STEVOR Is a Plasmodium falciparum Erythrocyte Binding Protein that Mediates Merozoite Invasion and Rosetting

Abstract

Summary Variant surface antigens play an important role in the pathogenesis of Plasmodium falciparum malaria. To date, intensive work has mainly focused on the role in parasite virulence of the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) encoded by the var multigene family. Two other multigene families coding for STEVOR and RIFIN have recently also been shown to be expressed in the invasive merozoite as well as on the surface of the infected erythrocyte, implicating them as potential parasite virulence factors. Here we report that STEVOR is an erythrocyte-binding protein recognizing Glycophorin C on the red blood cell (RBC) surface. STEVOR expression on the RBC leads to PfEMP1-independent rosette formation, while antibodies targeting STEVOR in the merozoite can effectively inhibit invasion. Our results suggest a novel role of STEVOR in enabling infected erythrocytes at the schizont stage to bind uninfected erythrocytes to form rosettes, thereby protecting released merozoites from immune detection.

Plasmodium falciparum STEVOR phosphorylation regulates host erythrocyte deformability enabling malaria parasite transmission

“…[14][15][16] The encoded STEVOR proteins exhibit a semiconserved N-terminal domain and a central variable domain exposed on the erythrocyte surface, whereas the conserved C-terminal domain is cytoplasmic. 17,18 Besides their role in invasion, adhesion, and rosetting in asexual stages, [19][20][21][22] STEVOR proteins have been shown to impact the deformability of the infected erythrocyte in mature asexual parasites and immature sexual stages. 6,23 However, the mechanism underlying STEVOR-mediated changes in erythrocyte deformability remains unclear.…”

From the blood to the brain: avenues of eukaryotic pathogen dissemination to the central nervous system

“…Based on studies using human brain microvascular endothelial cells, distinct domains of PfEMP1 were found to mediate rosetting and cytoadhesion [31]. STEVOR, which is encoded by a multi-gene family, is expressed on the iRBC surface and interacts with Glycophorin C to mediate rosette formation independently of PfEMP1 [32]. The binding of pentameric IgM to iRBCs is also associated with rosetting, and recent data suggest that IgM may function by binding to PfEMP1 and strengthening the interactions between RBCs and iRBCs [33].…”

The immunological balance between host and parasite in malaria

“…This process may be beneficial for the parasite by shielding epitopes on the iRBC from opsonizing IgGs. Another possible role is to facilitate merozoite invasion by bringing uninfected RBCs into close proximity of the bursting schizont, and to protect against invasion-inhibiting Abs (Niang et al 2014). With P. falciparum, both hypotheses seem plausible, and probably depend on the adhesin variant and the host molecule mediating rosetting.…”