Molecular Mechanism for Switching of P. falciparum Invasion Pathways into Human Erythrocytes

Abstract

The malaria parasite, Plasmodium falciparum, exploits multiple ligand-receptor interactions, called invasion pathways, to invade the host erythrocyte. Strains of P. falciparum vary in their dependency on sialated red cell receptors for invasion. We show that switching from sialic acid-dependent to -independent invasion is reversible and depends on parasite ligand use. Expression of P. falciparum reticulocyte-binding like homolog 4 (PfRh4) correlates with sialic acid-independent invasion, and PfRh4 is essential for switching invasion pathways. Differential activation of PfRh4 represents a previously unknown mechanism to switch invasion pathways and provides P. falciparum with exquisite adaptability in the face of erythrocyte receptor polymorphisms and host immune responses.

Variation in use of erythrocyte invasion pathways by Plasmodium falciparum mediates evasion of human inhibitory antibodies

“…Changes in the expression and/or use of EBA and PfRh proteins enables the use of alternate invasion pathways (16,20,(22)(23)(24)(25)(26)(27). Variation in invasion phenotypes or pathways has been demonstrated with clinical isolates and laboratory-adapted clones of P. falciparum.…”

“…When isolates using an SA-dependent invasion pathway are selected for invasion of neuraminidase-treated erythrocytes, there is a switch to the use of an SA-independent invasion pathway and induction of PfRh4 (20,32). Disruption of PfRh4 blocks the ability to switch from SA-dependent to SA-independent invasion (20). Similarly, disruption of the EBA175 gene results in switching from SA-dependent to SA-independent invasion, with activation of PfRh4 expression (20).…”

“…EBA181 binds to SA on the erythrocyte surface and to band 4.1 protein (15,31). PfRh2b and PfRh4 are important in SA-independent invasion, and interactions appear chymotrypsin sensitive (16,20,32); however, receptors for binding these ligands are unknown. PfRh2a shares approximately 80% sequence identity with PfRh2b, differing in the C-terminal region of the protein.…”

“…Activation of PfRh4 appears essential for SA-independent invasion. When isolates using an SA-dependent invasion pathway are selected for invasion of neuraminidase-treated erythrocytes, there is a switch to the use of an SA-independent invasion pathway and induction of PfRh4 (20,32). Disruption of PfRh4 blocks the ability to switch from SA-dependent to SA-independent invasion (20).…”

“…Secondary interactions are then required for activation of invasion processes. These involve 2 invasion ligand families: the erythrocyte-binding antigens (EBAs; EBA175, EBA140/BAEBL, EBA181/JESEBL) and P. falciparum reticulocyte-binding homolog (PfRh) proteins (PfRh1, -2a, -2b, and -4) (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Additional members of these families, EBA165 and PfRh3, occur as pseudogenes (18,20,21).…”