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

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.

Illuminating how malaria parasites export proteins into host erythrocytes

“…Notably, some of RIFINs and STEVORs are also expressed in gametocytes. For reviews on these antigens, see (Wahlgren et al, ; Yam, Niang, Madnani, & Preiser, ).…”

“…One of the parasite effector proteins that is exported into erythrocytes and which distinguishes P. falciparum from all other malaria species is P. falciparum erythrocyte membrane protein 1 (PfEMP1; Smith, Rowe, Higgins, & Lavstsen, 2013;Wahlgren, Goel, & Akhouri, 2017; Figure 1). This large protein, which is a major contributor to virulence, is formed by one of 59 var genes that undergo antigenic switching, leading to the external display of a single PfEMP1 variant from knob-like structures (encoded by the knob-associated histidine rich protein, KAHRP) that protrude from the erythrocyte surface (Su et al, 1995).…”

“…Notably, some of RIFINs and STEVORs are also expressed in gametocytes. For reviews on these antigens, see (Wahlgren et al, 2017;Yam, Niang, Madnani, & Preiser, 2017). Several other P. falciparum effector proteins such as knobassociated histidine rich protein (KAHRP), ring-infected erythrocyte surface antigen (RESA), and the Plasmodium helical interspersed subtelomeric-domain proteins (PHIST) modulate the cytoskeleton to increase the rigidity of the erythrocyte to promote endothelial attachment and prevent parasite clearance through the spleen (reviewed in Spillman, Beck, & Goldberg, 2015;de Koning-Ward et al, 2016;Figure 1).…”

Das ungewöhnliche Leben der Malariaparasiten

“…Als Antwort besitzt der Parasit nicht nur ein PfEMP1‐Gen, sondern circa 60 verschiedene, von denen immer nur eines aktiv ist. Von Zeit zu Zeit wird eine anderes Gen abgelesen und die Immunantwort läuft ins Leere, was ein weiteres Beispiel für Antigenvariation ist .…”

Towards an anti-disease malaria vaccine

“…This revealed important principles that are likely to be shared by other PfEMP1s or other parasite surface protein families such as the RIFINs, which are less well studied, but have been suggested to contribute to the pathogenesis of malaria [48]. For example, genuine binding phenotypes are likely to be found in multiple family members and to be predicable from sequence when understood at a molecular level.…”