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

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.

The Plasmodium falciparum exported protein PF3D7_0402000 binds to erythrocyte ankyrin and band 4.1

“…This domain is approximately 150 amino acids and is composed of 4 alpha helical regions [50–53]. In PF3D7_0402000 the PHIST domain resides between amino acids 150 and 300 and is flanked by low complexity regions.…”

Plasmodium Helical Interspersed Subtelomeric (PHIST) Proteins, at the Center of Host Cell Remodeling

“…GEXP5 (gametocyte exported protein 5) was originally classified as PHISTb (15) but is now grouped among the PHISTc proteins (16), which is confirmed by the position of its conserved tryptophan residues (Fig. 4).…”

“…For the monkey malaria parasite P. cynomolgi, 21 PHIST genes were identified, while the number of PHIST genes in the rodent malaria parasite is unclear and varies in different publications or databases. For P. berghei, 1 to 3 phist genes have been found, and 1 to 2 have been found in both P. chabaudi and P. yoelii (15,16,26). Moreira et al recently characterized two PHIST proteins in P. berghei and demonstrated potentially similar roles for these PHIST proteins, as has been attributed to P. falciparum PHIST proteins (26).…”

“…Based on the presence and position of several conserved tryptophan residues within the PHIST domain, the PHIST protein family has been further divided into three subgroups: PHISTa, PHISTb, and PHISTc (15). With more recent data included, PlasmoDB has annotated additional PHIST domains in proteins, resulting in a total of 89 currently known PHIST proteins in P. falciparum (15,16). Some of the newly added PHIST proteins were not grouped into the already existing subgroups but were classified as PHISTa-like or simply PHIST proteins.…”

Malaria Parasites: The Great Escape

“…In ADCI, anti-merozoite cryophilic (IgG1 or IgG3) antibodies bind to merozoites and the immune complexes stimulate phagocytes to release cytokines such as TNF-α, which in turn stimulate the phagocytes to produce mediators that lead to the killing of intra-erythrocytic parasites (59, 60). Plasmodium parasites express antigens at the surface of iRBC (61). These antigens are mainly encoded by multigene families such as the var (62), stevor (63), and rifins gene families (64, 65) for P. falciparum or the pir gene family for P. vivax, P. knowlesi , and the rodent malaria species (66).…”