Model uncovers malaria parasite causes red blood cell changes
PENN STATE UNIVERSITY -- A model of a malaria-infected
red blood cell may lead to better ways to treat malaria, according to a team of
engineers and molecular biologists who investigated how this parasite infection
causes the red blood cells to stiffen.
Normal red blood cells are about 8 microns in size, but
can circulate in the microvascular system with a diameter of 1 to 2 microns
because they are flexible, deformable and durable. Cells infected with
the Plasmodium falciparum parasite, the most virulent form of malaria parasite,
become stiff and sticky and become lodged in small blood vessels while the
parasite is developing and so avoid the filtering action of the spleen.
"The malaria community knew about the fact that red blood cells get stiff and sticky when they are infected, " said Sulin Zhang, associate professor of engineering science and mechanics, Penn State. "They were also fairly certain why it becomes so sticky, but they are not certain why it becomes so stiff. You can't really treat the disease if you don't understand the mechanism."
Leann Tilley, professor of biochemistry and
molecular biology, University of Melbourne, suggested to Zhang that an
engineering approach might help.
Red blood cells are one of the simplest human
cells. A fatty, two-dimensional bilayer pairs with a protein-rich
cytoskeleton to form the membrane. Normally, the red blood cell's surface
is smooth and the cell is deformable, but when infected with a malaria
parasite, small protein nodules called knobs form on the surface. The
size and number of knobs change as the parasite matures.
To understand the stiffening process, the team developed
a model of the red blood cell that enabled them to understand what the knobs
did to stiffen the cell membrane.
"Models can be rough or detailed, " said Zhang. "If the model is too detailed, the computation becomes very expensive, if it is too coarse, we cannot capture the molecular detail. We created a model at the right scale with sufficient details but coarse enough for computation -- molecularly faithful and computationally affordable."
The researchers published the results of their
model in today's (Apr. 27) online issue of Proceedings of the National Academy
of Sciences.
The model found that the knobs, being stiff, contribute
to cell membrane stiffness. At the same time the presence of the knobs
elevates the strain in the cytoskeleton and because the cytoskeleton itself is
strain-hardening -- the higher the strain, the higher the stiffness --
this also stiffens the membrane. Also, as the number of knobs
increase, the number of linkages between the lipid bilayer and the protein
cytoskeleton also increases. This further stiffens the cell.
"A promising way to treat the disease is to soften the cells," said Zhang. "If we could find drug molecules that break the protein links between the knobs and the cytoskeleton, we could soften it."
Beside Tilley, Zhang, who works in theoretical and
applied mechanics, worked with Ju Li, Massachusetts
Institute of Technology, who is a materials physicist and Subra Suresh,
president, Carnegie Mellon
University, who specializes in materials science.
"It is not possible for one party to do this type of work," said Zhang. "Without molecular information, the model cannot be faithful. The experimental techniques have difficulty identifying the key factors out of many possibilities. Modeling, given molecular structures, can point to the underlying mechanism"
Also working on this project were Yao Zhang, graduate
students in engineering science and mechanics, Penn State; Changjin Huang,
former graduate student now at Northwestern University, and Mahdi Golkaram,
former Penn State graduate now at University of California, Santa Barbara;
Sangtae Kim, graduate student, MIT and Matt Dixon, postdoctoral fellow at
Melbourne.
CONTACTS:
A'ndrea Elyse Messer
aem1@psu.edu
The National Science Foundation supported
this work.
