Asian Scientist (Jan. 24, 2014) – A new study by scientists in Singapore and the U.S. has revealed how immune cells are critical in combating the malaria parasite in early stages of infection.
The parasites that cause malaria are exquisitely adapted to the various hosts they infect — so studying the disease in mice does not necessarily reveal information that could lead to drugs effective against human disease.
Now, an international team of researchers, led by scientists in Singapore, 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, 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,” said Prof. Jianzhu Chen, the lead principal investigator of the Infectious Disease Interdisciplinary Research Group at the Singapore-MIT Alliance for Research and Technology (SMART). Chen is one of the senior authors of a paper describing the findings published in the Proceedings of the National Academy of Sciences.
“This paves the way to start dissecting how the host human immune system interacts with the pathogen.”
The malaria parasite is carried by mosquitoes and 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 study grew out of an interdisciplinary program initiated in 2003 involving researchers from the U.S., Singapore and France to study the mechanobiology of human red blood cells invaded by malaria parasites and its consequences for the pathogenesis of malaria. In 2007, a collaboration was established 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.
In this latest study, 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.
The researchers hope to use these mice to study experimental malaria vaccines or drugs. 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: MIT; Image: NIAID/Flickr/CC.
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