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Researchers in Germany have identified a handful of mosquito genes they say could be crucial in the control of malaria, a disease that kills more than a million people a year across the world.

Fotis Kafatos, Mike Osta and George Christophides of the European Molecular Biology Laboratory (EMBL) in Heidelberg have pinpointed three mosquito genes that control the insect's immune response to the malaria parasite Plasmodium.

The genes thus directly affect whether the parasite, which causes the disease when it is injected into the human blood stream through a mosquito bite, can survive in the mosquito gut. Their results appear in today's Science.

The team say this confirms that focusing on the vector – i.e. the mosquito – rather than the human victim could be the key to a successful strategy for combating the disease.

"Many researchers focus on the direct effects of Plasmodium on the human body, but the mosquito is an equally important battleground in fighting the disease," notes Kafatos. "We now see a way to potentially stop the parasite in its tracks."

The researchers worked with a model of Anopheles gambiae, the principal vector of human malaria in Africa, and the rodent malaria parasite Plasmodium berghei.

They showed that two mosquito genes make proteins, CTL4 and CTLMA2, that protect the parasite from the mosquito's immune system while it grows in the gut. In contrast, a third mosquito protein, LRIM1, is lethal to the parasite.

When the two CTL genes were switched off, the mosquitoes' immune systems killed off most of the invading parasites. But inactivating the LRIM1 gene triggered a substantial increase in Plasmodium numbers.

The results with the CTL genes indicate the parasite has successfully co-evolved with its host, effectively subverting insect proteins in order to facilitate its own development.

"It is now clear that if we strip away [the] protective proteins, the parasite becomes vulnerable to the mosquito's immune system," says Christophides. "Developing novel chemicals to inhibit the ability of such proteins to protect the parasite is a promising avenue for reducing the prevalence of malaria."

Kafatos agrees. "These studies are the first to show the power of the mosquito's immune system, and give us some very real options for fighting the disease in the insect before it even has a chance to be passed to a human," he explains.

"There is no single 'magic bullet' for controlling this ancient scourge of humanity, but we want to exploit this new lead to contribute to the defeat of malaria."

In a 'Perspective' article accompanying the paper in Science, Janet Hemingway and Alister Craig of the Liverpool School of Tropical Medicine are optimistic about the prospects that the new findings will open up an effective way of controlling the spread of the disease. But they warn that "this achievement is only the first small step along the difficult road to practical implementation of such strategies."

This team's study is not the only EMBL breakthrough in the war on malaria. A second team, led by Elena Levashina, has demonstrated that another mosquito gene makes a protein, TEP1, that kills off the parasite directly in the gut.

This study, whose results were published earlier this month in the journal Cell, also provides important insight into the reasons that individual mosquitoes of the same species display genetic variation in their susceptibility to parasites.

"Our studies on TEP1 represent an important step because they show that it specifically locks on to Plasmodium, and it is this binding that mediates the killing of the parasite," says Levashina.

Stephanie Blandin, a co-author of the Cell article, says that both studies demonstrate that the mosquito's immune system has the ability to defend itself against malaria. "By enhancing these natural defenders, we may be able to block the parasite-mosquito cycle."

Link to 'New ways to control malaria' by Janet Hemingway and Alister Craig

Link to 'Effects of mosquito genes on Plasmodium development' by Osta, M.A. et al.

References: Science 303, 2030 / 303, 1994 (2004) / Cell 116, 661 (2004)

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