Malaria is a major global health threat, infecting more than 200 million people and killing approximately 800,000 every year. It is caused by the protozoan parasite Plasmodium falciparum, which is carried and transmitted by mosquitoes. Laurent Rénia at the A*STAR Singapore Immunology Network and co-workers have now determined how red blood cells infected with the malaria parasite accumulate in the brain.
Cerebral malaria—the accumulation of infected red blood cells in the brain—is one of the most severe complications of malaria. The condition causes an unrousable coma and is often associated with seizures, but the underlying mechanisms are unclear.
Rénia and his co-workers infected several different strains of mice with P. berghei parasites that had been genetically engineered to express the fluorescent luciferase reporter gene. They then used in vivo imaging to visualize in real time the distribution of infected red blood cells during infection (see image).
They found that normal mice died of experimentally induced cerebral malaria 6 to 12 days after being infected. Mutant mice lacking both B and T immune cells due to a genetic mutation, however, did not develop cerebral malaria, suggesting that these cells mediate the accumulation of the parasite in the brain.
Further experiments revealed that the accumulation of the parasite in the brain is mediated by one particular type of T cell, called CD8+. Mutant mice lacking this cell type had significantly reduced numbers of infected red blood cells in both the brain and the spleen, as shown by fluorescent imaging. The imaging further revealed that the mutant mice lacking CD8+ T cells accumulated fewer parasites in their brains during the first week of infection, the period during which cerebral malaria normally develops, but not at later time points.
The researchers then examined the role of Interferon-gamma (IFN-γ), a pro-inflammatory cytokine known to play an important role in experimental models of cerebral malaria by inducing the migration of CD8+ T cells into the brain. When they infected mutant mice lacking the IFN-γ gene with P. berghei, the mutant mice showed similar amounts of the parasite in their blood as normal mice, but had less infected red blood cells in the brain and were completely resistant to cerebral malaria. “Our findings will help to design studies to see if these mechanisms occur in people,” says Rénia. “We are now in the process of identifying how the parasites are sequestered in deep tissues.”
The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network.