realistic spatial scale, researchers from Johns Hopkins Bloomberg School of Public Health's Malaria Research Institute and Macha Research Trust teamed up to build a 1,000 m³ testing arena in Choma District, Zambia.

"This is the largest system to assess olfactory preference for any mosquito in the world," says neuroscientist Diego Giraldo (@dags263), a postdoctoral fellow at Johns Hopkins Bloomberg School of Public Health, o­ne of the study's first authors. "And it's a very busy sensory environment for the mosquitoes."

Illustration by Observer Design

The testing arena contained a ring of evenly spaced landing pads that were heated to human skin temperature (35ºC). Each night, the researchers released 200 hungry mosquitoes into the testing arena and monitored their activity using infrared motion cameras. Specifically, they took note of how often mosquitoes landed o­n each of the landing pads (which is a good sign that they're ready to bite).

First, the team compared the relative importance of heat, CO₂, and human body odor for attracting mosquitoes. They found that mosquitoes were not attracted to the heated landing pads unless they were also baited with CO₂, but human body odor was a more attractive bait than CO₂ alone.

Next, the team tested the mosquitoes' choosiness. To do this, they had six people sleep in single-person tents surrounding the arena over six consecutive nights, and they used repurposed air conditioner ducting to pipe air from each tent-;containing the aromas of its sleeping occupant-;onto the heated landing pads. As well as recording the mosquitoes' preferences, the researchers collected nightly air samples from the tents to characterize and compare the airborne components of body odor.

These mosquitoes typically hunt humans in the hours before and after midnight. They follow scent trails and convective currents emanating from humans, and typically they'll enter homes and bite between around 10 PM and 2 AM. We wanted to assess mosquito olfactory preferences during the peak period of activity when they're out and about and active and also assess the odor from sleeping humans during that same time window."

Conor McMeniman (@McMenimanLab), senior author and vector biologist, assistant professor at Johns Hopkins Bloomberg School of Public Health and Johns Hopkins Malaria Research Institute

They found that, night after night, some people were more attractive to mosquitoes than others, and o­ne of the volunteers, who had a strikingly different odor composition from the others, consistently attracted very few mosquitoes.

The team identified 40 chemicals that were emitted by all of the humans, though at different rates. "It's probably a ratio-specific blend that they're following," says analytical chemist Stephanie Rankin-Turner (@stephrankin2), a postdoctoral fellow at Johns Hopkins Bloomberg School of Public Health, the study's other first author. "We don't really know yet exactly what aspect of skin secretions, microbial metabolites, or breath emissions are really driving this, but we're hoping we'll be able to figure that out in the coming years."

Though each person's odor profile varied from night to night, the researchers found some stable patterns. People who were more attractive to mosquitoes consistently emitted more carboxylic acids, which are probably produced by skin microbes. In contrast, the person who was least attractive to mosquitoes emitted less carboxylic acids but approximately triple the amount of eucalyptol, a compound found in many plants; the researchers hypothesize that elevated levels of eucalyptol may be related to the person's diet.

The researchers were surprised by how effectively the mosquitoes could locate and choose between potential human meals within the huge arena. "When you see something moved from a tiny laboratory space where the odors are right there, and the mosquitoes are still finding them in this big open space out in a field in Zambia, it really drives home just how powerful these mosquitoes are as host seekers," says Rankin-Turner.

This research was supported by funding from the Johns Hopkins Malaria Research Institute, Bloomberg Philanthropies, and the Human Frontier Science Program.

Are you a mosquito magnet? Help may be at hand

The earliest signs of summer herald my annual metamorphosis - from woman to lifesize pincushion. Whether at home or abroad, when mosquitoes begin their hunt for blood I am reminded, via a blanket of red blotches that have more than o­nce swelled to the size of a golf ball, that mine is a godlike nectar. o­n a single day last December, a tropical Christmas trip quickly became a less-than-festive scratchathon after a glut of bites arrived, following which I was stung by jellyfish, then wasps. At this point, I can o­nly assume the mosquitoes are giving other species ideas.

But there are signs that a solution for the 20% of the population who receive above-average numbers of bites may soon be at hand. Earlier this month, researchers at the Hebrew University of Jerusalem (HUJI) developed a new repellant capable of reducing the number of mosquitoes feeding by 80%. Applying a thin coating made from naturally occurring cellulose nanocrystals (CNC), a renewable raw material found in the likes of cotton and wood, and indole, an organic compound with an unpleasant odour, to skin served as "chemical camouflage", said the study published in PNAS Nexus. This combination - which derails the cues that mosquitoes use to select their victims - is "unprecedented", according to Jonathan Bohbot, a senior lecturer at HUJI and o­ne of the paper's co-authors. Indeed, the results are considered so promising that further human studies are planned, with a view to having the coating approved by regulators ahead of commercial use. "The CNC-repellant combination will have a longer efficacy and range of action than other products currently available o­n the market," says Bohbot, adding that they expect "high levels of product adoption" if and when it does hit shelves.

Whether you get bitten or not is, in large part, a foregone conclusion: by some estimates, genes account for 85% of a person's propensity to be stung, while DNA testing company 23andMe says it has identified 285 heritable genetic markers responsible for their frequency, itchiness and size.

Mosquitoes are attracted to humans by volatiles (organic compounds) we emit in our breath. But it is those we release through our skin that serve as signposts to where they should feed from; chemicals we naturally produce, such as lactic acid and ammonia. The more lactic acid your body produces, the worse the feeding frenzy is likely to be. Given the limitations in changing our physiology, repellants are, for now, really the o­nly defence we have - bought across the globe in such numbers that the market is predicted to reach $9bn (£7.2bn) by 2026.

HUJI's researchers aren't the o­nly o­nes looking to solve the bite problem. Earlier this year, a group of Italian scientists developed a repellant combining cyclic acetals and carbonyl compounds, creating a formula they say is four times as effective as DEET (diethyltoluamide, the chemical compound that makes up a large tranche of sprays and creams). Tested against the tiger mosquito, Aedes albopictus, it was found to protect 95% of people for eight hours at a time (DEET lasts for about two) and is a less toxic and odorous blend than those currently available. The results, published in the Journal of Agricultural and Food Chemistry, could make it another welcome addition to the market. "We didn?t think it was that easy to find new repellant," says Francesca Dani, associate professor of zoology at the University of Florence, adding: "We were pretty satisfied."

The team's next goal is to see whether their repellant can ward off other pests, too. Those currently in their sights are ticks (health officials warned last month that tick-borne encephalitis, a virus that can be fatal, had been found in the UK) and Anopheles gambiae, the mosquito species responsible for spreading malaria. Repellants are "the o­nly way you can keep vectors [of disease] away", says Dani. "It's a very simple way to protect people."

Being bitten is among the more minor issues caused by mosquitoes. Repellants do little to combat the likes of malaria

While ancient civilisations relied o­n the likes of vinegar or burnt snakeskin to deter mosquitoes, chemical remedies o­nly became an option in 1957, when DEET first hit shelves. Initially developed for the US military more than a decade earlier, the synthetic repellant cannot be sold in concentrations higher than 50% in the UK or Europe, such is its toxicity. Icaridin has become a popular alternative, along with IR3535 (ethyl butylacetylaminopropionate) and citriodiol (menthoglycol, a natural blend), though none are yet considered to have achieved the perfect nexus of being highly effective in small doses, odour-free, nontoxic to humans, animals and the planet, water-resistant, and non-greasy.

The Defense Advanced Research Projects Agency (Darpa), the research and development agency of the United States Department of Defense, is looking to overcome that hurdle. Given that current repellants are impractical for those in need of longer-term protection, such as soldiers, they are investigating a new possibility: altering the skin's microbiome (the bacteria and fungi that live there). Their ReVector programme is seeking to create a product that can be applied just hours before entering an area with a large mosquito population, produces no detectable scent, and can offer protection of up to two weeks at a time with a single application.

Your propensity to being bitten by mosquitoes - as well as to itching and swelling - seems to be determined by genetics. Photograph: kmatija/Getty Images

This involves "taking natural human skin microbes and engineering them to, for example, knock out an enzymatic pathway that produces a known mosquito attractant, like lactic acid, and then reapplying that same human skin microbe [to the skin as a repellant]," says Dr Linda Chrisey, a programme manager at Darpa's Biological Technologies Office. Should their hunch prove correct, a repellant of this kind "could be really gamechanging". Studies have thus far o­nly been carried out o­n animals, but have shown that "applying a human skin microbe engineered to reduce production of an attractive molecule appears to have some level of efficacy", Chrisey says.

Proof of concept is the ReVector team's chief aim: after that, says Chrisey: "We will then be looking for the right partners in industry, or within the Department of Defense, to either expand the human studies, or to try to commercialise the product." Like the Italian researchers, they also have ambitions of expanding the species targeted, hoping to extend ReVector?s reach to sandflies (which can cause leishmaniasis, a parasitic disease).

The discomfort of being bitten is, of course, among the more minor issues caused by mosquitoes - the deadliest animal to humans in the world, responsible for 725,000 deaths each year. Repellants can do little to combat the likes of malaria, says Dr Jan Kolaczinski, global malaria lead at the World Health Organization (WHO), with insecticide-treated nets (ITNs) and indoor residual spraying (IRS) considered the most effective options for disease control. (A 2015 Nature study found that ITNs were responsible for 68% of averted cases of Plasmodium falciparum, the most dangerous strain of malaria, between 2000 and 2015.) Caused in part by the climate crisis (warmer, wetter temperatures are optimal for the insects) and globalisation, in which the frequency of travel has boosted viral species' abilities to cross borders, cases of mosquito-borne diseases such as malaria and dengue fever are rising sharply around the world - a trajectory the WHO has warned will o­nly worsen. Effective control has never been more pressing, Kolaczinski says, "but we are faced with the challenge of insecticide resistance, which in turn requires new and more expensive ITNs and IRS products, while the funding to purchase these has flatlined or, in some countries, is even decreasing". A new malaria vaccine approved in Ghana and Nigeria earlier this month may go some way to changing the course of the rise in cases, it is hoped, although the WHO has yet to recommend it for use.

There is more optimism, perhaps, for the holidaymaking cohort keen for an itch-free break. But further testing, regulatory approvals and commercial tie-ups are required before any of the latest research becomes a reality (Dani says her team is currently discussing o­ne such partnership, but nothing has yet been formalised).

Meanwhile, as we wait for these remedies to arrive o­n the shelves, some scientists are hoping to galvanise the public to help track and thwart the blood-sucking insects. April saw the release of Mosquito Alert St Louis - an app using citizen science to combat the spread of the insects in Missouri. First developed in Catalonia in response to the arrival of the tiger mosquito, this American iteration is seeking to target both "nuisance and public health", explains John Palmer, associate professor at Universitat Pompeu Fabra and the app's co-director.

The Mosquito Alert app. Originally developed in Catalonia, it is now being used in Missouri to track the spread of the tiger mosquito. Photograph: MosquitoAlert.com

Users are charged with taking photos of adult mosquitoes and submitting them, along with information about their size and location, with volunteer experts o­n hand to help label each species. Creating a database will identify mosquito hotbeds and determine their disease-carrying potential, allowing locals to better protect themselves.

"You can get really good data from citizen scientists," enthuses Palmer; information about the times of day a mosquito is biting people "tells you a lot also about the species, because different species tend to bite at different times". The number of bites each user gets "is really important from an epidemiological modelling perspective"; ditto data o­n where o­n the body an individual has been bitten. While larger-scale prevention is typically reliant o­n government data, or costly installation and monitoring of treated nets, this rapid information provides a "much more high-resolution or fine-grained picture of where disease-vector mosquitoes are present".

There is another key benefit, he notes: that it leaves no environmental trace. This means of mosquito control is "less damaging than what happens when you are at a crisis moment, and [countries] have a major disease problem and authorities simply do things like major spraying of adults ... it's much, much better to control at the stage of the larvae ... and eliminate breeding sites, and you can often do that in ways that don't cause any environmental harm." This change in tactics, as well as being less of an eco-hazard, can be much more effective, he says, in staving off bites. "If you really know where the breeding sites are, you're going to the heart of the problem."

The race for the first bite-free summer may not yet have been won. But for the perma-bitten, there is finally hope that it has at least begun.

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