How the immune system fights off malaria findings by MIT's Scientists

Throughout history malaria has proved to be a significant threat to human health. Between 300 and 500 million clinical cases occur each year worldwide, approximately 2 million of which are fatal, primarily in children. The vast majority of malaria-related deaths are due to infection with Plasmodium falciparum; P. vivax causes severe febrile illness but is rarely fatal.
Now, a team of scientists has identified a key host defense mechanism.
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. Using this strain, the researchers have already identified a key host defense mechanism, and they believe it should lead to many more useful discoveries.

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.

“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)}.

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.

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.

"This indicates that NK cells may provide an important immune defense against malaria", says Lewis Lanier.

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.
 
The humanized mouse project described in the new PNAS (Proceedings of the National Academy of Sciences) study
The research was funded by the National Research Foundation Singapore through SMART’s Interdisciplinary Research Group in Infectious Disease.


 Reference:
 Adapted from a news release issued by MIT