Mosquitoes sense infrared from body heat to help track humans down

While a mosquito bite is often no more than a temporary bother, in many parts of the world it can be scary. One mosquito species, Aedes aegypti, spreads the viruses that cause over 100,000,000 cases of dengue, yellow fever, Zika and other diseases every year. Another, Anopheles gambiae, spreads the parasite that causes malaria. The World Health Organization estimates that malaria alone causes more than 400,000 deaths every year. Indeed, their capacity to transmit disease has earned mosquitoes the title of deadliest animal.

Male mosquitoes are harmless, but females need blood for egg development. It's no surprise that there's over 100 years of rigorous research on how they find their hosts. Over that time, scientists have discovered there is no one single cue that these insects rely on. Instead, they integrate information from many different senses across various distances.

A team led by researchers at UC Santa Barbara has added another sense to the mosquito's documented repertoire: infrared detection. Infrared radiation from a source roughly the temperature of human skin doubled the insects' overall host-seeking behavior when combined with CO2 and human odor. The mosquitoes overwhelmingly navigated toward this infrared source while host seeking. The researchers also discovered where this infrared detector is located and how it works on a morphological and biochemical level. The results are detailed in the journalNature.

"The mosquito we study, Aedes aegypti, is exceptionally skilled at finding human hosts," said co-lead author Nicolas DeBeaubien, a former graduate student and postdoctoral researcher at UCSB in Professor Craig Montell's laboratory. "This work sheds new light on how they achieve this."

Guided by thermal infrared

It is well established that mosquitoes like Aedes aegypti use multiple cues to home in on hosts from a distance. "These include CO2 from our exhaled breath, odors, vision, [convection] heat from our skin, and humidity from our bodies," explained co-lead author Avinash Chandel, a current postdoc at UCSB in Montell's group. "However, each of these cues have limitations." The insects have poor vision, and a strong wind or rapid movement of the human host can throw off their tracking of the chemical senses. So the authors wondered if mosquitoes could detect a more reliable directional cue, like infrared radiation.

Within about 10 cm, these insects can detect the heat rising from our skin. And they can directly sense the temperature of our skin once they land. These two senses correspond to two of the three kinds of heat transfer: convection, heat carried away by a medium like air, and conduction, heat via direct touch. But energy from heat can also travel longer distances when converted into electromagnetic waves, generally in the infrared (IR) range of the spectrum. The IR can then heat whatever it hits. Animals like pit vipers can sense thermal IR from warm prey, and the team wondered whether mosquitoes, like Aedes aegypti, could as well.

The researchers put female mosquitoes in a cage and measured their host-seeking activity in two zones. Each zone was exposed to human odors and CO2 at the same concentration that we exhale. However, only one zone was also exposed to IR from a source at skin temperature. A barrier separated the source from the chamber prevented heat exchange through conduction and convection. They then counted how many mosquitoes began probing as if they were searching for a vein.

Adding thermal IR from a 34º Celcius source (about skin temperature) doubled the insects' host-seeking activity. This makes infrared radiation a newly documented sense that mosquitoes use to locate us. And the team discovered it remains effective up to about 70 cm (2.5 feet).

"What struck me most about this work was just how strong of a cue IR ended up being," DeBeaubien said. "Once we got all the parameters just right, the results were undeniably clear."

Previous studies didn't observe any effect of thermal infrared on mosquito behavior, but senior author Craig Montell suspects this comes down to methodology. An assiduous scientist might try to isolate the effect of thermal IR on insects by only presenting an infrared signal without any other cues. "But any single cue alone doesn't stimulate host-seeking activity. It's only in the context of other cues, such as elevated CO2 and human odor that IR makes a difference," said Montell, the Duggan and Distinguished Professor of Molecular, Cellular, and Developmental Biology. In fact, his team found the same thing in tests with only IR: infrared alone has no impact.

A trick for sensing infrared

It isn't possible for mosquitoes to detect thermal infrared radiation the same way they would detect visible light. The energy of IR is far too low to activate the rhodopsin proteins that detect visible light in animal eyes. Electromagnetic radiation with a wavelength longer than about 700 nanometers won't activate rhodopsin, and IR generated from body heat is around 9,300 nm. In fact, no known protein is activated by radiation with such long wavelengths, Montell said. But there is another way to detect IR.

Consider heat emitted by the sun. The heat is converted into IR, which streams through empty space. When the IR reaches Earth, it hits atoms in the atmosphere, transferring energy and warming the planet. "You have heat converted into electromagnetic waves, which is being converted back into heat," Montell said. He noted that the IR coming from the sun has a different wavelength from the IR generated by our body heat, since the wavelength depends on the temperature of the source.

The authors thought that perhaps our body heat, which generates IR, might then hit certain neurons in the mosquito, activating them by heating them up. That would enable the mosquitoes to detect the radiation indirectly.

Scientists have known that the tips of a mosquito's antennae have heat-sensing neurons. And the team discovered that removing these tips eliminated the mosquitoes' ability to detect IR.

Indeed, another lab found the temperature-sensitive protein, TRPA1, in the end of the antenna. And the UCSB team observed that animals without a functional trpA1 gene, which codes for the protein, couldn't detect IR.

The tip of each antenna has peg-in-pit structures that are well adapted to sensing radiation. The pit shields the peg from conductive and convective heat, enabling the highly directional IR radiation to enter and warm up the structure. The mosquito then uses TRPA1 -- essentially a temperature sensor -- to detect infrared radiation.

Diving into the biochemistry

The activity of the heat-activated TRPA1 channel alone might not fully explain the range over which mosquitoes were able to detect IR. A sensor that exclusively relied on this protein may not be useful at the 70 cm range the team had observed. At this distance there likely isn't sufficient IR collected by the peg-in-pit structure to heat it enough to activate TRPA1.

Fortunately, Montell's group thought there might be more sensitive temperature receptors based on their previous work on fruit flies in 2011. They had found a few proteins in the rhodopsin family that were quite sensitive to small increases in temperature. Although rhodopsins were originally thought of exclusively as light detectors, Montell's group found that certain rhodopsins can be triggered by a variety of stimuli. They discovered that proteins in this group are quite versatile, involved not just in vision, but also in taste and temperature sensing. Upon further investigation, the researchers discovered that two of the 10 rhodopsins found in mosquitoes are expressed in the same antennal neurons as TRPA1.

Knocking out TRPA1 eliminated the mosquito's sensitivity to IR. But insects with faults in either of the rhodopsins, Op1 or Op2, were unaffected. Even knocking out both the rhodopsins together didn't entirely eliminate the animal's sensitivity to IR, although it significantly weakened the sense.

Their results indicated that more intense thermal IR -- like what a mosquito would experience at closer range (for example, around 1 foot) -- directly activates TRPA1. Meanwhile, Op1 and Op2 can get activated at lower levels of thermal IR, and then indirectly trigger TRPA1. Since our skin temperature is constant, extending the sensitivity of TRPA1 effectively extends the range of the mosquito's IR sensor to around 2.5 ft.

A tactical advantage

Half the world's population is at risk for mosquito-borne diseases, and about a billion people get infected every year, Chandel said. What's more, climate change and worldwide travel have extended the ranges of Aedes aegypti beyond tropical and subtropical countries. These mosquitoes are now present in places in the US where they were never found just a few years ago, including California.

The team's discovery could provide a way to improve methods for suppressing mosquito populations. For instance, incorporating thermal IR from sources around skin temperature could make mosquito traps more effective. The findings also help explain why loose-fitting clothing is particularly good at preventing bites. Not only does it block the mosquito from reaching our skin, it also allows the IR to dissipate between our skin and the clothing so the mosquitoes cannot detect it.

"Despite their diminutive size, mosquitoes are responsible for more human deaths than any other animal," DeBeaubien said. "Our research enhances the understanding of how mosquitoes target humans and offers new possibilities for controlling the transmission of mosquito-borne diseases."

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How evolution tamed a deadly virus and why we should still worry

The story of the rise and fall of western equine encephalitis as a lethal disease offers essential lessons about how a pathogen can gain or lose its ability to jump from animals to humans.

That story is captured in newly published research from Harvard Medical School that identifies the mechanisms the western equine encephalitis virus used to infect humans and matches changes in that ability over time to a decline in illness and deaths caused by the pathogen.

The study results, published July 24 in Nature, offer important lessons for public health experts looking to prepare for future outbreaks, the researchers said.

The work took many unexpected turns, the researchers said. The findings challenge some of the basic assumptions that scientists have relied on in their attempts to understand how viruses interact with human cells and what causes outbreaks to ebb and flow, such as the notion that any given virus targets one host receptor to gain entry and infect cells.

"This was a real scientific detective story," said study senior author Jonathan Abraham, associate professor of microbiology in the Blavatnik Institute at Harvard Medical School. "The virus kept surprising us and taught us some important lessons about how to study viruses."

The researchers identified the specific proteins expressed on host cells that different strains of the virus have used to infect a variety of animals, including horses, humans, and birds over the last century. Their findings tied differences in the virus's ability to sicken humans and horses to changes in the viral genome that left the virus unable to target proteins found in humans and horses, while leaving intact the virus's ability to infect birds and reptiles that serve as reservoirs for the virus.

The surprising diversity and variability in the virus's ability to infect host cells highlights the importance of studying viruses broadly across time, space, and host species to track potential outbreaks and monitor for emerging and re-emerging viruses.

A virus changes

The protagonist in the story is the western equine encephalitis virus (WEEV), a member of a viral family known as alphaviruses.

One key to understanding how a virus interacts with a host is identifying the precise path it takes to enter cells and cause infection.

WEEV and others in the alphavirus family typically attach a spike protein to a compatible protein -- the receptor -- on the surface of a host cell. Once attached to the host receptor, the virus enters the cell. Once inside the cell, the virus hijacks the cells' armamentarium to enable its own replication, spread, and survival.

The researchers made harmless replicas of various viral strains collected from different times and places and tested their ability to infect host cells in lab dishes. They also tested some of the strains in mice.

Several deadly strains of WEEV are known to cause severe brain inflammation in both horses and humans. Some years, thousands of horses were killed and hundreds of humans were sickened. Case fatality rates for people were as high as 15 percent in North America in the early and middle decades of the 20th century.

Abraham's group found that some of these early strains could stick their spike proteins to several different types of receptors to enter animal cells. That was an unexpected finding because the prevailing dogma in virology thus far has been that viruses typically attack by targeting only one type of host cell receptor.

The team observed that the strains circulating during the years of frequent outbreaks could use multiple receptors that are expressed on brain cells of humans and horses, including proteins known as PCDH10 and VLDLR.

Although the virus still circulates between birds, mosquitoes, and other animals, the most recent outbreak in the United States in humans was in 1987, according to the Centers for Disease Control and Prevention. Since then, there have been only five cases identified in the United States.

By contrast, when the researchers tested more recently isolated strains recovered from mosquitos in California in 2005, they found that the viral spike protein failed to recognize the human receptors, but could still interact with similar proteins found in birds.

Based on these findings, the researchers hypothesize that the virus had evolved, perhaps because horses can be vaccinated and are no longer prevalent enough in the agriculture or transportation industries to serve as effective amplifiers for the virus. Alternatively, the researchers note, the virus may have evolved through simple antigenic drifting, a process by which random mutations cause a series of small changes to a viral genome that, over time, may end up changing the way a virus interacts with its host. Whatever the reason, the researchers said, subtle shifts in the shape of the viral spike proteins changed the cellular receptors with which the virus could connect.

This change in targetable host receptors is likely the central reason why the virus "submerged" as a human pathogen in North America, the research team said. This newly gleaned appreciation of the dynamic complexity of viral receptors is an essential tool for understanding how this virus or others like it might one day re-emerge, the scientists said.

"We need to understand what happens to viruses when they submerge, to better prepare for when they re-emerge," said first author Wanyu Li, a Harvard Kenneth C. Griffin Graduate School of Arts and Sciences doctoral student in the virology program in the Harvard Division of Medical Sciences at HMS.

For example, knowing whether dangerous versions of the pathogen persist in isolated populations of insects, or if the virus has gained the ability to infect other animals, could provide important early warning signs for potential resurgences of illnesses that are thought to have disappeared.

A virus's complex behavior

Through their experiments, the researchers discovered that certain old WEEV strains behaved differently than expected.

The team used eastern equine encephalitis virus -- a deadlier cousin of WEEV -- as a control in some experiments. In one test, the team found that an old strain of WEEV could use the same receptor as the eastern virus, which is something that newer WEEV strains could not do. They also found different strains of WEEV that used different receptors. Some strains could stick to avian versions of the receptor protein but not those expressed in human or equine cells.

The findings serve as an important reminder that viruses are part of a dynamic system and that the viruses themselves are dynamic, with subtle but significant differences across time and geography -- a notion that was powerfully underscored by the rapidly shapeshifting SARS-CoV-2 virus that fueled the COVID-19 pandemic, the researchers said.

"It was a wake-up call," Abraham said. "It's telling us that we can't just study one strain of a virus and assume we know the whole story. Viruses seem simple, but they're quite complex, and they're constantly changing."

Applying lessons to pandemic preparedness

In standard virology, researchers often only check a limited number of viral strains. These new findings show that that's not enough to truly understand the virus.

"There's so much more biology to be learned by exploring the diversity of these complex systems," Abraham said. He also noted that it's necessary to explore as much of that viral diversity as possible in order to prepare for possible outbreaks.

Many viruses circulate in insects and animals that live around us, Abraham said. Some, like the tick-borne infection Powassan, which is endemic in New England, occasionally flare up to cause deadly or debilitating disease.

There could be many reasons for the flare-ups, Abraham said. Are there different strains of Powassan that carry different levels of risk? Is it an environmental change or an evolutionary shift in the pathogen itself that causes new outbreaks? Looking at all these aspects and the breadth of viral diversity will help researchers predict and protect against outbreaks.

In another twist, as Abraham and his team conducted their experiments, a new outbreak of WEEV occurred in South America, which had also seen steep declines in the disease in recent years. The viral populations in South and North America appear to be genetically distinct, and the South American strain of the virus doesn't remain viable long enough for migrating birds to transfer it from one continent to the other regularly. Still, Abraham noted, the new outbreak in South America emphasizes the importance of vigilance and of improving scientific understanding of these volatile, shapeshifting viruses.

"WEEV's return caught everyone by surprise," Li said. "Now with its cellular host receptors known, we have the tools to understand the molecular aspects of WEEV's re-emergence."

Abraham and collaborators are now investigating the strains associated with recent outbreak in South America.

"One small shift in the viral genome, in the intensity of a rainy season that allows mosquitos to proliferate, or in the place humans live or work, could trigger an outbreak," Abraham said. "The more we know, the better we'll be able to protect ourselves."

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Light pollution may extend mosquitoes' biting season

A new study's finding that urban light pollution may disrupt the winter dormancy period for mosquitoes that transmit West Nile virus could be considered both good news and bad news.

The good news is that the disease-carrying pests may not survive the winter if their plans to fatten up are foiled. The bad news is their dormancy period, known as diapause, may simply be delayed -- meaning they're biting humans and animals longer into the fall.

"We see the highest levels of West Nile virus transmission in the late summer and early fall in Ohio. If you have mosquitoes postponing or delaying diapause and continuing to be active longer in the year, that's at a time when the mosquitoes are most likely to be infected with West Nile virus and people could be at greatest risk of contracting it," said Megan Meuti, senior author of the study and an assistant professor of entomology at The Ohio State University.

This study and earlier findings by Meuti and her colleagues are among the first to show that artificial light at night could have a significant impact on mosquito behavior -- including effects that aren't necessarily predictable.

"We're finding that the same urban light at night can have very different effects under different seasonal contexts," she said.

Meuti conducted the study with first author Matthew Wolkoff and Lydia Fyie, both PhD candidates in entomology at Ohio State. The research was published recently in the journal Insects.

Diapause for female Northern house mosquitoes (Culex pipiens) is not quite a winter slumber, but rather a period of dormancy when the insects live in caves, culverts, sheds and other semi-protected locations. Prior to winter's arrival, mosquitoes convert sugary sources, such as plant nectar, into fat. As days get longer, females begin foraging for blood meals to enable egg production. Some get infected with West Nile virus by feeding on infected birds, and later transmit the virus when they feed on people, horses and other mammals.

This study builds upon two previous findings from Meuti's lab: For her dissertation, Meuti found that circadian clock genes differ between diapausing and non-diapausing mosquitoes, strongly suggesting that day length dictates when diapause should start. And more recent work led by Fyie found that female mosquitoes exposed to dim light at night averted diapause and became reproductively active -- even when short days indicated they should be dormant.

In the current study authored by Wolkoff, the researchers pursued both lines of inquiry, comparing daily activity and nutrient accumulation by mosquitoes reared in two lab conditions -- long days mimicking the insects' active season and short days that induced dormancy -- with and without exposure to artificial light at night.

The study provided more evidence associated with a circadian pattern to mosquito behavior, showing that insects' activity decreases during diapause, but the circadian rhythmicity of that activity is sustained even during this dormant period.

The introduction of artificial light at night was found to affect those activity patterns and to influence mosquitoes' acquisition of nutrient reserves needed for fattening up and weathering winter temperatures.

Exposure to light pollution suppressed the amount of water-soluble carbohydrates -- sugars that are an essential food source during winter -- that were accumulated by mosquitoes in both long- and short-day conditions. Patterns of accumulation of the sugar glycogen were reversed by exposure to artificial light at night: Under normal conditions, non-dormant mosquitoes had lots of glycogen in their bodies but diapausing bugs did not -- but in mosquitoes subjected to light pollution, the long-day mosquitoes didn't accumulate much glycogen and short-day mosquitoes showed an increase in glycogen accumulation.

The researchers observed consistent trends in activity-related effects of light at night, with slight increased activity among the dormant mosquitoes and slightly suppressed activity among long-day mosquitoes expected to be busy looking for food. Though the findings weren't statistically significant, Wolkoff said the combined observations suggest light pollution causes mosquitoes to ward off diapause -- perhaps by scrambling signals from their circadian clock.

"This could be bad for mammals in the short term because mosquitoes are potentially biting us later in the season, but it could also be bad for mosquitoes in the long term because they might be failing to fully engage in preparatory activities they need to survive the winter during diapause, and that might reduce their survival rate," Wolkoff said.

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Why some people are mosquito magnets

It's impossible to hide from a female mosquito -- she will hunt down any member of the human species by tracking our CO2 exhalations, body heat, and body odor. But some of us are distinct "mosquito magnets" who get more than our fair share of bites. Blood type, blood sugar level, consuming garlic or bananas, being a woman, and being a child are all popular theories for why someone might be a preferred snack. Yet for most of them, there is little credible data, says Leslie Vosshall, head of Rockefeller's Laboratory of Neurogenetics and Behavior.

This is why Vosshall and Maria Elena De Obaldia, a former postdoc in her lab, set out to explore the leading theory to explain varying mosquito appeal: individual odor variations connected to skin microbiota. They recently demonstrated through a study that fatty acids emanating from the skin may create a heady perfume that mosquitoes can't resist. They published their results in Cell.

"There's a very, very strong association between having large quantities of these fatty acids on your skin and being a mosquito magnet," says Vosshall, the Robin Chemers Neustein Professor at The Rockefeller University and Chief Scientific Officer of the Howard Hughes Medical Institute.

A tournament no one wants to win

In the three-year study, eight participants were asked to wear nylon stockings over their forearms for six hours a day. They repeated this process on multiple days. Over the next few years, the researchers tested the nylons against each other in all possible pairings through a round-robin style "tournament." They used a two-choice olfactometer assay that De Obaldia built, consisting of a plexiglass chamber divided into two tubes, each ending in a box that held a stocking. They placed Aedes Aegypti mosquitoes -- the primary vector species for Zika, dengue, yellow fever, and chikungunya -- in the main chamber and observed as the insects flew down the tubes towards one nylon or the other.

By far the most compelling target for Aedes aegypti was Subject 33, who was four times more attractive to the mosquitoes than the next most-attractive study participant, and an astonishing 100 times more appealing than the least attractive, Subject 19.

The samples in the trials were de-identified, so the experimenters didn't know which participant had worn which nylon. Still, they would notice that something unusual was afoot in any trial involving Subject 33, because insects would swarm towards that sample. "It would be obvious within a few seconds of starting the assay," says De Obaldia. "It's the type of thing that gets me really excited as a scientist. This is something real. This is not splitting hairs. This is a huge effect."

The researchers sorted the participants into high and low attractors, and then asked what differentiated them. They used chemical analysis techniques to identify 50 molecular compounds that were elevated in the sebum (a moisturizing barrier on the skin) of the high-attracting participants. From there, they discovered that mosquito magnets produced carboxylic acids at much higher levels than the less-attractive volunteers. These substances are in the sebum and are used by bacteria on our skin to produce our unique human body odor.

To confirm their findings, Vosshall's team enrolled another 56 people for a validation study. Once again, Subject 33 was the most alluring, and stayed so over time.

"Some subjects were in the study for several years, and we saw that if they were a mosquito magnet, they remained a mosquito magnet," says De Obaldia. "Many things could have changed about the subject or their behaviors over that time, but this was a very stable property of the person."

Even knockouts find us

Humans produce mainly two classes of odors that mosquitoes detect with two different sets of odor receptors: Orco and IR receptors. To see if they could engineer mosquitoes unable to spot humans, the researchers created mutants that were missing one or both of the receptors. Orco mutants remained attracted to humans and able to distinguish between mosquito magnets and low attractors, while IR mutants lost their attraction to humans to a varying degree, but still retained the ability to find us.

These were not the results the scientists were hoping for. "The goal was a mosquito that would lose all attraction to people, or a mosquito that had a weakened attraction to everybody and couldn't discriminate Subject 19 from Subject 33. That would be tremendous," Vosshall says, because it could lead to the development of more effective mosquito repellents. "And yet that was not what we saw. It was frustrating."

These results complement one of Vosshall's recent studies, also published in Cell, which revealed the redundancy of Aedes aegypti's exquisitely complex olfactory system. It's a failsafe that the female mosquito relies on to live and reproduce. Without blood, she can't do either. That's why "she has a backup plan and a backup plan and a backup plan and is tuned to these differences in the skin chemistry of the people she goes after," Vosshall says.

The apparent unbreakability of the mosquito scent tracker makes it difficult to envision a future where we're not the number-one meal on the menu. But one potential avenue is to manipulate our skin microbiomes. It is possible that slathering the skin of a high-appeal person like Subject 33 with sebum and skin bacteria from the skin of a low-appeal person like Subject 19 could provide a mosquito-masking effect.

"We haven't done that experiment," Vosshall notes. "That's a hard experiment. But if that were to work, then you could imagine that by having a dietary or microbiome intervention where you put bacteria on the skin that are able to somehow change how they interact with the sebum, then you could convert someone like Subject 33 into a Subject 19. But that's all very speculative."

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Chemical cocktail in skin summons disease-spreading mosquitoes

Mosquitoes that spread Zika, dengue and yellow fever are guided toward their victims by a scent from human skin. The exact composition of that scent has not been identified until now.

A UC Riverside-led team discovered that the combination of carbon dioxide plus two chemicals, 2-ketoglutaric and lactic acids, elicits a scent that causes a mosquito to locate and land on its victim. This chemical cocktail also encourages probing, the use of piercing mouthparts to find blood.

This chemical mixture appears to specifically attract female Aedes aegypti mosquitoes, vectors of Zika as well as chikungunya, dengue, and yellow fever viruses. This mosquito originated in Africa, but has spread to tropical and subtropical regions worldwide, including the U.S.

This new research finding, and how the team discovered it, is detailed in the journal Scientific Reports. "Though others have identified compounds that attract mosquitoes, many of them don't elicit a strong, rapid effect. This one does," said Ring Cardé, UCR entomologist.

Mosquitoes use a variety of cues to locate their victims, including carbon dioxide, sight, temperature, and humidity. However, Cardé's recent research shows skin odors are even more important for pinpointing a biting site.

"We demonstrated that mosquitoes land on visually indistinct targets imbued with these two odors, and these targets aren't associated with heat or moisture," Cardé said. "That leaves skin odor as the key guiding factor."

Given the significance of odor in helping mosquitoes successfully feed on humans, Cardé wanted to discover the exact chemicals that make our scent so potent for the insects. Part of the equation, lactic acid, was identified as one chemical element in the odor cocktail as long ago as 1968.

Since then, several studies have identified that carbon dioxide combined with ammonia, and other chemicals produced by humans also attract these mosquitoes. However, Cardé, who has studied mosquitoes for 26 years, felt these other chemicals were not strong attractants.

"I suspected there was something undiscovered about the chemistry of odors luring the yellow fever mosquito," Cardé said. "I wanted to nail down the exact blend."

Methods that chemists typically use to identify these chemicals would not have worked for 2-ketoglutaric acid, Cardé said. Gas chromatography, which separates chemicals by their molecular weight and polarity, would have missed this acid.

"I think that these chemicals may not have been found before because of the complexity of the human odor profile and the minute amounts of these compounds present in sweat," said chemist Jan Bello, formerly of UCR and now with insect pest control company Provivi.

Searching for mosquito attractors, Cardé turned to Bello, who extracted compounds from the sweat in his own feet. He filled his socks with glass beads and walked around with the beads in his socks for four hours per odor collection.

"Wearing the beads felt almost like a massage, like squeezing stress balls full of sand, but with your feet," said Bello. 'The most frustrating part of doing it for a long time is that they would get stuck in between your toes, so it would be uncomfortable after a while."

The inconvenience was worth the investment. Bello isolated chemicals from the sweat deposited on the sock beads and observed the mosquitoes' response to those chemicals. In this way, the most active combination emerged.

Future studies are planned to determine whether the same compound is effective for any other mosquitoes, and why there is such variation in how individuals are apt to be bitten. "Some are more attractive than others to these mosquitoes, but no one's yet established why this is so," Cardé said.

Though this discovery may not lead to insights for the development of new repellants, the research team is hopeful their discovery can be used to attract, trap, and potentially kill disease-spreading mosquitoes.

Read more at Science Daily

How mosquito brains encode human odor so they can seek us out

Mosquitoes. Bane of backyard picnics -- and deadly in Zika- and dengue-prone regions.

Most of the world's mosquitos are opportunistic, willing to drink blood from any nearby source. But in some regions, the mosquitoes that carry Zika, dengue and yellow fever -- Aedes aegypti -- have evolved to bite humans almost exclusively. But to succeed as a specialized feeder, depending on just one species -- ours -- to survive, they must have evolved incredibly precise targeting strategies. How do they do it?

"We set out to try to understand how these mosquitoes distinguish human and animal odor," said Carolyn "Lindy" McBride, an assistant professor of ecology and evolutionary biology and neuroscience, "both in terms of what it is about human odor that they cue in on and what part of their brain allows them to cue in on those signals."

After years of dedicated work, including countless scientific and technological challenges, her team has discovered answers to both parts of this equation. What is it that the mosquitos are detecting, and how do they detect it? Their results appear in the current issue of Nature.

McBride described their mosquito-centric approach: "We sort of dove into the brain of the mosquito and asked, 'What can you smell? What lights up your brain? What's activating your neurons? And how is your brain activated differently when you smell human odor versus animal odor?'"

Then-graduate student Zhilei Zhao, a 2021 Ph.D. alumnus who is now at Cornell, pioneered their novel approach: imaging mosquito brains at very high resolution to watch how the mosquito identifies its next victim. To do that, he had to first genetically engineer mosquitos whose brains lit up when active, and then the team had to deliver human- and animal-flavored air in ways that the mosquitos could detect while inside the team's custom-built imaging equipment.

Human odor is composed of dozens of different compounds, and those same compounds, in slightly different ratios, are present in most mammal odors. None of those compounds is attractive to mosquitoes by itself, so the challenge was to determine the exact blend of components that mosquitos use to recognize human odor.

The team concluded that two chemicals, decanal and undecanal, are enriched in human odor. They patented a blend featuring decanal that they hope could lead to baits attracting mosquitoes to lethal traps, or repellents that interrupt the signal.

To provide comparison mammals to test, graduate student Jessica Zung worked with former research specialists Alexis Kriete and Azwad Iqbal to collect hair, fur and wool samples. For this paper, the team used odor from sixteen humans, two rats, two guinea pigs, two quail, one sheep and four dogs. Howell Living History Farm in Hopewell, N.J., donated several fleeces from their spring sheep shearing; for another domesticated mammal, Zung went to a grooming salon and gathered trimmed hairs from recently groomed pet dogs.

"For the human samples, we had a bunch of great volunteers," Zung said. "We had them not shower for a few days, then strip down naked and lie down in a Teflon bag." Why naked? Because cotton, polyester and other clothing fibers have their own smells that would distort the data.

Once they conquered the technical challenges -- retrieving the human and animal odors nondestructively, designing a system that allowed them to puff human odor at the mosquitos in the imaging setup, creating a wind tunnel to test simple blends or single compounds, and breeding viable strains of mosquitos whose brains respond to the equipment -- they began gathering data.

Very surprising data.

Before this study, researchers speculated that mosquito brains must have a complicated, sophisticated technique for distinguishing humans from other animals. Quite the opposite, it turned out.

"The simplicity surprised us," said McBride. "Despite the complexity of human odor, and the fact that it doesn't really have any kind of human-specific compounds in it, the mosquitoes have evolved a surprisingly simple mechanism for recognizing us. To me, it's an evolutionary story: if we created a statistical test to differentiate human odor, it would be very complex, but the mosquito does something remarkably simple, and simple usually works pretty well, when it comes to evolution."

In other words, simple solutions tend to breed true, over evolutionary time.

Mosquito brains have 60 nerve centers called glomeruli (singular: glomerulus). The team had hypothesized that many -- maybe even most -- would be involved in helping these human-dependent mosquitos find their favorite food.

"When I first saw the brain activity, I couldn't believe it -- just two glomeruli were involved," Zhao said. "That contradicted everything we expected, so I repeated the experiment several times, with more humans, more animals. I just couldn't believe it. It's so simple."

Of the two nerve centers, one responds to many smells including human odor, essentially saying, "Hey, look, there's something interesting nearby you should check out," while the other responds only to humans. Having two may help the mosquitos home in on their targets, the researchers suggest.

That was one of the biggest "Eureka!" moments in the project, said McBride. "Zhilei had worked for a couple years to get the transgenic mosquitoes that he needed, and then we found that we didn't have a good way to deliver human odor. So we worked for another year or two, coming up with ideas to try to figure out how to deliver enough human odor in a controlled enough way to see a response. Then, the first time we tried this new technology that we described in the paper -- this new way of delivering odors -- he actually saw a brain respond. It was incredible."

By determining the glomeruli that mosquitos use to detect humans, and identifying what it is they are detecting -- decanal and undecanal -- the team has an elegantly straightforward answer to their questions, noted Zung.

"If this were purely a neuro imaging paper, there would be some questions remaining," she said. "If this were purely an odor analysis paper, there would still be unanswered questions. A purely behavior paper, same thing. But one real strength of this project is that we were able to bring in so many different methods and the expertise of so many people. And Lindy was just amazing and willing to learn about and invest in all these different methods."

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New technology designed to genetically control disease-spreading mosquitoes

Leveraging advancements in CRISPR-based genetic engineering, researchers at the University of California San Diego have created a new system that restrains populations of mosquitoes that infect millions each year with debilitating diseases.

The new precision-guided sterile insect technique, or pgSIT, alters genes linked to male fertility -- creating sterile offspring -- and female flight in Aedes aegypti, the mosquito species responsible for spreading wide-ranging diseases including dengue fever, chikungunya and Zika.

"pgSIT is a new scalable genetic control system that uses a CRISPR-based approach to engineer deployable mosquitoes that can suppress populations," said UC San Diego Biological Sciences Professor Omar Akbari. "Males don't transmit diseases so the idea is that as you release more and more sterile males, you can suppress the population without relying on harmful chemicals and insecticides."

Details of the new pgSIT are described September 10, 2021, in the journal Nature Communications.

pgSIT differs from "gene drive" systems that could suppress disease vectors by passing desired genetic alterations indefinitely from one generation to the next. Instead, pgSIT uses CRISPR to sterilize male mosquitoes and render female mosquitoes, which spread disease, as flightless. The system is self-limiting and is not predicted to persist or spread in the environment, two important safety features that should enable acceptance for this technology.

Akbari says the envisioned pgSIT system could be implemented by deploying eggs of sterile males and flightless females at target locations where mosquito-borne disease spread is occurring.

"Supported by mathematical models, we empirically demonstrate that released pgSIT males can compete, and suppress and even eliminate mosquito populations," the researchers note in the Nature Communications paper. "This platform technology could be used in the field, and adapted to many vectors, for controlling wild populations to curtail disease in a safe, confinable and reversible manner."

Although molecular genetic engineering tools are new, farmers have been sterilizing male insects to protect their crops since at least the 1930s. United States growers in the 1950s began using radiation to sterilize pest species such as the New World Screwworm fly, which is known to destroy livestock. Similar radiation-based methods continue today, along with the use of insecticides. pgSIT is designed as a much more precise and scalable technology since it uses CRISPR -- not radiation or chemicals -- to alter key mosquito genes. The system is based on a method that was announced by UC San Diego in 2019 by Akbari and his colleagues in the fruit fly Drosophila.

As envisioned, Akbari says pgSIT eggs can be shipped to a location threatened by mosquito-borne disease or developed at an on-site facility that could produce the eggs for nearby deployment. Once the pgSIT eggs are released in the wild, typically at a peak rate of 100-200 pgSIT eggs per Aedes aegypti adult, sterile pgSIT males will emerge and eventually mate with females, driving down the wild population as needed.

Beyond Aedes aegypti, the researchers believe the pgSIT technology could be directed to other species that spread disease.

"… This study suggests pgSIT may be an efficient technology for mosquito population control and the first example of one suited for real-world release," the researchers say. "Going forward, pgSIT may provide an efficient, safe, scalable, and environmentally friendly alternative next-generation technology for wild population control of mosquitoes resulting in wide-scale prevention of human disease transmission."

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Studying mosquito immune cells could improve understanding of disease transmission

A new study that details mosquito immune cells could shed light on the insect immune system and how mosquitoes transmit parasites that cause malaria.

A new study, published recently in the peer-reviewed scientific journal eLife, identifies several new forms of mosquito immune cells, providing new clarity into the mosquito immune system. Immune cells play a central role in the immune response of mosquitoes toward malaria parasites and viruses after these pathogens are taken up upon feeding on an infected person. It's a field of study that has remained poorly understood due to the lack of genetic tools, said Ryan Smith, an associate professor of entomology at Iowa State University and lead author of the study.

"These experiments lay the foundation for a better understanding of how these immune cells function that could lead to a future when humans are able to make mosquitoes unable to transmit disease," Smith said.

The new study utilized single-cell RNA sequencing, a relatively new technique that allows researchers to examine the cellular messages within individual cells, to characterize mosquito immune cells, known as hemocytes. The study found mosquito hemocytes show greater complexity than previously thought, evidence of cell differentiation, and that some cells may even undergo a maturation process. The authors also provided comparative analysis to single-cell studies in other insect systems, highlighting important similarities and differences between mosquitoes and other insects. The new study is an important first step for future exploration of the mosquito immune system, which could be important for gaining better understanding of how mosquitoes transmit pathogens, such as malaria parasites, to humans through their bite.

"There's a big body of evidence that suggests that immune cells of mosquitoes are really critical to their ability to transmit disease," Smith said. "From that perspective, we haven't really known a great deal about the molecular aspect of what those immune cells look like."

Previous evidence suggests immune cells mediate disease pathways in mosquitoes, and play vital roles in killing malaria parasites at multiple stages in the mosquito host. The new study sets the stage for future research aimed at answering those questions, he said.

Smith even envisions a future, though it's still years away, when this line of research could lead to the production of mosquitoes genetically modified to overexpress certain immune cell populations that reduce the ability of a mosquito to transmit pathogens that cause mosquito-borne disease. These resistant mosquitoes could then be introduced into wild mosquito populations to breed and spread these genetic traits. The result could be mosquito populations that are less likely to spread disease to humans, though Smith cautions it's all purely theoretical at this point.

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Gene editing could render mosquitoes infertile, reducing disease spread

Mosquitoes spread viruses that cause potentially deadly diseases such as Zika, dengue fever and yellow fever. New U.S. Army-funded research uses gene editing to render certain male mosquitoes infertile and slow the spread of these diseases.

Researchers at the Army's Institute for Collaborative Biotechnologies and the University of California Santa Barbara used a gene editing tool known as CRISPR-Cas9 to target a specific gene tied to fertility in male mosquitoes. CRISPR-Cas9 is a genome editing tool that is creating a buzz in the science world, according to yourgenome.org. It is "faster, cheaper and more accurate than previous techniques of editing DNA and has a wide range of potential applications."

Researchers experimented with the Aedes aegypti mosquitoes, which are found in tropical, subtropical and temperate regions throughout the world. The study, published in the Proceedings of the National Academy of Sciences, discerned how a mutation can suppress the fertility of female mosquitoes.

"This is yet one more important and exciting example of how synthetic biology tools are demonstrating unparalleled utility," said Dr. James Burgess, ICB program manager for the U.S. Army Combat Capabilities Development Command, now known as DEVCOM, Army Research Laboratory. "In this case, it's a precision increase from chainsaw to a scalpel leading to the correct biochemical outcome that could substantially reduce the population of a very infectious mosquito."

To manage populations, scientists use a vector-control practice called the sterile insect technique in which they raise a lot of sterile male insects and they then release these males in numbers that overwhelm their wild counterparts. Females that mate with sterile males before finding a fertile one are themselves rendered infertile, thereby decreasing the size of the next generation.

Repeating this technique several times has the potential to crash the population because each generation is smaller than the last; releasing a similar number of sterile males has a stronger effect over time.

The sterile insect technique is effective in managing a number of agricultural pests, including the Mediterranean fruit fly, a crop pest in California. It has also been attempted with Aedes aegypti mosquitoes, but with limited success.

In the past, scientists used chemicals or radiation to sterilize male Aedes aegypti, but the chemicals or radiation impacted the mosquitoes' health to such an extent that they were less successful in mating with females, which undercuts the effectiveness of the sterile insect technique.

The research team wanted to identify a more targeted approach with less collateral damage, mutating a gene in mosquitoes that specifically caused male sterility without otherwise impacting the insects' health.

"When CRISPR/Cas9 came out several years ago it just offered new opportunities to do things that you couldn't do before," said Dr. Craig Montell, distinguished professor at UC Santa Barbara. "So, the time seemed right to for us to start working on Aedes aegypti."

Using gene editing in male Aedes aegypti, researchers found that the mutant male mosquitoes produced no sperm, and unlike in previous efforts, the sterile studs were otherwise completely healthy; however, the team wasn't sure whether sperm, albeit defective sperm from the sterile males, was needed to render female mosquitoes infertile, or whether the transfer of seminal fluid was all it took.

In one experiment, researchers introduced 15 mutant males into a group of 15 females for 24 hours. Then they swapped the males for 15 wild-type males, and left them there.

"Essentially, all of the females remained sterile," Montell said. "This confirmed that males could suppress female fertility without producing sperm."

Next the researchers set out to determine how timing played into the effect. They exposed the females to mutant males for different lengths of time. The scientists noticed little difference after 30 minutes, but female fertility quickly dropped after that. Montell noted that females copulated twice on average, even during the first 10 minutes. This indicated that females have to mate with many sterile males before being rendered infertile themselves.

Combining the females with the males for four hours cut female fertility to 20% of normal levels. After eight hours the numbers began leveling out around 10%.

According to Montell, Aedes aegypti populations could easily bounce back from an 80% drop in fertility. The success of sterile insect technique comes from subsequent, successive releases of sterile males, where each release will be more effective than the last as sterile males account for an ever-growing proportion of the population.

The team plans to continue investigating mosquito mating behaviors and fertility. They are devising a way to maintain stocks of males so they are only sterile in the wild and not in the lab. In addition, they are characterizing male mating behavior to uncover new ways to suppress mosquito populations.

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Simple genetic modification aims to stop mosquitoes spreading malaria

Altering a mosquito's gut genes to make them spread antimalarial genes to the next generation of their species shows promise as an approach to curb malaria, suggests a preliminary study published today in eLife.

The study is the latest in a series of steps toward using CRISPR-Cas9 gene-editing technology to make changes in mosquito genes that could reduce their ability to spread malaria. If further studies support this approach, it could provide a new way to reduce illnesses and deaths caused by malaria.

Growing mosquito resistance to pesticides, as well as malaria parasite resistance to antimalarial drugs, has created an urgent need for new ways to fight the disease. Gene drives are being tested as a new approach. They work by creating genetically modified mosquitoes that, when released into the environment, would spread genes that either reduce mosquito populations or make the insects less likely to spread the malaria parasite. But scientists must prove that this approach is safe and effective before releasing genetically modified mosquitoes into the wild.

"Gene drives are promising tools for malaria control," says first author Astrid Hoermann, Research Associate at Imperial College London, UK. "But we wanted a clear pathway for safely testing such tools in countries where the disease most commonly occurs."

In the study, Hoermann and colleagues genetically modified the malaria-transmitting mosquito Anopheles gambiae. They used the CRISPR-Cas9 technology to insert a gene that encodes an antimalarial protein amidst genes that are turned on after the mosquito eats a blood meal. The team did this in a manner that allowed the whole section of DNA to also function as a gene drive that could be passed on to most of the mosquitoes' offspring. They initially inserted the gene along with a fluorescent marker to help them track it in three different spots in the DNA, and then later removed the marker, leaving only a minor genetic modification behind.

Next, the team bred the mosquitoes to see if they were able to successfully reproduce and remain healthy. They also tested how well the malaria parasite developed in the mosquitoes' guts. Their experiments provide preliminary evidence that this approach to genetic modifications could create successful gene drives.

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How day- and night-biting mosquitoes respond differently to colors of light and time of day

In a new study, researchers found that night- versus day-biting species of mosquitoes are behaviorally attracted and repelled by different colors of light at different times of day. Mosquitoes are among major disease vectors impacting humans and animals around the world and the findings have important implications for using light to control them.

The University of California, Irvine School of Medicine-led team studied mosquito species that bite in the daytime (Aedes aegypti, aka the Yellow Fever mosquito) and those that bite at night (Anopheles coluzzi, a member of the Anopheles gambiae family, the major vector for malaria). They found distinct responses to ultraviolet light and other colors of light between the two species. Researchers also found light preference is dependent on the mosquito's sex and species, the time of day and the color of the light.

"Conventional wisdom has been that insects are non-specifically attracted to ultraviolet light, hence the widespread use of ultraviolet light "bug zappers" for insect control. We find that day-biting mosquitoes are attracted to a wide range of light spectra during the daytime, whereas night-biting mosquitoes are strongly photophobic to short-wavelength light during the daytime," said principal investigator Todd C. Holmes, PhD, a professor in the Department of Physiology and Biophysics at the UCI School of Medicine. "Our results show that timing and light spectra are critical for species-specific light control of harmful mosquitoes."

The new study titled, "Circadian Regulation of Light-Evoked Attraction and Avoidance Behaviors in Daytime- versus Nighttime-Biting Mosquitoes," is published in Current Biology. Lisa S. Baik, a UCI School of Medicine graduate student researcher who recently completed her PhD work, is first author.

Mosquitoes pose widespread threats to humans and other animals as disease vectors. It is estimated historically that diseases spread by mosquitoes have contributed to the deaths of half of all humans ever to have lived. The new work shows that day-biting mosquitoes, particularly females that require blood meals for their fertilized eggs, are attracted to light during the day regardless of spectra. In contrast, night-biting mosquitoes specifically avoid ultraviolet (UV) and blue light during the day. Previous work in the Holmes lab using fruit flies (which are related to mosquitoes) has determined the light sensors and circadian molecular mechanisms for light mediated attraction/avoidance behaviors. Accordingly, molecular disruption of the circadian clock severely interferes with light-evoked attraction and avoidance behaviors in mosquitoes. At present, light-based insect controls do not take into consideration the day versus night behavioral profiles that change with daily light and dark cycles.

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Researchers convert female mosquitoes to nonbiting males with implications for mosquito control

Mosquito biting skin

Virginia Tech researchers have proven that a single gene can convert female Aedes aegypti mosquitoes into fertile male mosquitoes and identified a gene needed for male mosquito flight.

Male mosquitoes do not bite and are unable to transmit pathogens to humans. Female mosquitoes, on the other hand, are able to bite.

Female Aedes aegypti mosquitoes require blood to produce eggs, making them the prime carriers of the pathogens that cause Zika and dengue fever in humans.

"The presence of a male-determining locus (M locus) establishes the male sex in Aedes aegypti and the M locus is only inherited by the male offspring, much like the human Y chromosome," said Zhijian Tu, a professor in the Department of Biochemistry in the College of Agriculture and Life Sciences.

"By inserting Nix, a previously discovered male-determining gene in the M locus of Aedes aegypti, into a chromosomal region that can be inherited by females, we showed that Nix alone was sufficient to convert females to fertile males. This may have implications for developing future mosquito control techniques."

These findings were published in the Proceedings of the National Academy of Sciences.

"We also discovered that a second gene, named myo-sex, was needed for male flight. This work sheds light into the molecular basis of the function of the M locus, which contains at least 30 genes," said Azadeh Aryan, a research scientist in Tu's lab and the first author on the paper.

Aryan and colleagues generated and characterized multiple transgenic mosquito lines that expressed an extra copy of the Nix gene under the control of its own promoter. Maria Sharakhova, an assistant professor of entomology in the College of Agriculture and Life Sciences, and Anastasia Naumencko, a former graduate research assistant, mapped the chromosomal insertion site of the extra copy of Nix.

The Virginia Tech team, in collaboration with Zach Adelman's lab in the Department of Entomology at Texas A&M University and Chunhong Mao of the Biocomplexity Institute & Initiative at the University of Virginia, found that the Nix transgene alone, even without the M locus, was sufficient to convert females into males with male-specific sexually dimorphic features and male-like gene expression.

"Nix-mediated sex conversion was found to be highly penetrant and stable over many generations in the laboratory, meaning that these characteristics will be inherited for generations to come," said Michelle Anderson, a former member of the Adelman and Tu labs and currently a senior research scientist at the Pirbright Institute in the United Kingdom.

Although the Nix gene was able to convert the females into males, the converted males could not fly as they did not inherit the myo-sex gene, which is also located in the M locus.

Knocking out myo-sex in wild-type males confirmed that the lack of myo-sex in the sex-converted males is the reason why they could not fly. Although flight is needed for mating, the sex-converted males were still able to father viable sex-converted progeny when presented with cold-anesthetized wild-type females.

"Nix has great potential for developing mosquito control strategies to reduce vector populations through female-to-male sex conversion, or to aid in the Sterile Insect Technique, which requires releasing only nonbiting males," said James Biedler, a research scientist in the Tu lab.

Genetic methods that rely on mating to control mosquitoes target only one specific species. In this case, the Tu team is targeting Aedes aegypti, a species that invaded the Americas a few hundred years ago and poses a threat to humans.

However, more research is needed before potentially useful transgenic lines can be generated for initial testing in laboratory cages. "One of the challenges is to produce transgenic lines that convert females into fertile, flying male mosquitoes by inserting both the Nix and myo-sex genes into their genome together," said Adelman.

As the Tu team looks to the near future, they wish to explore the mechanism by which the Nix gene activates the male developmental pathway. The team is also interested in learning about how it evolves within mosquito species of the same genus.

"We have found that the Nix gene is present in other Aedes mosquitoes. The question is: how did this gene and the sex-determining locus evolve in mosquitoes?" said Tu, who is also an affiliated faculty member of the Fralin Life Sciences Institute.

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Mosquitoes engineered to repel dengue virus

Aedes aegypti mosquito

An international team of scientists has synthetically engineered mosquitoes that halt the transmission of the dengue virus.

Led by biologists at the University of California San Diego, the research team describes details of the achievement in Aedes aegypti mosquitoes, the insects that spread dengue in humans, on January 16 in the journal PLOS Pathogens.

Researchers in UC San Diego Associate Professor Omar Akbari's lab worked with colleagues at Vanderbilt University Medical Center in identifying a broad spectrum human antibody for dengue suppression. The development marks the first engineered approach in mosquitoes that targets the four known types of dengue, improving upon previous designs that addressed single strains.

They then designed the antibody "cargo" to be synthetically expressed in female A. aegypti mosquitoes, which spread the dengue virus.

"Once the female mosquito takes in blood, the antibody is activated and expressed -- that's the trigger," said Akbari, of the Division of Biological Sciences and a member of the Tata Institute for Genetics and Society. "The antibody is able to hinder the replication of the virus and prevent its dissemination throughout the mosquito, which then prevents its transmission to humans. It's a powerful approach."

Akbari said the engineered mosquitoes could easily be paired with a dissemination system, such as a gene drive based on CRISPR/CAS-9 technology, capable of spreading the antibody throughout wild disease-transmitting mosquito populations.

"It is fascinating that we now can transfer genes from the human immune system to confer immunity to mosquitoes. This work opens up a whole new field of biotechnology possibilities to interrupt mosquito-borne diseases of man," said coauthor James Crowe, Jr., M.D., director of the Vanderbilt Vaccine Center at Vanderbilt University Medical Center in Nashville, Tenn.

According to the World Health Organization, dengue virus threatens millions of people in tropical and sub-tropical climates. Severe dengue is a leading cause of serious illness and death among children in many Asian and Latin American countries. The Pan American Health Organization recently reported the highest number of dengue cases ever recorded in the Americas. Infecting those with compromised immune systems, dengue victims suffer flu-like symptoms, including severe fevers and rashes. Serious cases can include life-threatening bleeding. Currently no specific treatment exists and thus prevention and control depend on measures that stop the spread of the virus.

"This development means that in the foreseeable future there may be viable genetic approaches to controlling dengue virus in the field, which could limit human suffering and mortality," said Akbari, whose lab is now in the early stages of testing methods to simultaneously neutralize mosquitoes against dengue and a suite of other viruses such as Zika, yellow fever and chikungunya.

"Mosquitoes have been given the bad rap of being the deadliest killers on the planet because they are the messengers that transmit diseases like malaria, dengue, chikungunya, Zika and yellow fever that collectively put 6.5 billion people at risk globally," said Suresh Subramani, professor emeritus of molecular biology at UC San Diego and global director of the Tata Institute for Genetics and Society (TIGS). "Until recently, the world has focused on shooting (killing) this messenger. Work from the Akbari lab and at TIGS is aimed at disarming the mosquito instead by preventing it from transmitting diseases, without killing the messenger. This paper shows that it is possible to immunize mosquitoes and prevent their ability to transmit dengue virus, and potentially other mosquito-borne pathogens."

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Mosquitoes can sense toxins through their legs

Researchers at LSTM have identified a completely new mechanism by which mosquitoes that carry malaria are becoming resistant to insecticide.

After studying both Anopheles gambiae and Anopheles coluzzii, two major malaria vectors in West Africa, they found that a particular family of binding proteins situated in the insect's legs were highly expressed in resistant populations.

First author on a paper published today in the journal Nature, Dr Victoria Ingham, explains: "We have found a completely new insecticide resistance mechanism that we think is contributing to the lower than expected efficacy of bed nets. The protein, which is based in the legs, comes into direct contact with the insecticide as the insect lands on the net, making it an excellent potential target for future additives to nets to overcome this potent resistance mechanism."

Examining the Anopheline mosquitoes, the team demonstrated that the binding protein, SAP2, was found elevated in resistant populations and further elevated following contact with pyrethroids, the insecticide class used on all bed nets. They found that when levels of this protein were reduced, by partial silencing of the gene, susceptibility to pyrethroids were restored; conversely when the protein was expressed at elevated levels, previously susceptible mosquitoes became resistant to pyrethroids.

The increase in insecticide resistance across mosquito populations has led to the introduction of new insecticide treated bed nets containing the synergist piperonyl butoxide (PBO) as well as pyrethroid insecticides. The synergist targets one of the most widespread and previously most potent resistance mechanisms caused by the cytochrome P450s. However, mosquitoes are continually evolving new resistance mechanisms and the discovery of this new resistance mechanism provides an excellent opportunity to identify additional synergists that could be used to restore susceptibility

Professor Hilary Ranson is senior author on the paper. She said: "Long-lasting insecticide treated bed nets remain one of the key interventions in malaria control. It is vital that we understand and mitigate for resistance within mosquito populations in order to ensure that the dramatic reductions in disease rates in previous decades are not reversed. This newly discovered resistance mechanism could provide us with an important target for both the monitoring of insecticide resistance and the development of novel compounds able to block pyrethroid resistance and prevent the spread of malaria."

From Science Daily