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Topic Name: ID's cell mechanics of hallmark malaria protein
Category: Biodesign
Research persons: ,Subra Suresh, Diez-Silva and John P. Mills,
Location: 77 massachusetts avenue,,cambridge, ma 02139-4307, United States
Details
During the first 24 hours of invasion by the malaria-inducing
parasite Plasmodium falciparum, red blood cells start to lose their ability to
deform and squeeze through tiny blood vessels--one of the hallmarks of the
deadly disease that infects nearly 400 million people each year. Now, an
international team of researchers led by an MIT professor has demonstrated just
why that happens.By knocking out the gene for a parasite protein called RESA
(ring-infected erythrocyte surface antigen), the researchers found that the
protein, transferred from the parasite to the cell's interior molecular network,
causes red blood cells to become less deformable.
"This is the first time a particular protein has been
shown to have such a large effect on red blood cell deformability," said
Subra Suresh, Ford Professor of Engineering and senior author of a paper on the
work appearing in the online edition of the Proceedings of the National Academy
of Sciences the week of May 21.
The work, a collaboration between researchers at MIT, the
Institut Pasteur in Paris, France and the National University of Singapore,
could ultimately lead to the development of treatments that target the parasite
protein.
Suresh, who holds appointments in materials science and
engineering, biological engineering, mechanical engineering and the Harvard-MIT
Division of Health Sciences and Technology, has been studying the mechanics of
red blood cells and the effects of malaria on those cells for several years.
When the malaria parasite, Plasmodium falciparum, infects red
blood cells, the blood cells lose their ability to deform and eventually clump
together and get stuck in tiny blood vessels, or capillaries.
The RESA protein has long been suspected to be involved in the
early stages of that process. The parasite produces RESA during the first stage
of malaria (known as the ring stage) and then transports it to the cell surface.
In this experiment, the researchers cloned the parasite and
then knocked out the gene that produces RESA and then measured the red blood
cells' deformability with "optical tweezers," which use lasers to
stretch cell membranes.
They found that in red blood cells infected by parasites
without RESA, deformability remained normal during the first 24 hours of
infection. In other parasites where RESA was turned back on after being knocked
out, deformability was affected just as it was by (wild type) parasites in which
RESA was never knocked out.
"That the deformability changed several-fold was a big
surprise," said Suresh.
Because malaria patients usually experience high fever
episodes, the researchers also performed their experiments at fever temperatures
(about 41 degrees Celsius), as well as normal body temperature (37 degrees
Celsius). They found that RESA has a much greater impact on deformability at
fever temperatures.
The research team believes that when RESA travels to the cell
membrane, it binds to the cell's cytoskeleton--a scaffolding of proteins that
lies just inside the cell membrane. In a paper published earlier this year,
Suresh and colleagues demonstrated that healthy red blood cells' ability to
deform depends on the structure of this network. (See web.mit.edu/newsoffice/2007/blood.html)
When the bonds in the protein network are broken, holes open
up in the cytoskeleton, allowing the cell to become more fluidic and squeeze
through narrow passages. But when RESA binds to the network, it likely
interferes with the proteins' ability to break and form bonds with each other,
decreasing deformability, according to Suresh. In an unrelated parallel study,
researchers at the New York Blood Center and their collaborators have recently
identified specific sites in the red cell cytoskeleton to which RESA binds.
In future studies, the researchers plan to study the effects
of proteins produced by the malaria parasite during later stages of infection.
They also plan to look at whether the RESA protein plays any role in why another
strain of the malaria parasite, Plasmodium vivax, is less lethal than P.
falciparum.
The collaboration between MIT and the Institut Pasteur began
with a serendipitous encounter: In a crowded cafeteria at the École des Mines
in Paris, where Suresh was visiting a few years ago, he met a colleague from
Institut Pasteur. She introduced him to the researchers studying malaria at
Pasteur, who included microbiologist Monica Diez-Silva, now an MIT and GEM4
postdoctoral fellow and a lead author of the PNAS paper.
Shortly after this meeting, Suresh started a formal
collaboration known as GEM4 (Global Enterprise for MicroMechanics and Molecular
Medicine), which brings together researchers from MIT, Institut Pasteur, the
National University of Singapore and other universities around the world. This
year, GEM4 will holds its second summer school, where scientists learn about one
another's work and form research partnerships. This GEM4 activity is supported
by a number of institutions, including the National Science Foundation.
Multidisciplinary, multinational research at the intersections
of engineering, life sciences and medicine, with major implications for public
health is "exactly what GEM4 was designed to facilitate and
accomplish," Suresh said.
About Researchers:
Subra Suresh,
Ford Professor of Engineering
Professor of Materials Science and Engineering, Professor of Biological
Engineering, Affiliated Faculty of the Harvard-MIT Division of Health Sciences
and Technology, Professor of Mechanical Engineering
Bachelor of Technology, Indian Institute of Technology, 1977
MS, Iowa State University, 1979
ScD, MIT, 1981
Room 4-140, 77 Mass. Ave., Cambridge, MA 02139
617-253-3320 617-253-0868
ssuresh@mit.edu
Lead authors of the PNAS paper are Diez-Silva and John P.
Mills, both postdoctoral associates in materials science and engineering. Other
MIT authors are David J. Quinn, graduate student in mechanical engineering; Ming
Dao, research scientist in materials science and engineering; and Matthew Lang,
assistant professor of biological engineering and mechanical engineering.
Authors from Institut Pasteur are Genevieve Milon, Peter H. David, Odile
Mercereau-Puijalon and Serge Bonnefoy. Authors from the National University of
Singapore are Kevin S.W. Tan and Chwee Teck Lim.
Funded:
The research was funded by an interuniversity grant received
by GEM4, a Pasteur Institut research grant, Agence Nationale de Recherche sur le
Sida, the National University of Singapore and the Computational Systems Biology
Program of the Singapore-MIT Alliance.
In The Images:
Part of the global team responsible for confirming the protein
RESA's role in causing malaria by binding to red blood cells, in a lab at MIT.
Professor Subra Suresh, left, research scientist Ming Dao, standing, post-doc
Monica Diez Silva, seated, graduate student David Quinn, seated, graduate
student John Mills, and professor Matthew Lang
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