

By adding life-shortening bacteria to disease-carrying mosquitoes, Australian researchers might have found a clever way to control Dengue fever, a developing world scourge now becoming common in the southern United States.

Thus infected, mosquitoes live long enough to reproduce, ensuring contagion within their own population — but their lives are too short for the Dengue-causing virus inside them to become fully mature and deadly to humans.

"We're not trying to eliminate the population, but to let a bacterial symbiont in, and then shift the population," said University of Queensland bacterial geneticist Scott O'Neill. "There will still be mosquitoes around, but only young ones. It's a biological control."

Dengue fever infects between 50 and 100 million people worldwide, causing severe flu-like symptoms and — in especially severe cases — a hemorrhagic fever that kills more than 20,000 people each year. Though treatable, the disease cannot be prevented — but not for lack of trying.

Many Dengue control plans, from pesticides to sterilized mosquitoes, have worked in a laboratory but fallen short in reality. Nevertheless, O'Neill's bacterial hack has drawn praise from grizzled Dengue control experts, and its promise comes at an opportune time.

Disease burden is greatest in the developing world, but climate change has driven Dengue's tropical mosquito vectors into previously-inhospitable regions, and incidence is rising in the southern United States and Puerto Rico.

"This isn't just a problem in Central America and Africa and Southeast Asia. It's a growing problem as well in the United States," said Joe Cummins, a University of Western Ontario geneticist who called O'Neill's technique "simple and elegant."

Years ago, O'Neill and his colleagues noticed that Wolbachia, a common bacterial parasite in insects, shortened the lives of fruit flies. If it did the same in Dengue-carrying mosquitoes, they reasoned, it would kill them before virus reached maturity. Dengue only affects humans during the last stages of its life cycle.

But repeated efforts to infect mosquitoes with Wolbachia failed until, as described in a paper published Thursday in Science, his team cultured the bacteria in dishes of mosquito cells for three years. The microbes adapted to their new host species' cellular environment.

O'Neill's Wolbachia strain now has a taste for mosquitoes. Once infected, the insects live for about a month — just half their normal lifespan, but long enough to reproduce.

Through a quirk of mosquito physiology, if an uninfected female mates with a Wolbachia-carrying male, she goes sterile. Meanwhile, infected females produce infected offspring, regardless of the male's disease status.

The mathematical inexorability of this phenomenon will make it difficult for mosquitoes to develop resistance, hopes O'Neill, and will guarantee Wolbachia's Dengue-crippling spread through entire mosquito populations. All he has to do is inject Wolbachia into a few starter bugs, breed them, and send them into the world.

"It'll spread the trait out there 100 percent, despite the fitness cost," he said. "We're in the sweet spot. All individuals will get the parasite. That's the key to this whole strategy."

The Dengue virus itself could also evolve into a more rapidly-maturing form, but O'Neill thinks this unlikely. Only a few mosquitoes now live long enough for Dengue to reach full virulence: selection already favors accelerated development.

"I think we're being close to up against some genetic constraint, where Dengue virus is going through mosquitoes as fast as it possibly can," said O'Neill.

Duane Gubler, director of the Asia-Pacific Institute of Tropical Medicine and Infectious Diseases, said the early results "look very promising." However, he cautioned that many earlier Dengue control approaches "worked beautifully in the laboratory, but failed miserably when taken to the field. The real test is if they can show that this works in field populations."

O'Neill, his research funded by the Gates Foundation, next plans on testing the method in large, enclosed cages. That puts his developmental timeline behind another Gates Foundation-supported Dengue control plan, developed by biotechnology company Oxitec.

The company, which is scheduled to begin wild-release trials in Malaysia over the next three years, has developed genetically-engineered male mosquitoes whose offspring die shortly after hatching. However, unless sustained by steady releases of engineered mosquitoes, the technique may only clear a path for fresh waves of disease carriers. Modified mosquitoes could also face activist opposition, especially in the developed world.

As an alternative to such techniques, said Cummins, "I'm unabashedly positive" about using Wolbachia to hobble Dengue. "The thing that's so attractive is that it's a green proposal, using organic techniques. Hopefully it'll work."

"I don't see any down side to using this approach. Wolbachia is ubiquitous in other species," said Gubler. Its use, he said, "should have no deleterious effects on the ecology."

Gubler called the potential Dengue benefits "immeasurable" — and that, said O'Neill, could be just the beginning.

"The underlying principle applies to a range of other pathogens, including elephantiasis and malaria," he said. "We'd like to see if this could be used for a range of other diseases as well."

Citation: "Stable Introduction of a Life-Shortening Wolbachia Infection into the Mosquito Aedes aegypti." By Conor J. McMeniman, Roxanna V. Lane, Bodil N. Cass, Amy W.C. Fong, Manpreet Sidhu, Yu-Feng Wang,Scott L. O’Neill. Science Vol. 323, Jan. 2, 2009

Image: Fundacion Proteger

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