Project Details

Characterizing Metabolic Dysfunction in the Pathogenesis and Survival from Cerebral Malaria

Ian Drobish, MD

Summary

BACKGROUND: Malaria causes more than 600,000 deaths annually, over 70% of which are children under five. Cerebral malaria, the most severe manifestation of Plasmodium falciparum infection, carries a mortality rate of 15–21% despite standard of care antimalarial therapy, and up to half of survivors experience persistent neurodevelopmental impairment. GAP: One emerging contributor to neurological injury is dysfunction of cerebral energy metabolism, which has been shown to impact an array of neurodevelopmental processes. However, the specific metabolic pathways disrupted during pediatric cerebral malaria that drive brain injury and neurologic sequelae remain incompletely understood, limiting development of adjunctive therapies to prevent the neurologic disability that affects up to half of survivors. HYPOTHESIS: Our central hypothesis is that pediatric cerebral malaria is characterized by distinct brain-specific and systemic alterations in energy metabolism pathways, and these molecular signatures and their trajectories determine neurologic injury and recovery. METHODS: We will leverage a multinational, multicenter network of hospitals in Sub-Saharan Africa that enroll children with cerebral malaria. This collaboration provides access to an existing biospecimen repository of over 100 pediatric cases to perform a comprehensive metabolomic, lipidomic, and proteomic analysis of cerebrospinal fluid and blood to define molecular signatures of energy metabolism and related pathways, and their relationship to neurologic outcomes. RESULTS: Pending. IMPACT: This study will define the role of brain and systemic-specific energy metabolism dysfunction in neurologic injury following pediatric cerebral malaria and may identify candidate pathways for future adjunctive therapeutic intervention.