As drug-resistant malaria spreads, researchers have stepped up their search for new ways to combat the mosquito-borne scourge. Now they have pinpointed three genes that control how well mosquitoes themselves fight off the malaria parasite. The results mean that drugs or genetic modifications that beef up mosquitoes' immune response could one day help stop malaria from spreading.
When a mosquito bites someone infected with malaria, it ingests single-celled Plasmodium parasites that cause the disease. Within 10 minutes, the parasite mates; within a day it establishes itself in the mosquito's gut wall; and after 3 weeks it makes its way to the bug's salivary glands, ready to jump into the next human the mosquito bites. But even within a given species only some mosquitoes transmit malaria. Researchers suspected that differences in mosquito immune proteins might be responsible.
To identify such proteins, molecular biologists Mike Osta, George Christophides, and Fotis Kafatos of the European Molecular Biology Laboratory in Heidelberg, Germany, engineered mosquitoes to lack certain immune genes. One at a time, they inactivated 100 such genes using strands of RNA that block a specific gene from making its corresponding protein. A week later, they let the altered mosquitoes feed on a mouse infected with a line of malarial parasite that was genetically modified to glow green when alive, but turn black after death. Then they killed the mosquitoes, dissected out their guts, and counted the live and dead parasites under a microscope.
Silencing a gene called LRIM1 more than tripled the number of live parasites, the researchers report in the 26 March issue of Science. That suggests the gene normally helps the insects kill Plasmodium. In contrast, silencing either of two other genes, CTL4 and CTLMA2, caused the mosquitoes to kill many more parasites than usual, suggesting that the proteins they make somehow protect Plasmodium. If the results hold for the human malarial parasite, chemicals that block the two protective genes or stimulate the parasite-killing gene could slow malaria's spread, Osta says.
"It's impressive work," says parasitologist Kim Williamson of Loyola University in Chicago. But there's a long way to go before wild mosquitoes can be controlled this way; for example, researchers must show that the three genes control resistance to the Plasmodium species that infects humans. Nevertheless, the approach is promising, she says, because when it's infecting mosquitoes, "the parasite is relatively vulnerable."