Defining the mechanism of coma in cerebral malaria

Project: Research project

Project Details


ABSTRACT Malaria remains a significant public health challenge that has resisted worldwide control efforts. Some individuals who become infected with Plasmodium falciparum develop cerebral malaria (CM), which presents as a coma and is associated with high morbidity and mortality. The etiology of CM coma, which is reversible in survivors, remains unknown. We have identified high blood levels of pipecolic acid (PA) in children with CM compared to mild malaria. PA has been shown to induce coma in animal models, and we will test the hypothesis that high blood levels in CM result in abnormally elevated PA central nervous system (CNS) concentrations to result coma in CM. We will determine if PA cerebral spinal fluids are elevated in CM compared with defined non-CM cases of encephalopathy. We will determine if PA is enriched in the brain of mice in infected with P. berghei ANKA in the experimental cerebral malaria model and not in the brains of mice infected with strains P. yoelii and P. chabaudi, which are infection models where mice maintain wakefulness. We will investigate the hypothesis that PA reduces consciousness through γ-aminobutyric acid (GABA) receptors, which has been suggested by prior studies using a rat model. PA has been shown by multiple groups including ours to be produced by Plasmodium, and its role in parasite biology is unknown. We will define the metabolic pathway that produces PA and test whether PA protects the malaria parasite from oxidative stress, similar to its protective role observed in mammalian cells. Overall, our goals are to define the role of PA in coma induction and parasite biology to characterize a novel mechanism of coma in humans, potentially identify a biomarker of CM etiology of coma, and characterize a potential novel target for improving the health outcomes of CM.
Effective start/end date7/8/226/30/23


Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.