DARC extracellular domain remodeling in maturating reticulocytes explains Plasmodium vivax tropism

Elina Ovchynnikova, Francesca Aglialoro, Arthur E. H. Bentlage, Gestur Vidarsson, Nichole D. Salinas, Marieke von Lindern, Niraj H. Tolia and Emile van den Akker

Key points

  • Plasmodium vivax duffy binding protein associates exclusively to a small population of immature reticulocytes.

  • Increased DARC-DBP binding site accessibility in immature reticulocytes compared to erythrocytes is key to infection by Plasmodium Vivax.


Plasmodium vivax (P.vivax) is the most prevalent parasite species that causes malaria in humans, and exclusively infects reticulocytes. Reticulocyte infection is facilitated by P.vivax Duffy Binding Protein (DBP), which utilizes DARC (Duffy Antigen Receptor for Chemokines) as an entry point. However, the selective tropism of P.vivax for Transferrin Receptor (CD71)-positive reticulocytes remained unexplained, given the constitutive expression of DARC during reticulocyte maturation. CD71/RNA double staining of reticulocytes enriched from adult peripheral blood reveals four distinct reticulocyte populations: CD71high/RNAhigh (~0.016%), CD71low/RNAhigh (~0.059%), CD71neg/RNAhigh (~0.37%), CD71neg/RNAlow (~0.55%) and erythrocytes CD71neg/RNAneg (~99%). We hypothesized that selective association of DBP with a small population of immature reticulocytes could explain the preference of P.vivax for reticulocytes. Binding of specific monoclonal anti-DARC antibodies and recombinant DBP to CD71high/RNAhigh reticulocytes was significantly higher compared to other reticulocyte populations and erythrocytes. Interestingly, the total DARC protein throughout reticulocyte maturation was constant. The data suggest that selective exposure of the DBP binding site within DARC is key to the preferential binding of DBP to immature reticulocytes, which is the potential mechanism underlying the preferential infection of a reticulocyte subset by P.vivax.

  • Submitted March 21, 2017.
  • Accepted June 21, 2017.