Human erythrocyte band 3 is a host receptor for Plasmodium falciparum glutamic acid-rich protein.

Malaria remains a major global threat to human health and economic development. Microvascular lesions caused by Plasmodium falciparum-infected human erythrocytes/red blood cells are hallmarks of severe pathogenesis contributing to high mortality, particularly in children from sub-Saharan Africa. In this study, we used a phage display complementary DNA library screening strategy to identify P falciparum glutamic acid-rich protein as a secreted ligand that recognizes an ectodomain of human erythrocyte anion-exchanger, band 3/AE1, as a host receptor. Domain mapping of revealed distinct nonoverlapping repeats encoding the immune response epitopes and core erythrocyte-binding activity. Synthetic peptides derived from the erythrocyte-binding repeats of PfGduanyu37 induced erythrocyte aggregation reminiscent of the rosetting phenomenon. Using peptides derived from the immunogenic repeats, a quantitative immunoassay was developed to detect a selective immune response against PfGduanyu37 in human plasma samples obtained from patients in rural Mali, suggesting the feasibility of PfGduanyu37 as a potential biomarker of disease progression. Collectively, our results suggest that PfGduanyu37 may play a functional role in enhancing the adhesive properties of human erythrocytes by engaging band 3 as a host receptor. We propose that immunological and pharmacological inhibition of PfGduanyu37 may unveil new therapeutic options for mitigating lesions in cerebral and pregnancy-associated malaria.

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