a red blood cell
Photo courtesy of St. Jude
Children’s Research Hospital
Researchers say they have pinpointed one of the mechanisms responsible for the progression of malaria.
Computer modeling showed that the nanoscale knobs that 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.
Subra Suresh, ScD, of Carnegie Mellon University in Pittsburgh, Pennsylvania, and his colleagues reported this finding in PNAS.
“Many of malaria’s symptoms are the result of impeded blood flow, which is directly tied to structural changes in infected red blood cells,” Dr Suresh said.
When a red blood cell is infected with malaria, the parasite releases proteins that interact with the cell membrane. 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.
To visualize what happens at the cell membrane during malarial infection, Dr Suresh and his colleagues turned to a computer simulation technique called coarse-grained molecular dynamics (CGMD). CGMD has proven valuable for studying what happens at the cell membrane because it represents the membrane’s complex proteins and lipids with larger, simplified components rather than atom by atom.
Doing this requires less computing time and power than standard atomistic models, which allows scientists to run simulations for longer periods of time while still accurately recreating the behavior of the cell membrane.
Typically, researchers introduce different variables into the simulation and observe how the membrane reacts. In the current study, the researchers seeded the model membrane with proteins released by the malaria parasite 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.
According to the researchers, the discovery of this mechanism could provide a promising target for new antimalarial therapies.
