A team of researchers has discovered one of the mechanisms responsible for the progression of malaria, providing a new target for possible treatments.
Using computer modeling, researchers from Carnegie Mellon, the Pennsylvania State University, the Massachusetts Institute of Technology and the University of Melbourne found that nanoscale knobs, which form at the membrane of infected red blood cells, cause the cell stiffening that is in part responsible for the reduced blood flow that can turn malaria deadly.
Many of malaria's symptoms are the result of impeded blood flow, which is directly tied to structural changes in infected red blood cells, said co-author Subra Suresh, adding that computer modeling gives them an unprecedented opportunity to investigate these structural changes and improve their understanding of this often deadly disease.
When red blood cells are infected by Plasmodium parasites, two changes occur: the cells become stiff, so they can't stretch to fit through narrow capillaries, and the cells become sticky and adhere to the walls of veins. As a result, the infected cells obstruct blood flow, preventing healthy red blood cells from expediently reaching and delivering oxygen and nutrients to organs, including the brain. The infected cells also can't make their way to the spleen, which would eliminate them from the body.
When a cell is infected, the Plasmodium parasite releases proteins that interact with the cell membrane of the host red blood cell. The cell membrane undergoes a series of changes that result in stiffness and stickiness. In order to visualize what happens at the cell membrane during malarial infection, the research team turned to a computer simulation technique called coarse-grained molecular dynamics (CGMD).
They seeded the model membrane with proteins released by one of the most common, and the most deadly, malarial parasites, Plasmodium falciparum and found that the stiffening of the red blood cell membrane had little to do with the remodeling of spectrin. Instead, the nanoscale knobs that cause the red blood cells to stick to the vein's walls also cause the membrane to stiffen through a number of different mechanisms, including composite strengthening, strain hardening and density-dependent vertical coupling effects.
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According to the researchers, the discovery of this new mechanism responsible for the stiffening of infected red blood cells could provide a promising target for new antimalarial therapies.
The study appears online in the Proceedings of the National Academy of Sciences (PNAS).