DARC extracellular domain remodeling in maturating reticulocytes explains tropism.

is the most prevalent parasite species that causes malaria in humans and exclusively infects reticulocytes. Reticulocyte infection is facilitated by Duffy binding protein (DBP), which utilizes DARC (Duffy antigen receptor for chemokines) as an entry point. However, the selective tropism of 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 4 distinct reticulocyte populations: CD71/RNA (∼0.016%), CD71/RNA (∼0.059%), CD71/RNA (∼0.37%), CD71/RNA (∼0.55%), and erythrocytes CD71/RNA (∼99%). We hypothesized that selective association of DBP with a small population of immature reticulocytes could explain the preference of for reticulocytes. Binding of specific monoclonal anti-DARC antibodies and recombinant DBP to CD71/RNA reticulocytes was significantly higher compared with 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 .