Parasite hijacks red cell membrane proteins

In this issue of Blood, Baro et al explored the role of CD44, a glycoprotein expressed on the surface of human red cells, in regulating malarial parasite invasion of red cells.(1) Using CRISPR/Cas9 genome editing, they abrogated the surface expression of CD44 in erythroid cells and found that the lack of CD44 had little effect on in vitro erythropoiesis and on the enucleation of orthochromatic erythroblasts. Interestingly, however, they observed that the rate of Plasmodium falciparum invasion was reduced in these CD44-null culture-derived red cells, validating CD44 as an important host factor for parasite invasion of red cells. Molecularly, 2 previously well-characterized parasite invasion ligands, erythrocyte-binding antigen 175 (EBA-175) and EBA-140, identified as the ligands for glycophorin A (GYPA) and glycophorin C (GYPC), respectively, were shown to be binding partners for CD44, and, finally, the authors demonstrated that EBA-175-induced phosphorylation of erythrocyte cytoskeletal proteins following invasion is CD44 dependent. These findings imply that CD44 is a coreceptor during invasion of human erythrocytes, which, by stimulating CD44-dependent phosphorylation of host cytoskeletal proteins, alters host cell deformability and facilitates parasite entry (see figure).