Pathogenesis of Cerebral Malaria in Nigerian Children: A Transcriptomic and Neuropathological Investigation

Cerebral malaria is the most devastating neurological complication of Plasmodium falciparum infection in African children, yet the transcriptomic basis of cerebral vascular pathology, neuroinflammation, and breakdown of the blood-brain barrier in the Nigerian context remains incompletely characterised. This doctoral research investigates the pathogenesis of cerebral malaria in Nigerian children using an integrated transcriptomic and neuropathological approach. A prospective case-control design was employed at the University of Calabar Teaching Hospital and the University of Maiduguri Teaching Hospital. Children with WHO-defined cerebral malaria, non-cerebral severe malaria, uncomplicated malaria, and healthy malaria-exposed controls were enrolled, with 60 participants in each group. Peripheral blood transcriptomics via RNA sequencing assessed host gene expression signatures distinguishing cerebral from non-cerebral malaria at hospital admission and 48 hours post-treatment. Cerebrospinal fluid samples from lumbar puncture were analysed for neuroinflammatory biomarkers including glial fibrillary acidic protein, neurofilament light chain, angiopoietin-2, and CXCL10 as markers of blood-brain barrier disruption and neuronal injury. Post-mortem brain tissue from four fatal cerebral malaria cases was examined histologically and by immunohistochemistry for sequestration-associated pathology. Evidence from 2020 to 2024 identifies interferon-stimulated gene upregulation and complement activation as the dominant transcriptomic signatures of cerebral malaria, with GFAP as the strongest predictor of neurological sequelae. This study generates the first transcriptomic-neuropathological integration dataset from Nigerian cerebral malaria patients. Keywords: cerebral malaria, transcriptomics, neuropathology, blood-brain barrier, Nigerian children.