Plasmodium falciparum, the parasite that causes malaria infections in humans throughout sub-Saharan Africa and Southeast Asia, doesn’t have any effect on most mice. The parasite has a specific taste for mosquitos and humans and passes up the cells of other animals. Since most infectious disease researchers rely on mice to study how a disease infects its host and interacts with the mammalian immune system, those studying Plasmodium falciparum have struggled to find ways to probe the biology of the parasite. Now, with the development of a mouse that has not only human red blood cells, but a complete human immune system, biologists in the United States and Singapore have made advances in understanding how human immune cells interact with the malaria parasite. The mouse model and the novel findings are described in a new PNAS Early Edition paper.
“A few years ago, people found ways to supplement immunodeficient mice with human red blood cells,” says biologist Jianzhu Chen of the Massachusetts Institute of Technology and Singapore-MIT Alliance for Research and Technology, a senior author of the new paper. “And those mice can support a good level of the malaria parasite in the red blood cells, but you can’t study how other components of the immune system interact with the parasite.”
Chen and his collaborators aimed to develop mice that would support this broader level of study, and that meant developing mice with a full human immune system. They’ve spent the past few years working on the project.
The new mice are bred to lack typical mouse immune cells, and the researchers transfer human hematopoetic stem cells—those that give rise to blood and immune cells—into the mice. Then, the animals receive injections that contain human genes for cytokines—signaling molecules that coax the stem cells to develop properly—as well as injections of human red blood cells.
“The parasite will now infect the human cells inside the mouse,” says Chen. “This helps you study the immune system-parasite interaction.” Indeed, when the researchers exposed the mice to Plasmodium falciparum, it flourished in the bloodstreams of the mice.
To show the usefulness of the mouse model for studying the blood stage of the malaria parasite, Chen’s team next studied the effects of removing different components of the immune system from the mice. When they removed human macrophages—a type of white blood cell—from the mice, the parasites infected cells at the same rate as they previously had. But when they removed another type of human immune cell—natural killer cells—from the mice, Plasmodium falciparum became even more efficient at infecting the mice, and levels of the parasite in the mice’s bloodstreams skyrocketed.
The role of natural killer cells in fighting the malaria parasite had only been hypothesized about previously, Chen says. He and his colleagues went on to find that a direct interaction is needed between natural killer cells and Plasmodium falciparum-infected red blood cells to activate the natural killer cells.
“If we can identify the molecules that mediate the interaction between natural killer cells and the parasite, they could become targets for drugs,” Chen says. That’s one of the questions his team will be trying to answer with the new mouse model. They are also aiming to expand the mouse model to include human liver cells as well as immune cells, letting them study the liver stage of a malaria infection. And they want to study other malaria parasites using similar models. Plasmodium falciparum is most abundant in Africa, but other parasites—such as Plasmodium vivax—infect humans in other parts of the world.