Defeating dengue by releasing mosquitoes with virus-blocking bacteria

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Over the last three years, a group of scientists have been going round two suburbs of Cairns, Australia, and asking local people if they could release mosquitoes on their properties. Ninety percent said yes. These were no ordinary mosquitoes. They had been loaded with bacteria that stop them from passing on the virus that causes dengue fever.

Dengue fever affects thousands of Queenslanders every year. It is caused by an alliance of two parasites – the dengue virus, and the Aedes aegypti mosquito that spreads it. In an ambitious plan to break this partnership, Scott O’Neill from the University of Queensland turned to yet another parasite – a bacterium called Wolbachia. It infects a wide variety of insects and other arthropods, making it possibly the most successful parasite of all. And it has a habit of spreading with great speed.

Wolbachia is transmitted in the eggs of infected females, so it has evolved many strategies for reaching new hosts by screwing over dead-end males. Sometimes it kills them. Sometimes it turns them into females. It also uses a subtler trick called “cytoplasmic incompatibility“, where uninfected females cannot mate successfully with infected males. This means that infected females, who can mate with whomever they like, enjoy a big advantage over uninfected females, who are more restricted. They lay more eggs, which carry more Wolbachia. Once the bacterium gets a foothold in a population, it tends to spread very quickly.

O’Neill started trying to exploit this ability around 20 years ago. It was a long struggle. Wolbachia infects several species of mosquitoes, but none of the ones that cause human diseases. O’Neill had to find or engineer versions of the bacterium that could live inside these species.

At first, he thought he could get Wolbachia to carry an antibody against dengue virus, and spread it through a mosquito population. That didn’t work. More recently, he had more luck with a strain that halves the lifetimes of infected females. Only older mosquitoes can transmit dengue fever because it takes several weeks for the virus to reproduce in the insects’ guts. If you knock off the older ones early, you could slash their chances of spreading disease.

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Now, O’Neill’s team, together with Ary Hoffmann at the University of Melbourne, have infected A.aegypti mosquitoes with a strain of Wolbachia called wMel, which has spread through the world’s fruit flies in the last 80 years. It spreads even more quickly among caged populations than the life-shortening strains and it doesn’t harm the insect in any significant way. Best of all, its very presence seems to interfere with the mosquito’s ability to transmit dengue, as if the bacterium and virus were fighting an internal battle inside the insect.

Perhaps Wolbachia primes the mosquito’s immune system to fight off other invaders, such as dengue virus. Perhaps the bacterium uses up molecules like fatty acids that the virus needs to copy itself. Either way, here, at last, was a strain of Wolbachia that could turn Australia’s mosquitoes into dead-ends for dengue. All that was left was to test it.

Wolbachia doesn’t spread from mosquito to mosquito. They have to mate and pass the bacteria through the generations, so O’Neill had to start by releasing infected mosquitoes into local communities. “That was a fairly big ask!” he says. For three years, his team explained their plans to the residents of Yorkeys Knob and Gordonvale in Cairns, while carrying out a thorough risk analysis. “The community was incredibly supportive,” says O’Neill. “Dengue is such a big problem and people really want to see a solution to it.”

Between January and February of this year, O’Neill’s team released almost 300,000 mosquitoes at fences throughout the two suburbs. Every two weeks, they placed traps throughout the neighbourhoods and counted the proportion of eggs that carried Wolbachia.

The results were astonishing. By May, the proportion of Wolbachia-infected mosquitoes had risen from nothing to 80 percent in Gordonvale and over 90 percent in Yorkeys Knob. In just five months, the bacteria had swept through virtually the entire A.aegypti population. O’Neill also found that Wolbachia had started to spread beyond the two suburbs into surrounding neighbourhoods. “We were extremely happy,” he says. “It went better than we could have hoped for.”

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This is the first time when scientists have transformed a population of wild insects to reduce their ability to pass on human diseases. “There is no precedent for this,” says Jason Rasgon, who studies mosquito-borne diseases at Johns Hopkins School of Public Health, who describes the study as “important and groundbreaking”.  Jan Engelstadter from ETH Zurich, who studies host-parasite evolution, is also impressed. He says, “There is a lot of very hard work behind this. The idea to use Wolbachia in this way has been around for a long time, but finally it seems that this may really work.”

The same approach might even work for other diseases. Wolbachia also seems to prevent the growth of other mosquito-borne parasites, including West Nile virus and Plasmodium, which causes malaria. However, it’s proving more difficult to get the bacterium to stably infect the species of mosquito that carry these diseases.

Meanwhile, Engelstadter sounds a note of caution. “The virus cannot be expected to sit around passively,” he says. Dengue virus mutates very quickly and it might rapidly evolve to circumvent Wolbachia’s protection. There might already be precedent for this. The fruit fly where wMel comes from also carries sigma-virus, a type that Wolbachia does nothing to protect against. “One could speculate that this might be a case where the virus has overcome a protection that Wolbachia may once have conferred,” says Engelstadter.

Engelstadter is also concerned that the strategy might change how good dengue virus is at causing disease – its virulence. It could become more or less virulent, but it is impossible to predict. “When one imposes such a strong reduction in fitness on the virus life cycle, there might be also strong and unexpected responses,” he says.

O’Neill acknowledges these problems. “No matter what your intervention is, you should expect resistance to occur,” he says. “It’s difficult to predict how quickly it’ll occur or what its nature will be. We’ll have to wait and see.” But Rasgon adds, “Evolutionary issues are not unique to this. They are common to every mosquito control strategy, including ones that are currently used today.” Dengue control involves spraying a lot of insecticides and mosquitoes have already started to evolve resistance to them. The Wolbachia strategy would be less toxic and much cheaper. “It’s a fraction of the cost,” says O’Neill. “Once you implement it, it stays in place whereas for insecticides, you need to keep spraying.”

For his next trick, O’Neill is headed to Vietnam, where he plans on testing his mosquitoes in an even larger trial, to see if they actually lead to fewer dengue cases. It is easier to do this in a country where the disease is endemic, rather than Queensland, where outbreaks are unpredictable. “We wanted to do it in Australia to show that we were prepared to do it in our own backyard. Having shown we can implement it, we want directly measure the impact on disease.”

Reference: Walker, Johnson, Moreira, Iturbe-Ormaetxe, Frentiu, McMeniman, Leong, Dong, Axford, Kriesner, Lloyd, Ritchie, O’Neill & Hoffmann. 2011. The wMel Wolbachia strain blocks dengue and invades caged Aedes aegypti populations. Nature

Hoffmann, Montgomery, Popovici, Iturbe-Ormaetxe, Johnson, Muzzi, Greenfield, Durkan, Leong, Dong, Cook, Axford, Callahan, Kenny, Omode, McGraw, Ryan, Ritchie, Turelli & O’Neill. 2011. Successful establishment of Wolbachia in Aedes populations to suppress dengue transmission. Nature

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