Differences in PfEMP1s recognized by antibodies from patients with uncomplicated or severe malaria.

Michael Duffy ,Louise Turner,Leily Trianty,Nicholas M Anstey,Rintis Noviyanti,Freya J I Fowkes,Peter Siba,Takafumi Tsuboi,Fransisca Sumardy,Thomas Lavstsen,Jutta Marfurt,Stephen J Rogerson,Daniel A Lampah,Ric N Price,Anthony T Papenfuss,Boni F Sebayang,Graham V Brown,Thor G Theander,Eizo Takashima,Zhiping Feng

doi:10.1186/s12936-016-1296-4

Abstract

BackgroundPlasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variants are encoded by var genes and mediate pathogenic cytoadhesion and antigenic variation in malaria. PfEMP1s can be broadly divided into three principal groups (A, B and C) and they contain conserved arrangements of functional domains called domain cassettes. Despite their tremendous diversity there is compelling evidence that a restricted subset of PfEMP1s is expressed in severe disease. In this study antibodies from patients with severe and uncomplicated malaria were compared for differences in reactivity with a range of PfEMP1s to determine whether antibodies to particular PfEMP1 domains were associated with severe or uncomplicated malaria.MethodsParts of expressed var genes in a severe malaria patient were identified by RNAseq and several of these partial PfEMP1 domains were expressed together with others from laboratory isolates. Antibodies from Papuan patients to these parts of multiple PfEMP1 proteins were measured.ResultsPatients with uncomplicated malaria were more likely to have antibodies that recognized PfEMP1 of Group C type and recognized a broader repertoire of group A and B PfEMP1s than patients with severe malaria.ConclusionThese data suggest that exposure to a broad range of group A and B PfEMP1s is associated with protection from severe disease in Papua, Indonesia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1296-4) contains supplementary material, which is available to authorized users.

Highlights

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variants are encoded by var genes and mediate pathogenic cytoadhesion and antigenic variation in malaria
Some DBL and CIDR domain subtypes mediate adhesion to different host receptors, and some are organized in semi-conserved domain cassettes (DC) that are present in most parasites [4]. var genes are classified using their upstream sequence into groups A, B, C [16, 17] which comprise 20, 60 and 20 % respectively of the var gene repertoire [4]; the unique var gene called var2csa has a different upstream sequence and is only involved in malaria during pregnancy [18]
Reads that mapped to the 399 full length var gene sequences available [4] were merged with reads that did not map to the P. falciparum 3D7 strain genome nor Homo sapiens, and the merged reads were subjected to two rounds of de novo assembly to generate 623 contigs that included 362 contigs with homology to var genes

Summary

Introduction

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variants are encoded by var genes and mediate pathogenic cytoadhesion and antigenic variation in malaria. PfEMP1s can be broadly divided into three principal groups (A, B and C) and they contain conserved arrangements of functional domains called domain cassettes. Despite their tremendous diversity there is compelling evidence that a restricted subset of PfEMP1s is expressed in severe disease. PfEMP1 is the immunodominant antigen of the malaria parasite Plasmodium falciparum expressed on the surface of the infected erythrocyte (IE). The expression of particular subtypes of DBLα domains in severe malaria suggests severe disease may be preferentially caused by a restricted subset of var genes [19, 20]. Cerebral malaria in Africa was associated with increased expression of group A [20, 24, 25] or group B [26] var genes

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Conclusion