Freer Sackler Reopened

To Fight Deadly Dengue Fever in Humans, Create Dengue-Resistant Mosquitoes

How manipulating the immune systems of mosquitoes can halt the spread of dengue virus

Standing water in urban areas is ideal breeding ground for mosquitoes that can spread dengue and other tropical diseases. (Ulrich Doering / Alamy)
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There’s a reason this tropical disease is known as “breakbone fever”: To its victims, that's how it feels. Dengue fever can cause such severe muscle and joint pain that it can be excruciating for an infected person to even move. It can also cause burning fever, delirium, internal bleeding and even death as the body attempts to fight off the disease. There is no effective treatment, and won’t be anytime soon.

Nevertheless, new research identifies a hope for stemming the epidemic—and it lies in genetic engineering.

Dengue virus, which is passed on by the same Aedes Aegypti mosquito that spreads Zika, has been plaguing humans since at least the late 1700s. But in the past few decades, skyrocketing human population and increased urbanization—particularly in warm, moist regions like South America, Southeast Asia and West Africa—have fueled a growing number of cases. Like the Zika virus, dengue has no symptoms for the majority of those who contract it (roughly three-quarters). But nearly 100 million people annually do develop at least some of its dangerous and excruciating symptoms—and roughly 20,000 of those die each year.

Even if you do survive dengue fever, you aren’t out of the woods yet. In fact, overcoming the disease once actually makes you more likely to die if you contract a different strain later. That’s because the various types of the virus appear so similar on the surface, that the immune system will often respond using the same antibodies it developed to fight the last bout. But these are ineffective against the new strain. Moreover, the immune system’s efforts to fight the virus can attack the body instead—causing hemorrhaging, seizures and even death.

So far, preventing the spread of dengue has mostly taken the form of old-fashioned mosquito warfare: nets, insecticide and draining still water, where mosquitoes like to breed. In 2015, researchers finally developed a partially effective dengue virus vaccine, which was green-lighted in three countries. But the vaccine only reduced chances of getting the virus by 60 percent in clinical trials, and because of the risk of developing antibodies, some experts think it may only be safe for people who have already survived an infection.

Today the vaccine is only being used in limited quantities in the Philippines. "There is really an urgent need for developing new methods for control," says George Dimopoulos, a John Hopkins University entomologist who studies mosquito-borne diseases like malaria and dengue.

Instead of focusing on how people get infected with dengue, Dimopoulos has turned his efforts to how mosquitoes themselves contract the virus. Usually, the virus makes its home in a mosquito after the insect bites an infected human; it rarely passes between mosquitoes. So theoretically, by figuring out how to block that infection from ever occurring, you could effectively eliminate dengue virus, Dimopoulos says.

In a study published today in the journal PLOS Neglected Tropical Diseases, lead author Dimopoulos explained how that would work. Using genetic engineering, he and his team manipulated two genes that help control the immune system of the Aedes aegypti mosquito, which most commonly spreads dengue. The manipulated genes caused the mosquitoes' immune systems to become more active when the bugs fed on blood, which is when they contract dengue virus. This stimulation made the mosquitos significantly more resistant to the different types of dengue virus.

"This impressive body of work is an important step forward in understanding mosquito-[dengue virus] immunology," says University of Melbourne dengue researcher Lauren Carrington, who was not involved in the study.

However, Dimopoulos says this breakthrough is just the first step. While the mosquitoes in his study became roughly 85 percent more resistant to some types of dengue virus, other types were much less affected by the genetic engineering. Furthermore, the manipulation didn't seem to create any significant resistance to the related Zika and Chikungunya viruses that Aedes aegypti also spread.

Dimopoulos hopes to fine-tune the method to make it more effective. While genetic engineering comes laden with controversy, he points out that his technique doesn't introduce any foreign genes into the mosquitoes; it simply manipulates the ones they already have. Eventually, he hopes to create mosquitoes that will be resistant to multiple tropical diseases. He also wants to take advantage of "gene drive" technology, which enhances the chances of a certain gene to be passed to offspring, to allow the genetically modified mosquitoes to quickly become dominant in any environment they're released into.

This isn’t the first time researchers have played with mosquitoes’ genes in an attempt to halt the spread of disease. The British biotechnology company Oxitec has worked to modify the genome of the Aedes aegypti mosquitoes to make males that produce dead offspring after mating. Brazil has already partnered with the company to release billions of these mosquitoes into the country, in hopes of suppressing the population of disease-spreading mosquitoes. The company has also worked to get approval to release its mosquitoes in other places, including India, the Cayman Islands and the Florida Keys, where Zika fears drove voters to approve a trial in a ballot measure last year.

Oxitec's methods are effective in the short term, Dimopoulos says. But eliminating the mosquito population from an area will not make it mosquito-free permanently, because mosquitoes from other areas will eventually fill the empty niche left behind. Authorities will be forced to regularly release more genetically modified mosquitoes to keep their population numbers suppressed, Dimopoulos notes—a costly method that would appeal to biotech companies like Oxitec.

Replacing the wild mosquitoes with live but resistant mosquitoes, however, will act as a lasting barrier to spreading tropical diseases, Dimopoulos says. Before we get there, though, he says he wants to work on upping the resistance of the mosquitoes to dengue, as well as making them resistant to other types of tropical diseases. Then, he’ll need to do trials in greenhouses and on islands to see if the resistance works outside the lab.

He doesn't expect any widespread releases of mosquitoes for another decade, but points out that 10 years is a small wait overall. "It's not going to happen quickly," Dimopoulos says, "but we have to remember that these diseases have been with us for a very long time."

There's no humane way to test in the lab whether or not humans will contract dengue less often from these mosquitoes, Dimopoulos says. As a result, we'll only know for sure how effective the gene manipulation is once the mosquitoes have been released. But even if they don't work as well outside the lab, Dimopoulos has no regrets about blazing new trails to combat tropical illnesses.

"The fight against these diseases is like a war," Dimopoulos says. "You can't win it with one weapon."

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