To Stop Malaria, Infect the Mosquitoes

Containing the invader. Malaria vaccine is based on antibody that locks the Plasmodium parasite (dark, rodlike shapes) inside red blood cells.

Containing the invader. A malaria parasite, filling this red blood cell, separates into smaller components (four round shapes bordered by whitish walls) before bursting out and infecting other cells. A new vaccine is based on an antibody that keeps

J. Kurtis

For thousands of years, mosquitoes have made people sick. But now humanity may have found a way to turn the tables. In a new study, researchers report that giving mosquitoes an infection of their own—with a strange bacterium that tinkers with the insects' sex lives—may prevent mosquitoes from transmitting malaria.

The advance is being hailed by some as a milestone in medical entomology. "I'm quite jealous," says entomologist Scott O'Neill of Monash University in Australia, who was not involved in the work. "We have all tried this for years and years and years." The mosquito species in question, Anopheles stephensi, is a key malaria vector in South Asia and the Middle East, and the study offers the tantalizing possibility of ridding entire cities such as New Delhi and Calcutta of malaria, says Willem Takken of Wageningen University in the Netherlands, who was also not involved in the work. In the future, the same technique might also work for other malaria-carrying mosquitoes, such as A. gambiae, which predominates in Africa, Takken says.

Scientists have long dreamed of replacing disease-carrying mosquito populations with new ones that pose no threat to humans because they cannot transmit disease. In the past decade, a bacterium called Wolbachia has emerged as a promising ally in their work. These intracellular bacteria spread from insect mothers to their offspring and play some bizarre tricks on their hosts' sex lives. For instance, by ensuring that infected males can't reproduce with uninfected females—a phenomenon called cytoplasmic incompatibility—the bacteria can maximize the number of infected offspring in the next generation and sweep through populations in very little time.

Scientists' initial idea was to introduce genes conferring resistance to human pathogens into mosquitoes, and then enlist Wolbachia to help these traits race through the population. The difficult part was infecting mosquitoes with Wolbachia in the first place; for some reason, they seemed not amenable to a long-term, stable infection. A landmark came in a 2005 Science paper, in which Xi Zhiyong, then at Johns Hopkins University in Baltimore, Maryland, and colleagues infected a mosquito species called Aedes aegypti, which is the main carrier for dengue fever, a debilitating viral disease that causes intense muscle and joint pains.

A few years later, O'Neill and others made a startling discovery: They didn't even need to couple Wolbachia to infection resistance genes. The bacterium alone made Ae. aegypti unable to transmit the virus. Others have shown that the same was true for several other viruses and parasites.

It's not clear exactly why this is; one hypothesis is that Wolbachia competes for resources with other intruders, such as the dengue virus. But that hasn't stopped scientists from trying to make use of the phenomenon. In 2011, O'Neill's group released Wolbachia-infected Ae. aegypti mosquitoes in Australia, where they found that the infection took hold and spread. Currently, experiments are also underway in Vietnam, where dengue is an important disease.

But dengue isn't the biggest mosquito-borne killer; that's malaria, which is responsible for the deaths of more than half a million people annually and is transmitted by Anopheles mosquitoes, a very different genus. They have proven even more difficult to infect with Wolbachia. The frustrating quest—and the fact that not a single Anopheles species is known to be naturally infected with the bacteria—had led some researchers to question whether it was possible at all, O'Neill says.

But Xi, who now leads his own group at Michigan State University in East Lansing, has done it again. In a new study reported online today in Science, the researchers showed that they can infect A. stephensi with Wolbachia, that the infection is passed down through at least 34 generations, and that it can take over entire populations in cages.

The secret? Part of it is luck, Takken says. The team worked with a strain called Wolbachia wAlbB that happened to catch on in this mosquito. Technical skill is another factor, says entomologist Jason Rasgon of Pennsylvania State University, University Park, who wasn't involved in the work. Injecting mosquito eggs is "very much an art," he says, and Xi "is probably the best person in the world to do it."

The team had to inject thousands of embryos before they had success. Xi says part of the trick is to suck a minuscule amount of cytoplasm out of egg cells first to make room for the injected bacteria and prevent cells from bursting. Despite their horrendous death toll, Anopheles mosquitoes are delicate critters, he says.

Xi's group also fed infected mosquitoes malaria parasites to test whether Wolbachia could block their life cycle inside the mosquito's body. They showed that Wolbachia-infected mosquitoes didn't become totally resistant to malaria, as hoped. Instead, the number of parasites in their saliva 14 days after their exposure went down only by about a factor of 3.4, which means the mosquitoes could still transmit the disease, although perhaps not as efficiently.

Another key issue is whether Wolbachia-infected mosquitoes can produce the same number of offspring as uninfected ones, Takken says. If they can't, they won't be able to outcompete wild populations, and the insects wouldn't fly as a malaria control scheme. Xi says he plans to publish another paper on that issue. Studies are also needed to determine how many infected mosquitoes need to be released in the field to get results fast enough. There might be other Wolbachia strains that do the job better, Rasgon says. For now, what's most important is that the researchers have succeeded in the first place, he says. He is inspired because his own group is trying to infect A. gambiae, the main malaria vector in Africa and an even more difficult target to infect. "It's very good for me to see that it can actually be done," he says. "We will keep pushing ahead."

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