Variant surface antigens of malaria parasites: functional and evolutionary insights from comparative gene family classification and analysis

Christian Frech,Nansheng Chen

doi:10.1186/1471-2164-14-427

Abstract

BackgroundPlasmodium parasites, the causative agents of malaria, express many variant antigens on cell surfaces. Variant surface antigens (VSAs) are typically organized into large subtelomeric gene families that play critical roles in virulence and immune evasion. Many important aspects of VSA function and evolution remain obscure, impeding our understanding of virulence mechanisms and vaccine development. To gain further insights into VSA function and evolution, we comparatively classified and examined known VSA gene families across seven Plasmodium species.ResultsWe identified a set of ultra-conserved orthologs within the largest Plasmodium gene family pir, which should be considered as high-priority targets for experimental functional characterization and vaccine development. Furthermore, we predict a lipid-binding domain in erythrocyte surface-expressed PYST-A proteins, suggesting a role of this second largest rodent parasite gene family in host cholesterol salvage. Additionally, it was found that PfMC-2TM proteins carry a novel and putative functional domain named MC-TYR, which is conserved in other P. falciparum gene families and rodent parasites. Finally, we present new conclusive evidence that the major Plasmodium VSAs PfEMP1, SICAvar, and SURFIN are evolutionarily linked through a modular and structurally conserved intracellular domain.ConclusionOur comparative analysis of Plasmodium VSA gene families revealed important functional and evolutionary insights, which can now serve as starting points for further experimental studies.

Highlights

Plasmodium parasites, the causative agents of malaria, express many variant antigens on cell surfaces
We were interested in all Plasmodium gene families that met one of the following criteria: (a) expressed at the parasite surface or the surface of infected erythrocytes; (b) predicted host cell localization by virtue of the presence of a Plasmodium export element (PEXEL)/vacuolar transport signal (VTS) export motif; any other gene family that is (c) species-specific or (d) located at subtelomeric regions of chromosomes
By examining the underlying BLAST alignments we found that BLAST consistently identified high-scoring segment pairs (HSPs) within the C-terminal intracellular regions of proteins, where, in SURFIN/PVSTP1 proteins, the HSPs overlapped with the previously described tryptophan-rich domain (WRD) [17]

Summary

Introduction

Plasmodium parasites, the causative agents of malaria, express many variant antigens on cell surfaces. In 2002, publication of the first two Plasmodium genomes, P. falciparum and P. yoelii, promised to revolutionize vaccine development by laying out the complete map of P. falciparum genes, including a comprehensive inventory of putative antigens that could serve as vaccine targets [7,8]. This monumental achievement was followed by the publication of the genomes of four additional Plasmodium species, including P. chabaudi and P. berghei in 2005 [9] as well as P. vivax and P. knowlesi in 2008 [10,11]. The availability of so many Plasmodium genome sequences provides a rich resource for (comparative) genomics studies to learn more about parasite biology and immune evasion strategies [12,13], the promise of an effective antimalarial vaccine has yet to be fulfilled

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