Three Is a Crowd - New Insights into Rosetting in Plasmodium falciparum.

The intracellular malaria parasites extensively modify host erythrocytes to allow nutrient uptake, ensure homeostasis, and evade the host's immune response. To achieve this, the parasite exports several proteins to the erythrocyte surface. In Plasmodium falciparum, the parasite responsible for the most severe form of human malaria, three major variant surface antigen families - PfEMP1, STEVOR, and RIFIN - have been implicated in contributing to immune evasion, parasite sequestration, and parasite-mediated rosetting of uninfected erythrocytes. Sequestration and rosetting have been linked to parasite-mediated pathology, making the variant surface antigens of P. falciparum major virulence factors. Here we review our current understanding of rosetting mechanism, recent findings of STEVOR, RIFIN-mediated rosetting, and their implication on the severity and pathology of the disease.

STEVOR is a Plasmodium falciparum erythrocyte binding protein that mediates merozoite invasion and rosetting.

Variant surface antigens play an important role in Plasmodium falciparum malaria pathogenesis and in immune evasion by the parasite. Although most work to date has focused on P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1), two other multigene families encoding STEVOR and RIFIN are expressed in invasive merozoites and on the infected erythrocyte surface. However, their role during parasite infection remains to be clarified. Here we report that STEVOR functions as an erythrocyte-binding protein that recognizes Glycophorin C (GPC) on the red blood cell (RBC) surface and that its binding correlates with the level of GPC on the RBC surface. STEVOR expression on the RBC leads to PfEMP1-independent binding of infected RBCs to uninfected RBCs (rosette formation), while antibodies targeting STEVOR in the merozoite can effectively inhibit invasion. Our results suggest a PfEMP1-independent role for STEVOR in enabling infected erythrocytes at the schizont stage to form rosettes and in promoting merozoite invasion.