Defining the mechanism of coma in cerebral malaria

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. High blood levels of pipecolic acid (PA) have been identified in children with CM compared to mild malaria. PA has been shown to induce coma in animal models, and this project 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. The project will determine if PA cerebral spinal fluids are elevated in CM compared with defined non-CM cases of encephalopathy. It 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. The project 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 to be produced by Plasmodium, and its role in parasite biology is unknown. The metabolic pathway that produces PA will be defined and test will be conducted to determine whether PA protects the malaria parasite from oxidative stress, similar to its protective role observed in mammalian cells.

Project details

Basic Science

Jul 2022 — Jun 2027

$529,291

United States