The enigmatic mechanisms by which Plasmodium vivax infects Duffy-negative individuals
The absence of the Duffy protein at the surface of erythrocytes was considered for decades
to confer full protection against Plasmodium vivax as this blood group is the receptor for the
key parasite ligand P. vivax Duffy binding protein (PvDBP). However, it is now clear that the
parasite is able to break through this protection and induce clinical malaria in Duffy-negative
people, although the underlying mechanisms are still not understood. Here, we briefly
review the evidence of Duffy-negative infections by P. vivax and summarize the current
hypothesis at the basis of this invasion process. We discuss those in the perspective of
malaria-elimination challenges, notably in African countries.
Fig. 1 Schematic representation of receptor-ligands involved in P. vivax invasion process of reticulocytes. At the end of the erythrocytic cycle, the schizonts burst and release merozoites in the blood stream, enabling the invasion of uninfected reticulocytes. The recognition of reticulocytes and the invasion process require interactions between parasite ligands and reticulocyte receptors. For Duffy-positive reticulocyte invasion, PvRBP2b binds first to the TfR1 present on reticulocytes, and subsequently, PvDBP engages with the Duffy protein allowing the entry of the merozoite in the cell. Other ligands such as PvEBP, PvRBPs, PvMSP1P, PvAMA1, or PvGAMA are currently being investigated for their involvement in this invasion process, and their putative receptors are unknown. PvRBP2b probably also recognizes TfR1 of Duffy-negative reticulocytes; however, the subsequent invasion steps are still unknown. Are there a few Duffy molecules present on the surface of the erythrocyte enabling parasites with multiple PvDBP gene copies to invade the cell? Conversely, is the invasion process of Duffy-negative reticulocytes occurring through alternate, yet-to-identity receptors of, perhaps, ligands such as PvEBP, PvMSP1P, or PvGAMA? Finally, the invasion process might occur through complete unknown pathways with both unidentified ligands (noted with X) and receptors. AMA1, anchored micronemal antigen 1; DBP, Duffy binding protein; EBP, erythrocyte-binding protein; GAMA, glycosylphosphatidylinositol-anchored micronemal antigen; MSP1P, merozoite surface protein-1 paralog; Pv, Plasmodium vivax; RBP, reticulocyte binding proteins; TfR1, transferrin receptor 1.
- Jean Popovici - Camille Roesch - Virginie Rougeron
- email@example.com - firstname.lastname@example.org
- Malaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, Phnom Penh Cambodia - Malaria Translational Research Unit, Institut Pasteur, Paris & Institut Pasteur du Cambodge, Phnom Penh, Cambodia - Laboratoire MIVEGEC (Universite´ de Montpellier-CNRS-IRD), Montpellier, France
- Agence Nationale de la Recherche Tremplin-ERC (TERC3) 2017 http://www.agence-nationale-recherche.fr/Project-ANR-17-ERC3-0002 (grant number EVAD: Evolutionary history and genetic adaptation of Plasmodium vivax). Received by VR. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Science Advances 28 Apr 2021:
Vol. 7, no. 18, eabc3713