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Broadly inhibitory antibodies against severe malaria virulence proteins

Raphael A Reyes1, Sai Sundar Rajan Raghavan2,3, Nicholas K Hurlburt4

  • 1Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.

Biorxiv : the Preprint Server for Biology
|February 8, 2024
PubMed

Insights

Two human antibodies broadly inhibit Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) binding to EPCR, a key factor in severe malaria. These antibodies target conserved regions, offering potential for new malaria vaccines and treatments.

Area of Science:

  • Immunology
  • Infectious Diseases
  • Structural Biology

Background:

  • Plasmodium falciparum pathology involves infected erythrocyte accumulation in microvessels, mediated by PfEMP1 adhesion proteins.
  • Severe malaria pathogenesis is linked to PfEMP1 variants binding the human endothelial protein C receptor (EPCR) via CIDRα1 domains.
  • A key question is whether antibodies can target the diverse PfEMP1 variants responsible for severe malaria.

Approach:

  • Characterized two broadly reactive human monoclonal antibodies against PfEMP1 CIDRα1 domains.
  • Assessed antibody inhibition of EPCR binding across 34 CIDRα1 domains and with native/recombinant PfEMP1 proteins.
  • Utilized structural analyses to elucidate antibody-antigen binding mechanisms and identify conserved interactions.

Key Points:

  • Two distinct human monoclonal antibodies demonstrated broad reactivity and EPCR-binding inhibition against 34 CIDRα1 domains from five subclasses.
  • Antibodies effectively inhibited EPCR binding of both recombinant and native PfEMP1 proteins.
  • Structural studies revealed conserved binding mechanisms involving three key amino acid residues in the EPCR-binding site of CIDRα1.

Conclusions:

  • These broadly reactive antibodies suggest a common mechanism for acquired immunity against severe malaria.
  • The findings provide novel insights for developing vaccines or therapeutics targeting severe malaria by focusing on conserved PfEMP1 epitopes.

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