Sticky Malaria Proteins Are Potential Drug Targets

Molecular parasitologists have employed a large-scale gene knockout strategy combined with functional screens to identify proteins exported into erythrocytes by the malaria parasite Plasmodium falciparum that cause changes in the red cell membrane's fluidity and adhesiveness.

Most of the clinical symptoms and the associated mortality and morbidity of falciparum malaria are a result of the parasite undergoing continuous cycles of asexual reproduction within human red blood cells. Infected red blood cells become rigid, poorly deformable, and develop the ability to cyto-adhere to a number of cell types such as vascular endothelial cells, a mechanism that prevents the parasitized host cells from passing through to the spleen where they would be cleared from the blood stream. These cellular modifications of the infected red blood cell are the result of a dramatic remodeling process induced by the parasite that ultimately serves to induce cyto-adherence by exposing various ligands on the erythrocyte surface for host cell receptors and facilitate nutrient import into the infecting parasite.
A paper published in the July 11, 2008, online edition of the journal Cell indicated that eight genes were required to encode the proteins necessary for export of the parasite adhesive protein (adhesin) PfEMP1 and assembly of knobs on the surface of the red cell that functioned as physical platforms to anchor the adhesin. Multiple proteins played a role in generating increased rigidity of infected erythrocytes.

"These findings greatly enhance our understanding of how the malaria parasite commandeers the red blood cell for its own survival and avoids our immune defenses,” said Dr. Alan Cowman, professor of infection and immunity at the Walter and Eliza Hall Institute of Medical Research (Melbourne, AU; www.wehi.edu.au). They also suggest that a drug that targets the "stickiness” proteins could be an effective treatment for malaria.


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Walter and Eliza Hall Institute of Medical Research