Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2

  1. Juan Feng
  2. Xianchi Dong
  3. Adam DeCosta
  4. Yang Su
  5. Fiona Angrisano
  6. Katarzyna A Sala
  7. Andrew M Blagborough
  8. Chafen Lu  Is a corresponding author
  9. Timothy A Springer  Is a corresponding author
  1. Boston Children's Hospital, United States
  2. Nanjing University, China
  3. Burnet Institute, Australia
  4. University of Cambridge, United Kingdom

Abstract

HAP2 is a transmembrane gamete fusogen found in multiple eukaryotic kingdoms and is structurally homologous to viral class II fusogens. Studies in Plasmodium have suggested that HAP2 is an attractive target for vaccines that block transmission of malaria. HAP2 has three extracellular domains, arranged in the order D2, D1, and D3. Here, we report monoclonal antibodies against the D3 fragment of Plasmodium berghei HAP2 and crystal structures of D3 in complex with Fab fragments of two of these antibodies, one of which blocks fertilization of Plasmodium berghei in vitro and transmission of malaria in mosquitoes. We also show how this Fab binds the complete HAP2 ectodomain with electron microscopy. The two antibodies cross-react with HAP2 among multiple plasmodial species. Our characterization of the Plasmodium D3 structure, HAP2 ectodomain architecture, and mechanism of inhibition provide insights for the development of a vaccine to block malaria transmission.

Data availability

Protein database accession IDs are 7LR3 for 2/6.14-Pb HAP2 D3 complex and 7LR4 for 2/1.12-Pb HAP2 D3 complex. Correspondence and requests for materials should be addressed to CL and TAS.

The following data sets were generated

Article and author information

Author details

  1. Juan Feng

    Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Xianchi Dong

    School of Life Sciences, Nanjing University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Adam DeCosta

    Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yang Su

    Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Fiona Angrisano

    Burnet Institute, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Katarzyna A Sala

    Department of Pathology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Andrew M Blagborough

    Department of Pathology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5257-8475
  8. Chafen Lu

    Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, United States
    For correspondence
    lu@crystal.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
  9. Timothy A Springer

    Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, United States
    For correspondence
    springer@crystal.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6627-2904

Funding

National Institutes of Health (R01AI95686)

  • Chafen Lu
  • Timothy A Springer

Royal Society

  • Andrew M Blagborough

Kidder Fund

  • Timothy A Springer

Medical Research Council (MR/N00227X/1)

  • Andrew M Blagborough

Isaac Newton Trust

  • Andrew M Blagborough

Alborada Fund

  • Andrew M Blagborough

Wellcome Trust ISSF

  • Andrew M Blagborough

University of Cambridge JRG Scheme

  • Andrew M Blagborough

GHIT

  • Andrew M Blagborough

Rosetrees Trust

  • Andrew M Blagborough

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Olivier Silvie, Sorbonne Université, UPMC Univ Paris 06, INSERM, CNRS, France

Publication history

  1. Received: October 14, 2021
  2. Accepted: December 3, 2021
  3. Accepted Manuscript published: December 23, 2021 (version 1)
  4. Version of Record published: February 1, 2022 (version 2)
  5. Version of Record updated: February 7, 2022 (version 3)

Copyright

© 2021, Feng et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 537
    Page views
  • 162
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Juan Feng
  2. Xianchi Dong
  3. Adam DeCosta
  4. Yang Su
  5. Fiona Angrisano
  6. Katarzyna A Sala
  7. Andrew M Blagborough
  8. Chafen Lu
  9. Timothy A Springer
(2021)
Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2
eLife 10:e74707.
https://doi.org/10.7554/eLife.74707

Further reading

    1. Evolutionary Biology
    2. Microbiology and Infectious Disease
    Pramod K Jangir et al.
    Research Article

    Bacterial pathogens show high levels of chromosomal genetic diversity, but the influence of this diversity on the evolution of antibiotic resistance by plasmid acquisition remains unclear. Here, we address this problem in the context of colistin, a ‘last line of defence’ antibiotic. Using experimental evolution, we show that a plasmid carrying the MCR-1 colistin resistance gene dramatically increases the ability of Escherichia coli to evolve high-level colistin resistance by acquiring mutations in lpxC, an essential chromosomal gene involved in lipopolysaccharide biosynthesis. Crucially, lpxC mutations increase colistin resistance in the presence of the MCR-1 gene, but decrease the resistance of wild-type cells, revealing positive sign epistasis for antibiotic resistance between the chromosomal mutations and a mobile resistance gene. Analysis of public genomic datasets shows that lpxC polymorphisms are common in pathogenic E. coli, including those carrying MCR-1, highlighting the clinical relevance of this interaction. Importantly, lpxC diversity is high in pathogenic E. coli from regions with no history of MCR-1 acquisition, suggesting that pre-existing lpxC polymorphisms potentiated the evolution of high-level colistin resistance by MCR-1 acquisition. More broadly, these findings highlight the importance of standing genetic variation and plasmid/chromosomal interactions in the evolutionary dynamics of antibiotic resistance.

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Kathrin Tomasek et al.
    Research Article Updated

    A key attribute of persistent or recurring bacterial infections is the ability of the pathogen to evade the host’s immune response. Many Enterobacteriaceae express type 1 pili, a pre-adapted virulence trait, to invade host epithelial cells and establish persistent infections. However, the molecular mechanisms and strategies by which bacteria actively circumvent the immune response of the host remain poorly understood. Here, we identified CD14, the major co-receptor for lipopolysaccharide detection, on mouse dendritic cells (DCs) as a binding partner of FimH, the protein located at the tip of the type 1 pilus of Escherichia coli. The FimH amino acids involved in CD14 binding are highly conserved across pathogenic and non-pathogenic strains. Binding of the pathogenic strain CFT073 to CD14 reduced DC migration by overactivation of integrins and blunted expression of co-stimulatory molecules by overactivating the NFAT (nuclear factor of activated T-cells) pathway, both rate-limiting factors of T cell activation. This response was binary at the single-cell level, but averaged in larger populations exposed to both piliated and non-piliated pathogens, presumably via the exchange of immunomodulatory cytokines. While defining an active molecular mechanism of immune evasion by pathogens, the interaction between FimH and CD14 represents a potential target to interfere with persistent and recurrent infections, such as urinary tract infections or Crohn’s disease.