Plasmodium vivax shows a strict host tropism for reticulocytes. We identify transferrin receptor 1 (TfR1) as the receptor for P. vivax reticulocyte-binding protein 2b (PvRBP2b). The structure of the N-terminal domain of PvRBP2b involved in red blood cell binding was determined, elucidating the molecular basis for TfR1 recognition. TfR1 was validated as the biological target of PvRBP2b engagement by TfR1 expression knockdown analysis. TfR1 mutant cells deficient in PvRBP2b binding were refractory to invasion of P. vivax, but not to invasion of P. falciparum. Using Brazilian and Thai clinical isolates, we show that PvRBP2b monoclonal antibodies that inhibit reticulocyte binding also block P. vivax entry into reticulocytes. These data show that TfR1-PvRBP2b invasion pathway is critical for the recognition of reticulocytes during P. vivax invasion.

The pivotal factor leading to the declining efficacy of the artemisinin-based combination on the Thailand–Myanmar border (mefloquine–artesunate) to a clinically unacceptable level is the increasing local prevalence of K13 mutations superimposed onto a long-standing background of Pfmdr1 amplification.