Team discovers new mechanism behind malaria progression

Graphic: Electron microscope image

This is a scanning electron microscope image and computer model of a malaria parasite-infected red blood cell membrane; © Eric Hanssen, Bio21 Institute, University of Melbourne, Australia and Yao Zhang, Penn State

A team of researchers from four universities has pinpointed one of the mechanisms responsible for the progression of malaria, providing a new target for possible treatments.

Using computer modeling, Carnegie Mellon President Subra Suresh and his colleagues 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. The findings represent a new understanding of the mechanisms behind the progression of malaria, opening a new avenue of research into therapies for the disease that infects close to 200 million people each year.

Malaria is caused by Plasmodium parasites, which are spread to people via infected Anopheles mosquitos. "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 Suresh. "Computer modeling gives us an unprecedented opportunity to investigate these structural changes and improve our understanding of this often deadly disease."

When a person contracts malaria, the parasites grow and multiply in the liver and then move into the red blood cells. 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. While researchers are fairly certain that the stickiness is caused by nanoscale knobs that protrude from the cell membrane, they were uncertain as to what caused the stiffness. They hypothesized that the parasite protein/cell membrane interaction caused spectrin, a cytoskeletal protein that provides a scaffold for the cell membrane, to rearrange its networked structure to be more rigid. However, the complexity of the cell membrane made it difficult for researchers to study and prove this hypothesis experimentally.

In order to visualize what happens at the cell membrane the research team turned to a computer simulation technique called coarse-grained molecular dynamics (CGMD). CGMD has proven to be very valuable for studying what happens at the cell membrane because it represents membrane's complex proteins and lipids with larger, simplified components rather than atom by atom.

In the current study, the researchers seeded the model membrane with proteins released by one of the most common, and the most deadly, malarial parasites, Plasmodium falciparum.

From their simulation, the researchers 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.; Source: Carnegie Mellon University

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