March 16, 2009

Understanding How Mosquitoes Fight Malaria

Photo of a mosquito feeding on finger

Scientists have discovered how the mosquito immune system detects and kills the deadly malaria parasite. The discovery could help researchers develop innovative methods to block transmission of the disease from mosquitoes to humans.

Malaria is one of the most common infectious diseases in the world and an enormous public health problem. Each year, between 1 and 3 million people die of the disease worldwide. The majority are young children in Sub-Saharan Africa.

Malaria is caused by a single-cell parasite. Female mosquitoes become infected after feeding on an infected human. Inside the insect, the parasites cross mosquito gut cells. Once on the other side, they transform into thick-walled oocysts that grow, multiply and then burst, releasing hundreds or thousands of new parasites. These parasites migrate through the mosquito's blood to the salivary glands, where they can infect a new person when the mosquito next bites.

Most of the parasites are killed by the mosquito's immune system when they cross the gut and come into contact with the mosquito's blood. The infection persists, however, because a few parasites sneak through undetected and continue to divide, mature and infect people.

A team led by Dr. George K. Christophides at Imperial College London set out to understand how the mosquito's immune system kills the vast majority of malaria parasites at the initial stage of infection. The researchers focused on 2 related mosquito proteins, LRIM1 and APL1C, that have been shown to help limit malaria infection. The work was funded by NIH's National Institute of Allergy and Infectious Diseases (NIAID), along with the UK's Biotechnology and Biological Sciences Research Council and the Wellcome Trust.

The researchers reported on March 5, 2009, in the online edition of Science that mosquitoes lacking LRIM1, APL1C—or both—had a 50-fold increase in live oocyst numbers. Biochemical analysis revealed that LRIM1 and APL1C form a complex linked together by chemical bonds called disulfide bonds. If either of the proteins was missing, the other was no longer secreted into the blood.

The scientists discovered that the LRIM1/APL1C complex interacts with another protein called TEP1. When TEP1 is activated, it binds to the surface of parasites and orchestrates their death by essentially punching holes in their cell membranes. In mosquitoes missing the LRIM1/APL1C complex, the researchers found, TEP1 is no longer active.

The researchers hope to use their findings to learn how to block disease transmission by enhancing the mosquito's immune defenses. "If we can figure out how some parasites manage to sneak through undetected," Christophides says, "hopefully we can find a way to bolster the mosquito's defenses to catch them all." This research may also one day help prevent the spread of other serious infectious diseases carried by mosquitoes, such as dengue, yellow fever, filariasis and encephalitides.

—by Nancy Van Prooyen

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