Modifying mosquitoes to stop transmission of dengue fever

Female Aedes aegypti mosquitoes transmit dengue fever when enjoying blood meals. James Gathany

Dengue is a virus spread via the Aedes aegypti mosquito that infects as many as 100 million people annually in more than 100 tropical countries worldwide. It causes fevers, extreme headaches, and muscle and joint pains. In a few extreme cases, leakage of blood plasma through the walls of small blood vessels into the body cavity occurs, resulting in bleeding. This is known as dengue hemorrhagic fever.

Global Dengue Transmission Risk Map. World Health Organization

The number and severity of dengue infections has been escalating since the Second World War, culminating in a 30-fold increase between 1960 and 2010. It is now 20 times more common than the flu. Because of global warming, decreased heavy pesticide use due to environmental concerns, and the Aedes mosquito’s preference for urban environments, the insect – and the virus it carries – are rapidly spreading around the world.

There is no treatment for dengue fever. At best, doctors can give their patients supportive care, such as painkillers and liquids to keep them hydrated. Untreated dengue fever has a mortality rate of about 5%; fortunately, with treatment that number drops to zero and each year “only” 20,000 dengue deaths are recorded.

As a result of its prevalence all around the world, scientists are looking for new ways to control Aedes mosquitoes – and thus dengue transmission.

I’ll take your blood, you can have some dengue virus. James Gathany

Helpful host

The dengue virus does not harm its mosquito host. When an infected female mosquito bites a person, the virus enters the blood stream with the mosquito’s saliva and anticoagulant.

Aedes aegypti are smaller and quieter than the mosquitoes typically found in the US. They thrive in urban environments and are more at home in the city than in the jungle. Controlling and limiting Aedes habitats is extremely difficult since they like to live indoors, residing in places such as dim closets and cupboards. They can lay eggs in a single drop of water. The stealthy bloodsuckers enjoy feeding around human beings’ ankles, biting as many as 20 people a day.

Transmission electron micrograph depicts a number of round, dengue virus particles in a tissue specimen. Frederick Murphy

Somehow, the simple dengue viruses with RNA genetic material coding for just 10 proteins can change the production of 147 different proteins expressed by Aedes. It makes the mosquito hungrier for human blood, its saliva more hospitable to the viruses, and changes the protein mix in the antennae of the mosquitoes making them more sensitive to odors – thereby increasing the mosquito’s ability to find a victim.

Inside a cross-section of a mosquito, Wolbachia show up as red dots. The blue circles are mosquito DNA. Penn State, CC BY-NC

Bombarding them with bacteria

An Australian group led by Scott O’Neill at Monash University has infected mosquitoes with bacteria that prevent the dengue viruses from taking up residence in the mosquito. It prevents the dengue’s carrier from hosting the virus.

The Wolbachia-infected mosquitoes are the result of an idea that O’Neill had 20 years ago. He knew that Wolbachia-infected fruit flies would not transmit any RNA virus. So he hoped Wolbachia-infected Aedes aegypi would act in the same way and not transmit dengue, an RNA virus. The trouble was, even though Wolbachia infections are common in many insects, including non-Aedes mosquitoes, he couldn’t infect sufficient numbers of Aedes with the bacteria. He says he persisted because, “I thought the idea was a good idea, and I don’t think you get too many ideas in your life, actually. At least I don’t. I’m not smart enough.”

It wasn’t easy, but by obsessively trying new and different ways to infect Aedes with a strain of the bacteria obtained from the fruit fly, his group managed to overcome the mosquitoes’ resistance to Wolbachia. Infecting young Aedes eggs worked best, particularly since all female eggs that were infected grew into adult Aedes mosquitoes that passed on the bacteria to all their offspring.

Field trials in Australia, China, Vietnam, Brazil and Thailand have been promising. In Australia, within 10 weeks of releasing the infected mosquitoes, the Wolbachia spread through 100% of the Aedes population of the two towns studied. The mosquitoes have remained infected ever since. O’Neill is now dreaming of world-wide dengue eradication by his Wolbachia-infected Aedes.

Release of genetically modified Aedes aegypti in Brazil. Fotos GOVBA, CC BY

Transgenic population crashers

A British biotech company, Oxitec, regularly releases millions of genetically modified mosquitoes in trials in Brazil. Its chief scientific officer, Luke Alphey, found a gene that kills off all Aedes offspring in their larval stage. In a neat trick, he also found a way to suppress the deadly gene’s expression using the antibiotic tetracycline. So in the presence of tetracycline, the larvae develop normally, allowing researchers to grow large batches of adult transgenic Aedes. Then they’re released into the wild, where of course the mosquitoes have no contact with the antibiotic antidote. The genetically modified mosquitoes breed with their wild counterparts, yielding offspring that will die as larvae.

Closeup of Aedes aegypti mosquito fourth stage larvae. CDC/ Dr. Pratt

When enough males are released, their mating with wild females will collapse the population. It’s like a form of birth control for the mosquitoes, since no offspring make it past the larval stage. In all field tests no genetically modified females are released. This is critical because Oxitec has to prevent the genetically modified insects from breeding with each other in the wild and to ensure that transgenic mosquitoes do not bite any humans – remember, only female mosquitoes bite.

In July 2012 the Minister of Health of Brazil, Alexandre Padilha, opened a new facility to create enough mosquitoes to protect a town of approximately 50,000 inhabitants from Aedes aegypti. At maximum production, the facility will produce 4 million sterile mosquitoes a week. Key West, Florida is next on the list. The US Food and Drug Administration is currently reviewing an application to release the Oxitec mosquitoes there.

Sex skew

While the Oxitec and Wolbachia mosquitoes are already being released in fairly large field trials, a new player has just entered the arena. Using computational methods, researchers at Virginia Tech have found a gene they call Nix that’s responsible for the male sexual characteristics of Aedes aegypti. More than two thirds of the females produced when the Nix gene is added to female Aedes embryos have male genitals and testicles, making them infertile and perfect vehicles, like the Oxitec mosquitoes, to collapse a local Aedes population.

The researchers acknowledge they’re still years from doing field tests. For example, they haven’t tested whether their masculinized females can bite and transmit disease. But Zach Adelman, one of the paper’s authors, sees some advantages of using the Nix gene over sterilization-based techniques, such as those used by Oxitec: “They’re throwing away half of the mosquitoes that they rear because they’re females. If we have a strain that doesn’t even make females then you don’t have to spend all the labor costs associating with separating those out, and you don’t have to spend the money rearing them and then throwing them away,” Adelman says.

Tiny mosquitoes, big problem. Joost Rooijmans, CC BY

Ongoing search for innovation

As long as there are no cures or vaccines for dengue fever, the only way to control the world’s fastest growing infectious disease is to manage the Aedes population, either by killing them or by making them inhospitable to the dengue viruses. The current techniques of removing all sources of stagnant water and using limited and targeted insecticide applications are insufficient.

These solutions that require scientifically altered mosquito releases are controversial. The most common fears people have are that the genetic modifications could cross over into other species, result in super-mosquitoes, or that the disappearance of Aedes from the ecosystem will affect other organisms that depend on them for survival.

Despite all the concerns about using genetically modified or bacterially infected Aedes mosquitoes, it’s hard to imagine a way to beat dengue that doesn’t involve them. And there are some clear advantages to using Wolbachia infections or genetically modified self-destructing mosquitoes. They are both species-specific and will not affect any other mosquitoes, butterflies or bees – as indiscriminate insecticide applications would – and they can reach places that only male mosquitoes could find.

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