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Open Access Highly Accessed Research article

Plasmodium falciparum antigenic variation: relationships between widespread endothelial activation, parasite PfEMP1 expression and severe malaria

Abdirahman I Abdi14*, Gregory Fegan12, Michelle Muthui1, Esther Kiragu1, Jennifer N Musyoki1, Michael Opiyo1, Kevin Marsh12, George M Warimwe13 and Peter C Bull12

Author Affiliations

1 KEMRI-Wellcome Trust Research Programme, P.O. Box 230–80108, Kilifi, Kenya

2 Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3, UK

3 The Jenner Institute, University of Oxford, ORCRB, Roosevelt Drive, Oxford OX3 9DU, UK

4 Department of Biochemistry and Chemistry, Pwani University, P.O. Box 195, 80108 Kilifi, Kenya

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BMC Infectious Diseases 2014, 14:170  doi:10.1186/1471-2334-14-170

Published: 28 March 2014

Abstract

Background

Plasmodium falciparum erythrocyte membrane protein 1(PfEMP1) is a family of variant surface antigens (VSA) that mediate the adhesion of parasite infected erythrocytes to capillary endothelial cells within host tissues. Opinion is divided over the role of PfEMP1 in the widespread endothelial activation associated with severe malaria. In a previous study we found evidence for differential associations between defined VSA subsets and specific syndromes of severe malaria: group A-like PfEMP1 expression and the “rosetting” phenotype were associated with impaired consciousness and respiratory distress, respectively. This study explores the involvement of widespread endothelial activation in these associations.

Methods

We used plasma angiopoietin-2 as a marker of widespread endothelial activation. Using logistic regression analysis, we explored the relationships between plasma angiopoietin-2 levels, parasite VSA expression and the two syndromes of severe malaria, impaired consciousness and respiratory distress.

Results

Plasma angiopoietin-2 was associated with both syndromes. The rosetting phenotype did not show an independent association with respiratory distress when adjusted for angiopoietin-2, consistent with a single pathogenic mechanism involving widespread endothelial activation. In contrast, group A-like PfEMP1 expression and angiopoietin-2 maintained independent associations with impaired consciousness when adjusted for each other.

Conclusion

The results are consistent with multiple pathogenic mechanisms leading to severe malaria and heterogeneity in the pathophysiology of impaired consciousness. The observed association between group A-like PfEMP1 and impaired consciousness does not appear to involve widespread endothelial activation.

Keywords:
Group A-like; Angiopoietin-2; Rosetting; Sequestration; Impaired consciousness; Cerebral malaria; Respiratory distress