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

Sarah J. Higgins, Lisa A. Purcell, Karlee L. Silver, Vanessa Tran, Valerie Crowley, Michael Hawkes, Andrea L. Conroy, Robert O. Opoka, John G. Hay, Susan E. Quaggin, Gavin Thurston, W. Conrad Liles, Kevin C. Kain*

*Corresponding author for this work

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Cerebral malaria is a leading cause of global morbidity and mortality. Interventions targeting the underlying pathophysiology of cerebralmalaria 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 mousemodel of cerebralmalaria. 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.

Original languageEnglish (US)
Article number358ra127
JournalScience translational medicine
Volume8
Issue number358
DOIs
StatePublished - Sep 28 2016

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria'. Together they form a unique fingerprint.

  • Cite this

    Higgins, S. J., Purcell, L. A., Silver, K. L., Tran, V., Crowley, V., Hawkes, M., Conroy, A. L., Opoka, R. O., Hay, J. G., Quaggin, S. E., Thurston, G., Liles, W. C., & Kain, K. C. (2016). Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria. Science translational medicine, 8(358), [358ra127]. https://doi.org/10.1126/scitranslmed.aaf6812