Lockdowns in Massachusetts – Why Mosquito Research is More Important than You Realize

The town of Plymouth in Massachusetts has gone under nighttime lockdown as it closes its parks and fields. Authorities meanwhile are recommending an outdoor night curfew in response to eastern equine encephalitis (EEE), a rare but life-threatening disease carried by mosquitoes. 

A couple of weeks ago, Massachusetts health officials announced the first human case of the disease since 2020 in the US state. 

Last weekend, Plymouth declared the closure of public outdoor recreation facilities from dusk till dawn after a horse was infected with the disease. Other towns are also urging people to avoid going outside at night until the end of September after authorities warned that four other cities are also at “critical risk.” 

People across the state are further recommended to use mosquito repellents and drain any standing water. This comes after a man in Oxford caught the virus, whose family reported  “terrible physical and emotional consequences, regardless if the person manages to live,” said its town manager Jennifer Callahan.

The presence of the virus in ‘The Bay State’ was actually confirmed last month in a mosquito sample. Sample testing of mosquitoes in Connecticut and Rhode Island have also turned up positive for EEE. Meanwhile, one human case of EEE has also been reported in both New Jersey and Vermont this year, in addition to Massachusetts.

Back in 2019, the outbreak in Massachusetts led to six deaths out of 12 confirmed cases and continued into the following year with additional cases.

The state’s Department of Public Health has stated that Massachusetts experiences an EEE outbreak every 10 to 20 years, and it lasts two to three years.

There are no treatments or vaccines for EEE. According to the Centers for Disease Control and Prevention (CDC), approximately 30% of those infected die, and survivors often suffer from permanent disabilities.

The virus can cause headaches, fever, vomiting, diarrhea, drowsiness, seizures, and behavioral changes. However, most people infected with the disease do not develop symptoms. Moreover, people of all ages are susceptible to EEE, but those younger than 15  and over 50 are at greatest risk.

In the US, only a few cases of EEE are reported every year, as per the CDC, commonly around Eastern or Gulf Coast states.

The disease is actually prevalent in birds, and though humans can catch it, they don’t spread it. This lethal virus usually spreads to humans from the bite of an infected mosquito.

This is not the first time that mosquitoes are causing trouble. In fact, they have been responsible for the death of half of the Earth’s population over 200,000 years.

As we have reported in our previous article, mosquitoes, who have been on this planet for over 100 million years now, reached a population of a massive 100 trillion in 2019. These numbers are set to increase in the future due to urbanization and inadequate mosquito control efforts. Climate change is also contributing to their growth as mosquitoes thrive in warm, humid weather.

Given their vast population and their role in spreading deadly diseases, it’s crucial to gain a deeper understanding of how mosquitoes function and explore effective ways to prevent these diseases. And this is exactly what the latest research aims to achieve. 

How Mosquitoes Track Humans: The Role of Infrared Detection

Mosquito-borne diseases affect hundreds of millions of people every year, with one particular species, Aedes aegypti, being the primary vector of viruses that cause yellow fever, chikungunya, and Zika. It is also responsible for dengue, of which over 100 million cases are reported annually. 

Anopheles gambiae is another mosquito species that is responsible for spreading the parasite that causes malaria. This life-threatening disease is the cause of over 400,000 deaths every year, according to the World Health Organization, and the subject of treatment efforts that have won Nobel Prizes.

These numbers have earned mosquitoes the title of ‘our deadliest predator,’ but how are they able to do this? For more than a century, scientists have been looking into how mosquitoes find their hosts, and it has been found that these insects rely on their different senses at various distances to gather information.

Now, researchers from UC Santa Barbara have discovered an important clue that helps mosquitoes locate their hosts, including where it is located and how it works on a biochemical level.

This clue is infrared detection. Yes, the same capability that is found in your night vision cameras, space missions, and are the core component of spectral analysis, flame sensors, and gas analyzers. 

Mosquitoes are naturally born with the ability to find their hosts. We already know that female mosquitoes need blood for egg development, and they integrate multiple cues such as skin odor, visuals, and CO2 from breath. All these cues are sensed across different ranges.

The latest study, published in Nature, demonstrates that there is yet another cue in the sensory arsenal of Aedes aegypti that they use to find humans. As per the study, this species senses the infrared (IR) radiation emanating from their targets and uses that information in combination with other cues for highly effective mid-range navigation. The study noted:

“The realization that thermal IR radiation is an outstanding mid-range directional cue expands our understanding as to how mosquitoes are exquisitely effective in locating hosts.” 

The study chose Aedes aegypti from a total of about 3,500 mosquito species for being “exceptionally skilled at finding human hosts,” and this study explains just how these mosquitoes can achieve this, said co-lead author Nicolas DeBeaubien, postdoc researcher at UCSB in Professor Craig Montell’s laboratory. 

This invasive mosquito species transmits flaviviruses, a vector-borne RNA virus that causes life-threatening disease symptoms like hemorrhagic fever and encephalitis, impacting a significant proportion of the world’s population. 

Instead of using a single stimulus, which tends to be inadequate in differentiating humans from other targets, these mosquito species integrate multiple cues to locate as well as navigate toward humans.

Using one cue actually increases a mosquito’s responsiveness to other stimuli derived from the host. For instance, detecting exhaled CO2 enhances their locomotor activity, which in turn elevates their responsiveness to visual cues. However, each of these cues has limitations, too.

Aedes aegypti has poor visual acuity, which limits its usefulness in discriminating between hosts. Then there are olfactory cues, whose efficacy is limited by wind or the human host’s rapid movement, which throws them off their tracking. 

So, the study authors went on to look for just what makes them detect a more reliable directional cue and that’s how they came upon infrared radiation. When mosquitoes are close to the skin surface, within a 10 cm distance, they detect the heat rising and sense the temperature just as they land. 

Given that other animals like pit vipers and vampire bats can sense thermal IR from warm prey, it made sense to look at whether Aedes aegypti mosquitoes possess the same capability.

To test this, female mosquitoes were put in a cage with two zones. Both zones were exposed to CO2 at the same concentration as human breath and human odors; however, one of the zones was also exposed to IR from a source at skin temperature. The researchers then counted the number of mosquitoes that started probing as if searching for a vein.

Adding thermal IR from a 34º Celcius source doubled the host-seeking activity of insects, which continued to be effective as far as 2.5 feet.

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

– DeBeaubien

While studies in the past didn’t notice thermal infrared having any effect on the behavior of mosquitos, senior author Craig Montell believes it could be due to methodology. Scientists may try to isolate the thermal IR effect by presenting only an infrared signal. 

This doesn’t work because a single clue in itself does not stimulate the insect’s host-seeking activity but rather “only in the context of other cues,” said Montell, a recipient of an NSF Presidential Young Investigator Award and the Duggan and Distinguished Professor of Molecular, Cellular, and Developmental Biology. 

When it comes to thermal infrared radiation, mosquitoes can’t detect it the same way as they would visible light because IR energy is too low for rhodopsin proteins’ activation that detect visible light in animal eyes.

Now, the question is how does it work then. This is where the antennae of mosquitoes come into the picture. The tips of antennae are known to have heat-sensing neurons and when the team removed these tips, they found that doing so eliminated the insect’s IR detection ability as well.

TRPA1, a temperature-sensitive protein, has been found in a separate lab to be present in an antenna’s end. It was then observed by the UCSB team that those with no functional trpA1 gene couldn’t detect IR.

So, mosquitoes can detect infrared radiation by using TRPA1. But this is not all. A couple of rhodopsins that are sensitive to small increases in temperature are also expressed in the same antennal neurons as TRPA1, which is what allows mosquitoes to be successful at IR detection at long range.

The team demonstrated this when they knocked out TRPA1, which then removed mosquitos’ sensitivity to IR. However, this wasn’t the case for insects with issues in either of their rhodopsins. While knocking out both rhodopsins together didn’t completely remove their sensitivity to IR, it did weaken their sense significantly.

Study results indicate that intense thermal IR directly activates TRPA1 while rhodopsins (Op1 and Op2) are activated at low thermal IR levels, which then indirectly trigger TRPA1. Because our skin temperature is constant, the sensitivity of TRPA1 is enhanced, which extends the mosquito’s IR sensor range to around 2.5 ft.

With this discovery, the study aims to increase the possibility of developing strategies to interfere with this attraction and design more effective baits. According to DeBeaubien:

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

Innovative Approaches to Mosquito Control: What the Future Holds

About a year ago, another paper from the Johns Hopkins Malaria Research Institute researchers studied the biology of Aedes aegypti. They detailed the main factors in the immune response of Aedes aegypti when infected with the chikungunya virus, dengue virus, yellow fever virus, Mayaro virus, and Zika virus to help create better ways to reduce the mosquito-to-human transmission of deadly viruses.

This mosquito species does not succumb to these viruses when infected, and because they continue their normal feeding, they end up passing their viral cargo on to us. What keeps these mosquitoes healthy despite being infected with the viruses is the Argonaute 2 protein.

In mosquitoes, the protein serves as part of a crucial antiviral mechanism known as the small interfering RNA (siRNA) pathway, which recognizes and destroys viral RNAs.

Ae. aegypti mosquitoes that lack the Ago2 gene have their siRNA pathway impaired which makes arborvirus infection more severe. In turn, the ability of mosquitoes to transmit the viruses fell dramatically as they died within just days of being infected.

In addition to the siRNA antiviral pathway becoming impaired, the raised mortality is also caused by defects in two other processes that depend on Ago2: DNA repair and autophagy. Ago2-deficient mosquitoes exposed to arboviruses had extensive DNA damage, hyper-infections, and molecular waste accumulation in dying cells.

The discovery opens up an avenue to make mosquitoes less tolerant and more susceptible to virus infection to damage their ability to pass on disease.

The team is now exploring ways to engineer Ae. aegypti to test a possible new disease-control strategy under which they are engineered to become sick and succumb to malaria infection.

Such research can also help in other studies such as to find solutions to the problem of blood clotting. As we have reported previously, researchers actually created a synthetic molecule to mimic one found in mosquitoes, which can only be possible if we have a deeper understanding of their biology. 

Yet another interesting and insightful new study from last month looked into just what makes mosquitoes so hungry for human blood. What mechanism is behind this, exactly? Michael Strand, an entomologist from the University of Georgia in Athens, found that a pair of hormones work together to activate or suppress these blood cravings.

The females consume blood for the development of their eggs, and once they’ve had their fill, they lose their appetite till they lay eggs.

During the research, Strand saw that the levels of F(NPF), a mosquito gut hormone, shot up when they looked for a host but fell drastically once they were done feasting. 

So Strand went on to further analyze enteroendocrine cells, which produce the gut hormone, and found that NPF levels spiked before the insects had their blood meal and dropped after six hours. The NPF levels also dictated the insects’ interest in humans. They weren’t interested in human blood after they had their feast but went straight for it after laying eggs.

RYamide, yet another gut hormone, was also found to be influencing mosquitoes’ blood lust. The levels of RYamide go up as NPF levels drop down after their feast and vice versa. So, both NPF and RYamide together encourage and suppress the attraction of humans and other hosts to mosquitoes.

With this discovery, new methods and pesticides are hoped to be developed to prevent mosquito reproduction as well as disease transmission.

To reduce the potential spread of deadly diseases, researchers are even considering fully automated machines as a chemical-free way of achieving this. Getting rid of mosquitoes involves spraying toxic chemicals on a large scale that end up hurting humans and harming beneficial insects like butterflies and bees.

So, researchers created a robotic device that can accurately identify and then use glasses to sort male and female pupae into separate groups. The study targets invasive mosquito species.

“The upscale of the use of these techniques is going to have very positive environmental impacts, since mosquito control is currently mainly based on the use of pesticides.”

– The study co-author Jérémy Bouyer

Now, let’s look at two companies actively involved in tackling the mosquito menace.

#1. Thermo Fisher Scientific 

Thermo Fisher Scientific is a major provider of advanced scientific solutions, offering diagnostic tools and technologies for controlling vectors and managing diseases transmitted by mosquitoes. They provide essential equipment for researching and tracking mosquito populations and the diseases they transmit, including Zika, dengue, and malaria.

On the financial front, Thermo Fisher Scientific reported a 5% decline in revenue for 2023, totaling $42.86 billion compared to the previous year. The company also returned $3.5 billion to shareholders through stock buybacks and dividends while continuing to invest in growth through acquisitions and innovative product development.

#2. Precigen, Inc. (Previously known as Intrexon Corporation)