Researchers will study how overwhelming brain inflammation develops in some patients with malaria and results in disabling and potentially deadly cerebral malaria.
More than 500 million people worldwide suffer from malaria infection, produced by the Plasmodium parasite that is transmitted by mosquito bite and enters the bloodstream. Some infected patients develop cerebral malaria and suffer severe damage to the brain; as many as one-third of them die. Scientists know that cerebral malaria is caused by excessive inflammation that promotes the adhesion of infected red blood cells to the layer of “endothelial” cells that line the inside of the narrow (blood vessel) capillaries in the brain. Still unknown, however, is what triggers this exaggerated inflammatory response. The investigators have observed that the infected red blood cells release uric acid, and they hypothesize that it contributes to the massive inflammation that triggers the onset of cerebral malaria. They further hypothesize that treatment aimed at inhibiting this uric acid-induced pathway can prevent cerebral malaria.
Collaborating with a leading patient-oriented malaria researcher in Malawi and a mouse model immunity expert, this established investigator will test her hypotheses in four steps in cells from malaria-infected patients and in the mouse model. They first will determine whether uric acid released by infected red blood cells promotes the release of inflammatory proteins (called “cytokines”) that induce endothelial cells lining the brain’s capillaries to form adhesive molecules to which the infected red blood cells then attach. Next they will explore how the cytokines are released: they anticipate that uric acid activates specific proteins in innate immune dendritic cells to cause them to release the cytokines. Third, they will quantify the amount of uric acid crystals in the brain in the mouse model and in autopsied brains of patients who died from cerebral malaria. If these steps confirm that this process results in massive brain inflammation, they then will explore a combination method to prevent inflammation in the mouse model: 1) drugs to inhibit uric acid and its induction of inflammation combined with 2) treatment to decrease oxidative stress, an important function usually performed by uric acid.
Significance: If cerebral malaria is produced by uric acid’s stimulation of massive immune inflammation in the brain, uric acid will become an important target for potential preventive strategies, including two tested in this study.