Research ArticleMalaria

Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria

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Science Translational Medicine  28 Sep 2016:
Vol. 8, Issue 358, pp. 358ra128
DOI: 10.1126/scitranslmed.aaf6812

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Bolstering the host to beat malaria

Cerebral malaria is a devastating disease associated with high death rates and brain injury despite the use of potent antimalarials. Understanding the role of the host response in determining the ability of the host to survive a severe malaria infection may enable development of host-based therapeutics to prevent infection-induced death. Higgins et al. now demonstrate how the loss of a key host vascular protective protein, angiopoietin-1, is associated with severe and fatal malaria in children and in a mouse model. Administering angiopoietin-1 to mice with cerebral malaria reinforced the blood-brain barrier and improved survival, even when initiated late in disease.


Cerebral malaria is a leading cause of global morbidity and mortality. Interventions targeting the underlying pathophysiology of cerebral malaria may improve outcomes compared to treatment with antimalarials alone. Microvascular leak plays an important role in the pathogenesis of cerebral malaria. The angiopoietin (Ang)–Tie-2 system is a critical regulator of vascular function. We show that Ang-1 expression and soluble Tie-2 expression were associated with disease severity and outcome in a prospective study of Ugandan children with severe malaria and in a preclinical murine model of experimental cerebral malaria. Ang-1 was necessary for maintenance of vascular integrity and survival in a mouse model of cerebral malaria. Therapeutic administration of Ang-1 preserved blood-brain barrier integrity and, in combination with artesunate treatment, improved survival beyond that with artesunate alone. These data define a role for dysregulation of the Ang–Tie-2 axis in the pathogenesis of cerebral malaria and support the evaluation of Ang–Tie-2–based interventions as potential adjunctive therapies for treating severe malaria.

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