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Stopping Malaria With a Chastity Belt

Unlocking a bug’s chastity belt could open doors to a targeted insecticide to provide new hope in the fight against malaria.

Meddling with the sex lives of malarial mosquitoes could stop the spread of the disease.

A recent study of Anopheles gambiae conducted at London’s Imperial College found that a “male mating plug” particular to these malaria-transmitting mosquitoes is the key to their reproduction — and possibly, therefore, to their control.

Scientists discovered that altering the male mating plug prevents its formation. Without this plug the female mosquito cannot be properly inseminated and cannot store the sperm in her sperm storage organ, a repository she draws on for a lifetime of egg laying. Since females of this species mate only once but reproduce many times, secure sperm storage is essential.

Fouling the male mating plug could, therefore, prove pivotal in curtailing this particular vector for malaria.

In studying mosquito reproduction, researchers Flaminia Catteruccia of the university's life sciences department and David W. Rogers, a postdoc at the university's Division of Cell and Molecular Biology, explored the genetic and molecular structure of the mosquito in hopes of identifying a key to its reproduction. “If we knew what was important in their reproduction we felt we could target for their control and reduction,” Catteruccia said. (Their paper was published in the December issue of PLoS Biology.)

Previously, the role of the mating plug had been unknown and was generally considered an evolutionary vestige. It intrigued Catteruccia, a chemist, because so little was known after many decades of speculation — or even dismissal — about its function. Most other mosquitoes that carry diseases like dengue fever or yellow fever do not have this plug. She hypothesized that the sperm storage and female changes might have something to do with the females’ monogamy: "We thought that the chemical composition of the mating plug may be a factor in shutting off female receptivity."

In her research, she discovered a mating interplay that is "every bit as remarkable as the most extravagant male plumage and courtship displays,” Catteruccia said, adding that the key to successful mating is … the plug. “We found that removing or chemically interfering with the mating plug makes copulation with a female ineffective.”

Using new genomic and proteomic techniques, sequence comparisons and bioimaging techniques on the plug, they examined its composition. The plug is formed through the action of an enzyme — transglutaminase — that links seminal fluid proteins together to coagulate semen. The male then deposits the coagulated secretions in the female’s sperm storage organ. The plug ensures correct sperm storage, which is essential for the fertilization of eggs.

The plug, the researchers wrote, becomes “a physical chastity belt in the sense of the first known historical description, 'hard iron breeches … closed at the front.'” Not only does this chastity belt deter competing males from copulating with her, the potent, protein-rich plug appears to deliver chemical messages that enter the female brain and modify her behavior and body chemistry. It stimulates muscle contractions, changes the appearance of her reproductive tract and causes her to release reproductive hormones. In fact, Catteruccia found, "The plug can collectively modify almost all aspects of female reproductive behaviour and physiology."

Her research team did a little finagling. By injecting double-stranded RNA into adult males, they interfered with the transglutaminase enzyme that produces the plug. A significant level of enzyme "knockdown" was achieved. Males that produced reduced amounts of transglutaminase did not form or transfer a plug to the females. The vast majority of females that were mated to these males were not inseminated.

"Our findings reveal a crucial role of the mating plug in mosquito reproductive biology and identify this important structure as a potential target for the manipulation of mosquito fertility," Catteruccia explained.

Malaria isn’t caused by the mosquitoes, but is spread by a parasite that lives in their digestive tract and is spread when the females bite mammals to suck out their blood to feed her eggs. Efforts to kill the mosquitoes that carry malaria, which the World Health Organization estimates kills a million people every year, have been complicated by the devastating effect of pesticides like DDT on other species, or by growing resistance among the mosquitoes themselves.

The ability to alter the plug could contribute to developing an insecticide that targets the malarial male but would not affect unrelated species. The team is currently collaborating with Stanford University to examine whether the inhibitors could be used to sterilize the male in a larger environment.

Does the elimination of the male mating plug also signal a kind of female mosquito liberation?

Catteruccia laughed. "There is good evidence that mating plugs sometimes function in reducing female remating, but we do not know with 100 percent certainty that females who do not receive the mating plug won't reproduce at all, and we don't know if they will mate again. Our focus is on the potential for male sterilization by targeting the mating plug. For me, that is the most fulfilling and exciting part of the research, its practical application in the field."