Plasmodium falciparum var genes expressed in children with severe malaria encode CIDRα1 domains.

Louise Turner,Christian W Wang,Daniel TR Minja,Sixbert I Mkumbaye,Jakob S Jespersen,Bent Petersen,John PA Lusingu,Thomas Lavstsen,Thor G Theander,Jens EV Petersen

doi:10.15252/emmm.201606188

Abstract

Most severe Plasmodium falciparum infections are experienced by young children. Severe symptoms are precipitated by vascular sequestration of parasites expressing a particular subset of the polymorphic P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion molecules. Parasites binding human endothelial protein C receptor (EPCR) through the CIDRα1 domain of certain PfEMP1 were recently associated with severe malaria in children. However, it has remained unclear to which extend the EPCR‐binding CIDRα1 domains epitomize PfEMP1 expressed in severe malaria. Here, we characterized the near full‐length transcripts dominating the var transcriptome in children with severe malaria and found that the only common feature of the encoded PfEMP1 was CIDRα1 domains. Such genes were highly and dominantly expressed in both children with severe malarial anaemia and cerebral malaria. These observations support the hypothesis that the CIDRα1‐EPCR interaction is key to the pathogenesis of severe malaria and strengthen the rationale for pursuing a vaccine or adjunctive treatment aiming at inhibiting or reducing the damaging effects of this interaction.

Highlights

The majority of children living in malaria endemic areas of Africa suffer at least one attack of severe malaria during early childhood (Goncalves et al, 2014)
Annotation of Duffy Binding-Like (DBL) and Cysteine-rich Inter Domain Region (CIDR) domains encoded by the var transcripts identified in the 44 individuals is shown in Appendix Fig S1
The epidemiology of severe malaria in areas of high transmission, serological typing of parasites from children with severe disease and antibody profiling in children surviving their first malaria attacks (Bull et al, 1998; Nielsen et al, 2002) suggest that severe paediatric malaria is precipitated by P. falciparum expressing a distinct set of PfEMP1 molecules on the surface of infected erythrocytes (Smith et al, 2013)

Summary

Introduction

The majority of children living in malaria endemic areas of Africa suffer at least one attack of severe malaria during early childhood (Goncalves et al, 2014). It is clear that severe malaria is associated with several different pathological processes such as proinflammatory and procoagulant activation of endothelial cells, compromised blood–brain barrier, and vascular congestion caused by infected erythrocytes (see recent review Wassmer et al, 2015). At their late stages, P. falciparum infected erythrocytes sequester in post-capillary venules and are not detected in peripheral blood. A fundamental question is whether parasites causing severe malaria as opposed to uncomplicated disease share common traits and whether different manifestations of severe malaria can be linked to particular parasite features

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Conclusion