The parasites that cause malaria are exquisitely adapted to the various hosts they infect -- so studying the disease in mice doesn't necessarily reveal information that could lead to drugs effective against human disease
Now, a team led by MIT researchers has developed a strain of mice
that mimics many of the features of the human immune system and can be
infected with the most common human form of the malaria parasite, known
as Plasmodium falciparum. Using this strain, the researchers
have already identified a key host defense mechanism, and they believe
it should lead to many more useful discoveries.
"Human malaria studies have been hampered by a lack of animal
models," says Jianzhu Chen, the Ivan R. Cottrell Professor of
Immunology, a member of MIT's Koch Institute for Integrative Cancer
Research, and the lead principal investigator of the Infectious Disease
Interdisciplinary Research Group at the Singapore-MIT Alliance for
Research and Technology (SMART). "This paves the way to start dissecting
how the host human immune system interacts with the pathogen."
Chen is one of the senior authors of a paper describing the findings in this week's Proceedings of the National Academy of Sciences,
along with Ming Dao, a principal research scientist in MIT's Department
of Materials Science and Engineering (DMSE); Subra Suresh, president of
Carnegie Mellon University (and a former MIT dean of engineering and
the Vannevar Bush Professor Emeritus of Engineering); and Peter Preiser,
a professor at Nanyang Technology University in Singapore.
Plasmodium falciparum, a parasite carried by mosquitoes,
usually infects the liver and red blood cells of its victims. Scientists
hoping to study malaria in mice have previously generated mice with
human red blood cells -- but these mice also have compromised immune
systems, so they can't be used to study the immune response to malaria
infection.
The humanized mouse project described in the new PNAS study
grew out of an interdisciplinary program Suresh initiated in 2003
involving researchers from MIT, several institutions in Singapore, and
the Institut Pasteur in France to study the mechanobiology of human red
blood cells invaded by malaria parasites and its consequences for the
pathogenesis of malaria. In 2007, Chen, Suresh, Dao, and Preiser
established a collaboration, through SMART, to develop a humanized mouse
model for malaria.
Over the past several years, Chen and colleagues have developed
strains of mice that have the human cells necessary for a comprehensive
immune response. To generate these cells, the researchers deliver human
hematopoietic stem cells, along with cytokines that help them mature
into B and T cells, natural killer (NK) cells, and macrophages -- all
critical components of the immune system. These mice have already proven
useful to study other diseases, such as dengue fever.
To adapt the mice for the study of malaria, the researchers injected
them with human red blood cells every day for a week, at which point 25
percent of their red blood cells were human -- enough for the malaria
parasite to cause an infection.
Natural defense
In the new PNAS paper, the researchers investigated the role
of NK cells and macrophages during the first two days of malaria
infection. They found that eliminating macrophages had very little
impact on the immune response during those early stages. However, in
mice lacking NK cells, parasite levels went up sevenfold, suggesting
that NK cells are critical to controlling infection early on.
To further investigate the role of NK cells, the researchers placed
human NK cells in a sample of infected and uninfected red blood cells.
The NK cells randomly interacted with both types of cells, but they
latched onto infected cells much longer, eventually killing them.
The researchers also identified a cell adhesion protein called LFA-1
that helps NK cells bind to red blood cells. They are now studying this
process in more detail and trying to figure out what other molecules,
including those produced by the malaria parasite, might be involved.
Chen and colleagues also hope to use these mice to study experimental
malaria vaccines or drugs. And in another future study, they plan to
inject the mice with human red blood cells from people with sickle cell
anemia to investigate how the sickle-shaped red blood cells help people
survive malaria infection.
source>>>science daily.
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