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A clinicopathological correlation of the expression of the angiopoietin-Tie-2 receptor pathway in the brain of adults with Plasmodium falciparum malaria

Panote Prapansilp123*, Isabelle Medana1, Nguyen Thi Hoan Mai4, Nicholas PJ Day12, Nguyen Hoan Phu4, Tsin W Yeo5, Tran Tinh Hien4, Nicholas J White12, Nicholas M Anstey4 and Gareth DH Turner123

Author Affiliations

1 Nuffield Department of Medicine, Centre for Tropical Medicine, Oxford University, Oxford, UK

2 Mahidol-Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, 3rd Floor, 60th Anniversary Chalermprakiat Building, 420/6 Rajvithi Road, Bangkok, 10400, Thailand

3 Department of Tropical Pathology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

4 Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam

5 Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia

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Malaria Journal 2013, 12:50  doi:10.1186/1475-2875-12-50

Published: 5 February 2013



Plasma angiopoietin (Ang)-2 is associated with disease severity and mortality in adults and children with falciparum malaria. However the mechanism of action of the angiopoietins in fatal malaria is unclear. This study aimed to determine whether the expression of Ang-1 and Ang-2 and their receptor Tie-2 in cerebral endothelial or parenchymal cells was specific to cerebral malaria (CM), correlated with coma or other severe clinical features, and whether plasma and CSF levels of these markers correlated with the clinical and neuropathological features of severe and fatal malaria in Vietnamese adults.


Immunohistochemistry was performed for Ang-1, Ang-2 and Tie-2 on post-mortem brain tissue from fatal malaria cases and controls. Quantitative ELISA for plasma and cerebrospinal fluid levels of Ang-1, Ang-2 and Tie-2 was done to compare fatal cases with surviving patients from the same study.


Immunohistochemistry revealed significant differences in expression in endothelial and parenchymal cells compared to controls. However there was no significant difference in expression of these markers on endothelial cells, astroglial cells or neurons between CM and non-cerebral malaria cases. Immunostaining of Ang-1, Ang-2 and Tie-2 was also not associated with Plasmodium falciparum-infected erythrocyte sequestration in the brain. However Ang-1 and Ang-2 expression in neurons was significantly correlated with the incidence of microscopic haemorrhages. Plasma levels of Ang-2 and Ang-2/Ang-1 ratio were associated with the number of severe malaria complications and were significant and independent predictors of metabolic acidosis and fatal outcome.


The independent prognostic significance of Ang-2 and the Ang-2/Ang-1 ratio in severe malaria was confirmed, although immunohistochemistry in fatal cases did not reveal increased expression on brain endothelium in cerebral versus non-cerebral cases. Activation of the Ang-Tie-2 pathway in severe malaria is therefore related to acidosis, number of severity criteria and outcome, but is not a specific event in the brain during cerebral malaria.

Malaria; Human; Plasmodium falciparum; Pathogenesis; Pathology; Cerebral; Angiopoietin; Tie-2 receptor; Immunohistochemistry; Biomarker; Blood brain barrier