Plasmodium vivax binds host CD98hc (SLC3A2) to enter immature red blood cells

More than one-third of the world's population is exposed to Plasmodium vivax malaria, mainly in Asia¹. P. vivax preferentially invades reticulocytes (immature red blood cells)^2-4. Previous work has identified 11 parasite proteins involved in reticulocyte invasion, including erythrocyte binding protein 2 (ref. ⁵) and the reticulocyte-binding proteins (PvRBPs)^6-10. PvRBP2b binds to the transferrin receptor CD71 (ref. ¹¹), which is selectively expressed on immature reticulocytes¹². Here, we identified CD98 heavy chain (CD98), a heteromeric amino acid transporter from the SLC3 family (also known as SLCA2), as a reticulocyte-specific receptor for the PvRBP2a parasite ligand using mass spectrometry, flow cytometry, biochemical and parasite invasion assays. We characterized the expression level of CD98 at the surface of immature reticulocytes (CD71⁺) and identified an interaction between CD98 and PvRBP2a expressed at the merozoite surface. Our results identify CD98 as an additional host membrane protein, besides CD71, that is directly associated with P. vivax reticulocyte tropism. These findings highlight the potential of using PvRBP2a as a vaccine target against P. vivax malaria.