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Variant surface antigens of Plasmodium falciparum and their roles in severe malaria

Key Points

  • In cases of severe malaria, most deaths occur within the first 24 h of hospitalization, when the characteristic features of high parasite load and obstructed microvasculature are present. Novel adjunct drugs need to be developed as it is crucial to stop the infection and restore blood flow without delay.

  • Plasmodium falciparum exports polypeptides to the surface of infected erythrocytes; for example, to import nutrients and to bind to other erythrocytes and the host microvasculature. Binding is mediated by the adhesive polypeptides Plasmodium falciparum-encoded repetitive interspersed families of polypeptides (RIFIN), subtelomeric variant open reading frame (STEVOR) and P. falciparum erythrocyte membrane protein 1 (PfEMP1).

  • P. falciparum has the ability to express allelic variants of hundreds of different versions of erythrocyte surface antigens. Most of these genes belong to three large multigene families, the repetitive interspersed family (rif), stevor and var families, which encode RIFIN, STEVOR and PfEMP1, respectively.

  • RIFIN, STEVOR and PfEMP1 mediate the binding of parasite-infected red blood cells (pRBCs) to the vascular endothelium (cytoadherence), to red blood cells (rosetting), and to leukocytes and serum proteins.

  • Cytoadherence and rosetting are involved in the pathogenesis of malaria by blocking blood flow when binding is excessive, leading to a lack of oxygen in tissues, excessive production of lactate and a reduction of the pH in blood and tissues, which can culminate in respiratory distress, coma, severe anaemia or combinations thereof — the hallmarks of severe malaria.

  • A correlation between the clinical severity of malaria and the ABO blood group of a patient suggests that the O blood group protects against severe disease, a hypothesis that is supported by genome-wide association studies. In addition, this suggestion is supported by results from various in vitro studies.

Abstract

Proliferation and differentiation inside erythrocytes are important steps in the life cycle of Plasmodium spp. To achieve these, the parasites export polypeptides to the surface of infected erythrocytes; for example, to import nutrients and to bind to other erythrocytes and the host microvasculature. Binding is mediated by the adhesive polypeptides Plasmodium falciparum-encoded repetitive interspersed families of polypeptides (RIFINs), subtelomeric variant open reading frame (STEVOR) and P. falciparum erythrocyte membrane protein 1 (PfEMP1), which are encoded by multigene families to ensure antigenic variation and evasion of host immunity. These variant surface antigens are suggested to mediate the sequestration of infected erythrocytes in the microvasculature and block the blood flow when binding is excessive. In this Review, we discuss the multigene families of surface variant polypeptides and highlight their roles in causing severe malaria.

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Figure 1: The Plasmodium falciparum life cycle and sequestration of pRBCs.
Figure 2: Plasmodium falciparum proteins form knobs on the erythrocyte surface.
Figure 3: Structure of PfEMP1.
Figure 4: Domain structure and suggested functions of RIFINs and STEVORs.
Figure 5: A model of sequestration of Plasmodium falciparum pRBC in the microvasculature and severe malaria.

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Acknowledgements

M.W. is supported by the Swedish Research Council, the Swedish Strategic Foundation, the EU Seventh-Framework Programmes (EviMalar Network of Excellence), the Söderberg Foundation and Swedish Academy of Sciences. The funders had no role in the preparation of the manuscript.

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Correspondence to Mats Wahlgren.

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M. W. holds shares in, and is a director of the board of, Modus Therapeutics AB, a company of the Karolinska Development AB involved in the development of adjunct treatment for severe malaria and sickle-cell disease. The authors declare no other competing financial interests.

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Glossary

Trophozoites

An asexual stage in the life cycle of Plasmodium spp. that is present during the first 20–32 h post-invasion of red blood cells. Young trophozoites (1–20 h) are commonly called ring-stage parasites owing to their ring-like appearance.

Schizonts

An asexual stage in the life cycle of Plasmodium spp. that occurs 30–48 h after red blood cell invasion, in which the parasite divides several times to produce daughter cells (merozoites) that then invade new red blood cells.

Syncytiotrophoblasts

Epithelial cells that replace the endothelium at the maternal–fetal blood interface of the placenta.

Allelic exclusion

A process by which only one allele (gene) of a gene family is expressed, whereas the other alleles are silenced.

Parasitophorous vacuole

A compartment that is formed in host cells in which apicomplexan parasites reside and develop.

Plasmodium export element

(PEXEL). A pentameric amino acid motif in the amino-terminal region of proteins that guides their export.

Merozoite

An asexual stage in the life cycle of Plasmodium spp. and the invasive form that invades new red blood cells.

Gametocytes

A sexual stage in the life cycle of Plasmodium spp., in which the parasite develops into male and female sexual gametocytes, which fertilize after ingestion by the mosquito vector.

ABO blood group antigens

Carbohydrate moieties that are physically exposed on the surface of red blood cells, endothelial cells, serum proteins, platelets and other cells of the microvasculature. The distribution of the blood groups A, B, O and AB varies between populations.

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Wahlgren, M., Goel, S. & Akhouri, R. Variant surface antigens of Plasmodium falciparum and their roles in severe malaria. Nat Rev Microbiol 15, 479–491 (2017). https://doi.org/10.1038/nrmicro.2017.47

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