Endothelial activation and dysregulation in malaria: a potential target for novel therapeutics

Despite parenteral artesunate therapy, the fatality rate of cerebral malaria remains high. Adjunctive therapy targeting the underlying pathophysiology of cerebral malaria may further improve the clinical outcome. Endothelial activation and dysfunction is a central process in the pathogenesis of cerebral malaria. An improved understanding of how endothelium is perturbed in cerebral malaria may yield novel strategies to diagnose and intervene. Here, we discuss recent findings on the key molecular mediators of endothelial activation/dysregulation in cerebral malaria, and innovative endothelial-based experimental approaches to improve detection and treatment.

Biomarkers of endothelial activation [e.g., angiopoietin (Ang)-1, Ang-2, and a soluble form of the Ang-receptor (soluble Tie-2)] have been shown to be reliable predictors of malarial disease severity and mortality, and may improve clinical triage and management. Moreover, they may represent novel therapeutic targets to improve clinical outcome. Restoring bioavailable nitric oxide by administration of inhaled nitric oxide or its substrate, L-arginine, may rescue endothelial function, decrease Ang-2, and improve disease outcome in cerebral malaria.

Interventions targeting the Ang-Tie-2 axis to promote endothelial quiescence, including agents to improve endothelial nitric oxide, represent potential adjunctive therapies for cerebral malaria.