Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria
Document Type
Article
Department
Paediatrics and Child Health (East Africa)
Abstract
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.
Publication (Name of Journal)
Randomized Controlled Trial
DOI
10.1126/scitranslmed.aaf6812
Recommended Citation
Higgins, S. J.,
Purcell, L. A.,
Silver, K. L.,
Tran, V.,
Crowley, V.,
Hawkes, M.,
Conroy, A. L.,
Opoka, R.,
Hay, J. G.,
Quaggin, S. E.,
Thurston, G.,
Liles, W. C.,
Kain, K. C.
(2013). Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria. Randomized Controlled Trial, 8(358), 358ra-128.
Available at:
https://ecommons.aku.edu/eastafrica_fhs_mc_paediatr_child_health/433
Comments
This work was published before the author joined Aga Khan University.