Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria
- 28 September 2016
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 8 (358), 358ra128
- https://doi.org/10.1126/scitranslmed.aaf6812
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.Keywords
Funding Information
- Canadian Institutes of Health Research (MOP-13721, MOP-115160, MOP-136813)
- CIHR foundation
- Canada Research Chairs
- CIHR Graduate Scholarship
- Tesari Foundation
This publication has 45 references indexed in Scilit:
- Platelet Activation Determines Angiopoietin-1 and VEGF Levels in Malaria: Implications for Their Use as BiomarkersPLOS ONE, 2013
- Neuroimmunological Blood Brain Barrier Opening in Experimental Cerebral MalariaPLoS Pathogens, 2012
- Impaired function of the Tie-2 receptor contributes to vascular leakage and lethality in anthraxProceedings of the National Academy of Sciences, 2012
- Angiopoietin-1 is essential in mouse vasculature during development and in response to injuryJCI Insight, 2011
- The Neuropathology of Fatal Cerebral Malaria in Malawian ChildrenThe American Journal of Pathology, 2011
- Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trialThe Lancet, 2010
- Blantyre Malaria Project Epilepsy Study (BMPES) of neurological outcomes in retinopathy-positive paediatric cerebral malaria survivors: a prospective cohort studyThe Lancet Neurology, 2010
- A Rapid Murine Coma and Behavior Scale for Quantitative Assessment of Murine Cerebral MalariaPLOS ONE, 2010
- Excess Circulating Angiopoietin-2 May Contribute to Pulmonary Vascular Leak in Sepsis in HumansPLoS Medicine, 2006
- Severe falciparum malariaTransactions of the Royal Society of Tropical Medicine and Hygiene, 2000