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

Haifa Almukadi, Christopher Schwake, Maima Kaiser, Ghislaine Mayer, James Schiemer, Michael Baldwin, Shreeya Hegde, Yunzhe Lu, Toshihiko Hanada and Athar H. Chishti

Key points

  • Plasmodium falciparum GARP (PfGARP) is a secreted protein that binds to human erythrocyte band 3.

  • PfGARP induces RBC aggregates in vitro and may serve as a biomarker of disease progression.

Abstract

Malaria remains a major global threat to human health and economic development. Microvascular lesions caused by Plasmodium falciparum-infected human erythrocytes/RBCs are hallmarks of severe pathogenesis contributing to high mortality, particularly in children from sub-Saharan Africa. In this study, we used a phage display cDNA library screening strategy to identify Plasmodium falciparum glutamic acid-rich protein (PfGARP) as a secreted ligand that recognizes an ectodomain of human erythrocyte anion-exchanger, Band 3/AE1, as a host receptor. Domain mapping of PfGARP revealed distinct non-overlapping repeats encoding the immune response epitopes and core erythrocyte-binding activity, respectively. Synthetic peptides derived from the erythrocyte-binding repeats of PfGARP 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 PfGARP in human plasma samples obtained from patients in rural Mali, suggesting the feasibility of PfGARP as a potential biomarker of disease progression. Collectively, our results suggest that PfGARP 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 PfGARP may unveil new therapeutic options for mitigating lesions in cerebral and pregnancy-associated malaria.

  • Submitted July 25, 2018.
  • Accepted December 10, 2018.