Human erythrocyte band 3 functions as a receptor for the sialic acid-independent invasion of Plasmodium falciparum. Role of the RhopH3–MSP1 complex

Abstract

Plasmodium falciparum takes advantage of two broadly defined alternate invasion pathways when infecting human erythrocytes: one that depends on and the other that is independent of host sialic acid residues on the erythrocyte surface. Within the sialic acid-dependent (SAD) and sialic acid-independent (SAID) invasion pathways, several alternate host receptors are used by Plasmodium falciparum based on its particular invasion phenotype. Earlier, we reported that two putative extracellular regions of human erythrocyte band 3 termed 5C and 6A function as host invasion receptor segments binding parasite proteins MSP1 and MSP9 via a SAID mechanism. In this study, we developed two mono-specific anti-peptide chicken IgY antibodies to demonstrate that the 5C and 6A regions of band 3 are exposed on the surface of human erythrocytes. These antibodies inhibited erythrocyte invasion by the Plasmodium falciparum 3D7 and 7G8 strains (SAID invasion phenotype), and the blocking effect was enhanced in sialic acid-depleted erythrocytes. In contrast, the IgY antibodies had only a marginal inhibitory effect on FCR3 and Dd2 strains (SAD invasion phenotype). A direct biochemical interaction between erythrocyte band 3 epitopes and parasite RhopH3, identified by the yeast two-hybrid screen, was established. RhopH3 formed a complex with MSP119 and 5ABC region of band 3, and a recombinant segment of RhopH3 inhibited parasite invasion in human erythrocytes. Together, these findings provide evidence that erythrocyte band 3 functions as a major host invasion receptor in the SAID invasion pathway by assembling a multi-protein complex composed of parasite ligands RhopH3 and MSP1.

Interaction of Plasmodium vivax Tryptophan-rich Antigen PvTRAg38 with Band 3 on Human Erythrocyte Surface Facilitates Parasite Growth

“…Band 3, which is defined here as potential erythrocyte receptor for PvTRAg38, is also known to interact with a number of known and unknown P. falciparum proteins and plays a crucial role in host cell invasion (29,(31)(32)(33)(34)(35)(36). This is based on the fact that the monoclonal antibodies against Band 3 blocked the invasion of rhesus monkey erythrocytes by the Plasmodium knowlesi merozoites in a primate model (37).…”

“…It is known that PfMSP1 forms complex with RhopH3, as well as with PfMSP9, to interact with 5ABC (defined here as B3F5 fragment) and 6A of Band 3 (29,31,34). In that case, the cooperative binding of several parasite proteins (the PvTRAg38, MSP 1, MSP9, and maybe other additional proteins) to the same host erythrocyte receptor through its different exofacial regions may be providing the parasite an opportunity to tighten its interaction with the host cell.…”

Merozoite surface protein 1 recognition of host glycophorin A mediates malaria parasite invasion of red blood cells

“…33 Consistent with these findings, our previous work showed that MSP1 19 interacts with host band 3 receptor, mediating parasite invasion of RBCs via the sialic acid-independent invasion pathway. 12,13,41 Host band 3 is the most abundant membrane protein in RBCs and forms a tight stoichiometric complex with GPA. Like band 3, GPA is also highly abundant and serves as a sialic acid-dependent receptor, binding the parasite ligand EBA-175.…”

“…12,13,41 Host band 3 is the most abundant membrane protein in RBCs and forms a tight stoichiometric complex with GPA. Like band 3, GPA is also highly abundant and serves as a sialic acid-dependent receptor, binding the parasite ligand 42 On the basis of these observations, we hypothesized that merozoites may display ligands that can potentially bind to band 3 and GPA simultaneously, thus integrating distinct invasion pathways.…”

Basigin Interacts with Plasmodium vivax Tryptophan-rich Antigen PvTRAg38 as a Second Erythrocyte Receptor to Promote Parasite Growth

“…The phenomenon of red cell invasion by merozoites of Plasmodium is highly complex because parasites use multiple invasion pathways thus utilizing large numbers of parasite ligands and their respective receptors on host erythrocytes. Complexity is further increased when the individual parasite ligand interacts with more than one erythrocyte receptor, and similarly, each erythrocyte receptor is recognized by more than one parasite ligand (4,14,(27)(28)(29). The numbers of erythrocyte receptors identified for the P. vivax merozoite proteins is very limited (3,10,12).…”