Diagnostic and prognostic biomarkers for pediatric cerebral malaria: a review
Year: 2026
Type: article
Abstract: Pediatric cerebral malaria (PCM) kills 15% to 25% of the African children in whom it is diagnosed and leaves many survivors with neurocognitive deficits. It is a disease of the cerebral microvasculature whose pathogenic sequence is now partly resolved at the molecular level. Plasmodium falciparum erythrocyte membrane protein 1 binds a broad range of endothelial cell receptors, of which binding to the endothelial protein C receptor, in some cases together with intercellular adhesion molecule 1, is the combination linked to severe and cerebral disease. CD36 is the receptor most commonly used by field isolates but is associated with uncomplicated malaria, at least two dozen further receptors have been described for parasitized erythrocytes, and a PfEMP1 binding domain has been identified for only a few of them. The ensuing endothelial activation releases von Willebrand factor and angiopoietin-2 and disables Tie − 2 signaling. Free heme, delivered in part by histidine-rich protein 2 nanoparticles internalized by caveolin-1-dependent endocytosis, is proposed to engage two separable innate arms, one through stimulator of interferon genes 1 (STING1) yielding type I interferon and CXCL10, the other through NLRP3 and caspase − 1 yielding interleukin-1-beta; the first was shown in murine brain endothelium and the second in a human cerebral endothelial cell line, and the two have not been demonstrated in one system. Junctional remodeling and ephrin type-A receptor 2 signaling open the blood–brain barrier in murine models, barrier disruption is documented histologically in human autopsy series, and neuronal and axonal proteins reach the circulation of affected children. The sequence summarized here therefore combines links established in human disease with links that remain experimental or proposed, and the review marks which is which at each step. This review treats candidate biomarkers as readouts of that cascade rather than as free-standing correlates. Because the clinical definition cannot separate malaria-attributable coma from coma with incidental parasitemia, we appraise malarial retinopathy as the in vivo reference standard and set out why a negative result is heterogeneous. Parasite-derived and host-derived markers are mapped onto those steps, with attention to the few evaluated against non-malarial coma rather than against milder malaria, and to what a marker adds at the bedside. Extracellular vesicles and microRNAs are assessed as emerging platforms. We close on druggable nodes in the cascade and on using molecular readouts to stratify children for host-directed therapy.
Source: Molecular Biology Reports
Institution: Poznan University of Medical Sciences
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,290
OpenAlex ID: W7225737259