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

Authors
  • Almukadi, Haifa1
  • Schwake, Christopher2
  • Kaiser, Maima M1
  • Mayer, D C Ghislaine3
  • Schiemer, James4
  • Baldwin, Michael R4
  • Hegde, Shreeya1
  • Lu, Yunzhe5
  • Hanada, Toshihiko5
  • Chishti, Athar H1, 2, 4, 5, 6
  • 1 Graduate Program in Pharmacology and Experimental Therapeutics and.
  • 2 Graduate Program in Cellular, Molecular, and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA.
  • 3 Department of Biology, Manhattan College, Riverdale, NY; and.
  • 4 Graduate Program in Cellular and Molecular Physiology, Sackler School of Graduate Biomedical Sciences.
  • 5 Department of Developmental, Molecular, and Chemical Biology, and.
  • 6 Graduate Program in Molecular Microbiology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA.
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
Jan 31, 2019
Volume
133
Issue
5
Pages
470–480
Identifiers
DOI: 10.1182/blood-2018-07-865451
PMID: 30545833
Source
Medline
Language
English
License
Unknown

Abstract

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 (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 nonoverlapping repeats encoding the immune response epitopes and core erythrocyte-binding activity. 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. © 2019 by The American Society of Hematology.

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