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Broadly inhibitory antibodies to 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, USA.

Nature
|November 20, 2024
PubMed

Insights

Two new human antibodies broadly inhibit Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) binding to EPCR, a key factor in severe malaria. These findings offer insights for developing new malaria vaccines and treatments.

Area of Science:

  • Immunology
  • Infectious Diseases
  • Structural Biology

Background:

  • Severe malaria pathogenesis involves Plasmodium falciparum-infected erythrocytes adhering to microvessels.
  • Erythrocyte membrane protein 1 (PfEMP1) mediates this adhesion, with specific variants binding the human endothelial protein C receptor (EPCR).
  • Identifying antibodies targeting the diverse PfEMP1 variants is crucial for understanding acquired immunity and developing interventions.

Purpose of the Study:

  • To identify broadly reactive human monoclonal antibodies targeting the CIDRα1 domain of PfEMP1.
  • To investigate the inhibitory potential of these antibodies against EPCR binding and parasite sequestration.
  • To elucidate the structural basis for the antibodies' broad reactivity and inhibitory mechanism.

Main Methods:

  • Isolation and characterization of human monoclonal antibodies against CIDRα1 domains.
  • In vitro assays to assess EPCR-binding inhibition of recombinant and native PfEMP1 proteins.
  • 3D bioengineered human brain microvessel model to evaluate parasite sequestration inhibition under flow.
  • Structural analysis (crystallography) of antibody-antigen complexes.

Main Results:

  • Two broadly reactive human monoclonal antibodies targeting CIDRα1 domains were identified.
  • These antibodies effectively inhibited EPCR binding across diverse CIDRα1 variants, including five subclasses.
  • Inhibition of parasite sequestration in a 3D brain microvessel model was demonstrated.
  • Structural studies revealed a conserved binding mechanism involving key residues in the EPCR-binding site.

Conclusions:

  • Broadly reactive antibodies targeting conserved epitopes on CIDRα1 domains represent a potential common mechanism of acquired immunity to severe malaria.
  • These antibodies demonstrate significant potential for the development of novel vaccines or therapeutics against severe malaria.
  • Understanding the structural basis of broad antibody recognition provides critical insights for rational drug and vaccine design.

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