Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria.
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.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, and the Tropical Disease Unit, Department of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada. Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Sarah J
SJ
Higgins
Regeneron Pharmaceuticals Inc, Tarrytown, NY 10591, USA.
Lisa A
LA
Purcell
Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, and the Tropical Disease Unit, Department of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada. Grand Challenges Canada, Toronto, Ontario M5G 1L7, Canada.
Karlee L
KL
Silver
Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, and the Tropical Disease Unit, Department of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
Vanessa
V
Tran
Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, and the Tropical Disease Unit, Department of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
Valerie
V
Crowley
Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, and the Tropical Disease Unit, Department of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada. Department of Pediatrics, University of Alberta, Edmonton, Alberta T6G 1C9, Canada.
Michael
M
Hawkes
Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, and the Tropical Disease Unit, Department of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
Andrea L
AL
Conroy
Department of Paediatrics and Child Health, Mulago Hospital and Makerere University, Kampala 7051, Uganda.
Robert O
RO
Opoka
New York University School of Medicine, New York, NY 10006, USA.
John G
JG
Hay
Feinberg Cardiovascular Research Institute and Division of Nephrology/Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Susan E
SE
Quaggin
Regeneron Pharmaceuticals Inc, Tarrytown, NY 10591, USA.
Gavin
G
Thurston
Departments of Medicine, Pathology, Pharmacology and Global Health, University of Washington, Seattle, WA 98195, USA.
W Conrad
WC
Liles
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, and the Tropical Disease Unit, Department of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada. kevin.kain@uhn.ca.
Kevin C
KC
Kain
D000256:Adenoviridae / Q000378:metabolism; D042683:Angiopoietin-1 / Q000378:metabolism*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use; D037621:Artemisinins / Q000494:pharmacology / Q000627:therapeutic use; D000077332:Artesunate; D001812:Blood-Brain Barrier / Q000473:pathology; D002675:Child, Preschool; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D007700:Kinetics; D016779:Malaria, Cerebral / Q000209:etiology* / Q000378:metabolism*; D016778:Malaria, Falciparum / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D010641:Phenotype; D010963:Plasmodium falciparum / Q000187:drug effects; D042787:Receptor, TIE-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D016019:Survival Analysis; D016896:Treatment Outcome; D014454:Uganda
D042683:Angiopoietin-1; D000962:Antimalarials; D037621:Artemisinins; D011994:Recombinant Proteins; D000077332:Artesunate; D042787:Receptor, TIE-2
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